Open Journal Systems

ORIGINAL CONTRIBUTIONS

Received: 15/10/2015

Accepted: 23/11/2015

Consensus on Systemic Arterial Hypertension In México

Martín Rosas-Peralta,^a Silvia Palomo-Piñón,^b Gabriela Borrayo-Sánchez,^c Alejandra Madrid-Miller,^d Eduardo Almeida-Gutiérrez,^e Héctor Galván-Oseguera,^f José Antonio Magaña-Serrano,^g Guillermo Saturno-Chiu,^h Erick Ramírez-Arias,ⁱ Efrén Santos-Martínez,^j Enrique Díaz-Díaz,^k Selene Janette Salgado-Pastor,^l Gerardo Morales-Mora,^l Luz Elena Medina-Concebida,^m Oliva Mejía-Rodríguez,ⁿ Claudia Elsa Pérez-Ruiz,^ñ Luis Raúl Chapa-Mejía,^o Cleto Álvarez-Aguilar,^p Gilberto Pérez-Rodríguez,^q María Guadalupe Castro-Martínez,^r Joaquín López-Bárcena,^s José Ramón Paniagua-Sierra^t

^aDivisión de Investigación en Salud, Hospital de Cardiología

^bUnidad de Investigación Médica en Enfermedades Nefrológicas, Hospital de Especialidades

^cDirección Médica, Hospital de Cardiología

^dServicio de Terapia Posquirúrgica, Hospital de Cardiología

^eDivisión de Desarrollo en la Investigación, Coordinación de Investigación en Salud

^fDivisión Médica, Hospital de Cardiología

^gDivisión de Insuficiencia Cardiaca, Hospital de Cardiología

^hServicio de Hospitalización de Adultos, Hospital de Cardiología

ⁱServicio de Urgencias, Hospital de Cardiología

^jServicio de Hipertensión Pulmonar y Función Ventricular Derecha, Hospital de Cardiología

^kServicio de Hospitalización de Adultos, Hospital de Cardiología

^lServicio de Urgencias, Hospital de Cardiología

^mServicio de Cardiología Pediátrica, Hospital de Cardiología

ⁿCentro de Investigación Biomédica de Michoacán, Morelia, Michoacán

^ñUnidad de Medicina Familiar 61, Veracruz, Veracruz

^oUnidad de Medicina Familar 33, Ciudad Reynosa, Tamaulipas

^pDelegación Michoacán, Morelia, Michoacán

^qDirección General, Hospital de Cardiología

^rDirección General, Escuela de Medicina, Universidad La Salle

^sDirección del Programa Universitario de Investigación en Salud, Universidad Nacional Autónoma de México

^tDivisión de Desarrollo de la Investigación, Coordinación de Investigación en Salud

^a-m,qCentro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social

^a-m,q,r,s,tCiudad de México

México

Communication with: Martín Rosas-Peralta

Email: mrosas_peralta@hotmail.com

This Consenso Nacional de Hipertensión Arterial Sistémica (National Consensus on Systemic Arterial Hypertension) brings together experiences and joint work of 79 specialists who have been in contact with the patient affected by systemic arterial hypertension. All concepts here presented were outlined on the basis of the real world practice of Mexican hypertensive population. The consensus was developed under strict methodological guidelines. The Delphi technique was applied in two rounds for the development of an appropriate statistical analysis of the concepts exposed by all the specialists, who posed key questions, later developed by the panel of experts of the Hospital de Cardiología, and specialists from the Centro Médico Nacional. Several angles of this illness are shown: detection, diagnosis, pathophysiology, classification, treatment and prevention. The evidence analysis was carried out using PRISMA method. More than 600 articles were reviewed, leaving only the most representative in the references. This document concludes with practical and useful recommendations for the three levels of health care of our country.

Key words: Hypertension; Consensus development conference; Risk factors; Cardiovascular diseases; Mexico

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Hypertension is the most common modifiable factor risk for cardiovascular disease (CVD) and death. The increased risk associated with elevated blood pressure (BP) can be significantly reduced by treatment with antihypertensive drugs that decrease both BP and the risk of organ damage. A total of 69 drugs from 15 different classes, many of which are also available in pill combinations, have been approved for the treatment of hypertension in the US.¹ Despite this plethora of treatment options, an estimated 10 to 15% of the general hypertensive population has resistant hypertension, defined as BP uncontrolled by the use of three antihypertensive drugs of different classes (including a non-potassium-sparing diuretic at optimal doses), which can be controlled with the use of more than four drugs.^2,3 In addition, approximately 0.5% of hypertensive patients have refractory hypertension, defined as BP that cannot be controlled unless more than five drugs are used.⁴

Hypertension is a major independent risk factor for coronary artery disease (CAD) for all age, race, and sex groups. Taking as a criterion over 140/90 mm Hg, there are an estimated 65 million American adults, or nearly a quarter of the adult population of the United States, who have hypertension (HT). Another quarter of the population has pre-hypertension, diagnosed with systemic blood pressure (SBP) of 120 to 139 mm Hg or diastolic blood pressure (DBP) of 80-89 mm Hg. In Mexico the 2015 population estimate by the National Population Council (CONAPO) is 121 million, of which 76.4 million are 20 years or older and have a 31% prevalence of HT; the estimated overall hypertensive population for 2015 is 23.7 million, and a similar number is estimated for the pre-hypertensive population. In general, each 20 mm Hg increase in SBP (or every 10 mm Hg increase in diastolic blood pressure -DBP) doubles the risk of a fatal coronary event (Figure 1).

Many more hypertensive patients are not controlled due to failure or intolerance to the available antihypertensive agents. Recent drug monitoring studies have shown that it is lack of adherence to antihypertensive therapy in 25-65% of patients with apparent treatment-resistant hypertension (TRH).^5-9 In a range from 24 to 34.5% of these individuals who were prescribed three, four, or five antihypertensive drugs, antihypertensive medication was not detected in blood or urine samples. The need to control blood pressure (BP) in these high-risk patients can be solved partly by developing new drugs, devices, and procedures that are designed to treat hypertension and comorbidities, such as heart failure (HF), chronic kidney disease, and diabetes mellitus. 

The epidemiological transition of HT in Mexico in the environment of other chronic diseases

The enormous growth in the prevalence of key chronic diseases in adults (KCDA), like systemic arterial hypertension (HT), diabetes mellitus type 2 (DM2), dyslipidemia, obesity, metabolic syndrome, and atherosclerosis, among others, has allowed these diseases to surpass the prevalence of communicable diseases, which has contributed significantly to the burden of expenditure in the health sector.¹ This transformation, which is occurring in many developed and developing countries, has been called the epidemiological transition. But perhaps the greatest value of this concept (as a global public health problem) is that it now recognizes the KCDA of cardiovascular risk (CVR) as the world's leading cause of morbidity and mortality in adults. The economic and social impact of the KCDA of CVR is devastating for any healthcare system in the world, because they are incurable entities with consequences that will mostly be incapacitating. Cardiovascular disease, especially ischemic heart disease, is considered to be in the category of diseases of catastrophic expenditures.

Hypertension is the KCDA of CVR with the highest global prevalence (Figure 1).² A prevalence of 25% was reported in 1993 in Mexico; however, for 2000 the reported prevalence of HT between ages 20 and 69 was 30.05%, i.e., more than 15 million Mexicans of that age group.3,4 The 2010 Encuesta Nacional de Salud (ENSANUT) reported that 31% of Mexicans had hypertension, i.e., in 2014 it was estimated that approximately 24 million adults over age 20 were carriers of HT.⁵

In the Instituto Mexicano del Seguro Social (IMSS) the results of disease burden in 2010 were reported in 2012; this said that 27% of total mortality was secondary to cardiovascular disease (Figure 2).

Regarding the prevalence of hypertension, the northern states of our republic have even higher prevalence figures. Although detection has definitely improved, unfortunately 61% of people detected with HT in the 2000 national survey were unaware of being having the disease, a situation which is extremely important because, in general in Mexico, the patient only goes to the doctor after several years have passed since the beginning of their HT, and there is probably already some degree of target organ damage.⁴ In addition, of the patients who knew they had HT, only half was taking antihypertensive medication, and of these, only 14.6% showed numbers considered to be controlled (< 140/90 mm Hg).⁴ This does not mention that the new criteria for control in diabetics or kidney damage patients must be stricter (< 130/80 mm Hg). As such, it is rigorously estimated that only 10% of the hypertensive population in Mexico actually has optimal control. This could help explain why our rate of hypertensive emergencies and cerebrovascular events, diabetes, chronic renal failure, ischemic heart disease, heart failure, and hypertensive retinopathy, among others, are increasing and not reducing as in other countries.^1,5-8

The prevalence of HT is closely related to age, environment, lifestyle, gender, and comorbid factors such as diabetes, obesity, dyslipidemia, smoking, and genetic predisposition.^9-12 Moreover, it is not only the severity of HT in terms of mm Hg, but its interaction with these factors that determines the magnitude and rate of progression of target organ damage, a situation that must be considered essential for the indication of rational medical treatment. That is why when reading these recommendations one must not lose sight of all the individual characteristics of the person with HT.^11-14 It is important to recognize that most international guidelines (whose impact on daily practice is not entirely reflected)¹⁵ are based on studies in Anglo-Saxon or Caucasian populations.^14-16 Thus, in general, these studies include people over 55 years. However, the population distribution in Mexico is still pyramidal, i.e., most of the adult population is between 20 and 54 years. Therefore, while it is true that the prevalence of HT in percentage terms is directly related with age, when quantifying the absolute number of patients with HT, it was found that in Mexico about 75% of hypertensive patients are less than 54 years of age (Figure 3). Therefore, we must demystify that HT is a disease of adults older than 60.^16,17

In general, HT is asymptomatic in its early days, or it produces nonspecific symptoms that are difficult to link with it. Thus, in 2000 it was found that 20% of patients between 20 and 35 years old knew they were carriers of HT, while nearly 50% of those between 55 and 69 years old knew it.^16,17 For all the above, the approach to our recommendations will be regarding age and gender groups, simultaneously considering the coexistence of other risk factors; thus we apply the method called conjunctive consolidation.¹⁸ This multi-categorical analysis model emphasizes that the clinical and therapeutic approach to the patient with HT should be done on the basis of their individual characteristics and in the context of the presence or absence of other risk factors. This method is also applicable to any KCDA of CVR (Figure 4).

It is important to emphasize that this document and its recommendations are auxiliary elements suggested by an institutional review board for clinical practice, but are not sole, regulatory, or dogmatic determinants. So, it will be the treating physician’s clinical judgment that must always prevail before a comprehensive analysis of the patient with HT.

Methods

The consensus of the Unidad Médica de Alta Especialidad (UMAE) of the Hospital de Cardiología del Centro Médico Nacional Siglo XXI, presented on the detection, diagnosis, and treatment of HT, is based on a systematic review of national and international literature. It applies the Delphi method for consensus and the PRISMA strategy for the systematic review of clinical trials. The approach used was outlined by an interdisciplinary working group that thoroughly analyzed the available scientific evidence using electronic search systems (Internet) and books in the related area and their references, as well as the results of their own investigations. The Delphi method¹⁹ consisted of two phases: first sending an electronic questionnaire with related key questions, which were collected and analyzed. A second phase consisted of evaluating the first phase and declaring the recommendations supported by consensus. 

The working group took into account various topics to achieve a comprehensive, systematic review directed at solving specific questions. Our approach was to review and summarize published reviews for the established concepts, in addition to an analysis of original articles and the epidemiological data itself for the establishment of new concepts. The level of impact of the recommendations was graded according to the level of strength of scientific evidence. The classification system and the recommendations of these guidelines were also analyzed independently by external reviewers, in addition to the internal working group.

The systematic review consisted of consulting the bibliographic sources of more than 600 articles, of which 133 were original papers tabulated and graded according to four levels of scientific strength: 1) study size, 2) applicability, 3) feasibility of widespread use of the information, and 4) methodological quality depending on the study type. It also took into account the critical analysis of the recent recommendations of the Joint Committee of the United States (US) (JNC-8)²⁰ and the guidelines proposed by the Canadian Committee²¹ and the European Committee.²² A selection was made of 123 citations that, in the authors’ opinion, gave scientific support to these guidelines; however, the reader may ask authors for the complete bibliography.

The Delphi technique consisted of 20 predesigned questions sent to the experts. The recorded results were based primarily on the recommendations based on their knowledge and experience in daily clinical practice. 70 experts from different parts of Mexico participated.

The proposal for the therapeutic-pharmacological approach took into account the operational levels of health care, according to the health care programs in force in our country. The recommendations were also based on common agreement with the level of scientific evidence, and secondary treatment alternatives are proposed for situations in which for whatever reason the drug backed by the highest level of scientific strength is not available.²³ These guidelines are not coercive rules, but, on the contrary, they just represent a tool for the physician, who must use them only as a frame of reference for their clinical judgment.²⁴

This update of the Consensus and Guidelines for the Detection, Control, and Treatment of HT in Mexico takes into account the geo-demographic, anthropometric, and socio-medical characteristics of our country. Beta-blockers, for example, have been widely sanctioned in Europe; however, for young people (under 40 years) without carbohydrate metabolism disorders, who are not obese, and who have a strong hyperreactive component, these remain first-line therapy, in the authors’ opinion.

Impact of prevalence and concatenation of other key chronic diseases and cardiovascular risk factors

Treating only hypertension without controlling other factors that, as is well known, can increase cardiovascular risk, can dramatically reduce the expected results of antihypertensive treatment in the medium and long term.

Therefore it is crucial to know the prevalence of other factors and how they create synergy and affect cardiovascular damage, the higher their number. In Mexico, the prevalence of other KCDAs, which at the same time are cardiovascular risk factors such as type 2 diabetes and dyslipidemia, has increased dramatically in the last decade. Thus, a national prevalence of 10.8 and 16% was reported for DM2.^4,5 Obesity and smoking have also increased their prevalence (30.4 and 36.6%, respectively).⁵ Knowledge of these data is relevant, since there is a strong association with the presence of HT. This supports the hypothesis that there are underlying interactions among KCDAs that increase cardiovascular morbidity and mortality in adults (Figure 4). It is therefore recommended that the clinical and therapeutic approach to KCDA and other risk factors such as obesity and smoking be viewed holistically and not separately.¹⁵ The national survey 2010 ENSANUT, whose results were recently released globally, confirms that chronic noncommunicable diseases continue to rise and that obesity and overweight probably stand out for their remarkable increase. Hypertension generally maintained its prevalence, and an increase was noted in the percentage of detection.⁵

Definition and classification of hypertension

New knowledge regarding the HT indicates that it is not only the numerical level in mm Hg that establishes the risk, but there are other factors that must be taken into account when stratifying the patient’s risk. Of course, blood pressure remains a cornerstone in risk stratification, but our approach must be comprehensive. According to the World Health Organization (WHO), the limit to define a person as hypertensive is above 140 mm Hg elevation in systolic pressure or ≥ 90 mm Hg in diastolic pressure.²⁵ However, one must consider some recommendations before categorizing a person as having HT:

1. Confirmation of diagnosis: it is necessary to confirm that the elevated blood pressure is genuine, that is, one must rule out the possibility that some external factors may cause transient blood pressure elevation at a given time (recent prior physical or mental exertion, intake of coffee, tea, or any other stimulating substance at least one hour prior to taking blood pressure); personality type should also be considered (there are very anxious or apprehensive people who, upon arriving at the office, the simple fact of being there, and seeing or talking with their doctor causes them such stress that it may cause a transient elevation of blood pressure without necessarily being sustained HT; for example, white coat hypertension). Therefore in patients with hypertension stage I (Tables I and II), or borderline hypertension, it is preferable to perform various measurements (two or three per week under ideal conditions, preferably in the morning) before establishing the definitive diagnosis of hypertension.




Table I Reference values for human blood pressure
Category	Systolic pressure (mm Hg)	Diastolic pressure (mm Hg)
Optimum level	< 120	< 80
Normal	120-129	80-84
Normal high*	130-139	85-89
Hypertension	140 or more	90 or more
Hypertension in DM2 or with established renal damage	135 or more	85 or more
Pure systolic hypertension	140 or more	< 90
Pure diastolic hypertension	< 140	90 or more
DM2 = diabetes mellitus 2 *If it is a diabetic patient with kidney disease (albuminuria) or there is hypertensive retinopathy ≥ II or left ventricle hypertrophy, these figures should be considered hypertension and this requires considering pharmacological treatment with renin-angiotensin system blockers. It is also advisable to observe their behavior in a stress test (hyperreactive). A study of ambulatory blood pressure monitoring (ABPM) is also recommended. The highest level of pressure, whether systolic or diastolic, defines the patient’s group




Table II Stages of systemic arterial hypertension30*
Category	Systolic (mmHg)	Diastolic (mmHg)
Stage I	140-159	90 - 99
Stage II	160-179	100 - 110
Stage III	180 or more	> 110
* Modified from the International Society of Hypertension (ISH). Chalmers J, MacMahon S, Mancia G, Whitworth J, Beilin L, Hansson L, et al. The category is according to the highest value. Usually stages II and III require combined treatment from the start. If there are associated autonomic symptoms or papilledema in the fundus oculi, the case should be considered urgent and be brought to a secondary care hospital for observation. If there are signs of neurological targeting or seizure, they should be brought to a tertiary care hospital. If the patient is asymptomatic, do not resort to sudden action to suddenly lower systemic arterial pressure (sublingual or intravenous). If within 4 to 6 hours after giving combined treatment with optimum doses, this is not lower or is higher, it is preferable to send them to the hospital clinic for observation and treatment. Sudden reductions tend to be counterproductive in coronary patients, with coarctation of the aorta, renal artery stenosis, aortic insufficiency, or pheochromocytoma

2. Borderline numbers: however, when borderline numbers or slightly elevated blood pressure is detected, regardless of the cause, this must, per se, be a matter of deliberate search for the diagnosis of HT. It is even advisable to search for other risk factors, as the "clinical impact" of borderline or normal high blood pressure figures will not be the same in one young subject (over 35 years) without other risk factors, as in another (same age group) who has other risk factors detected (e.g., diabetes, obesity, dyslipidemia, glucose intolerance, hyperuricemia, micro or macroalbuminuria). Thus, the so-called pre-hypertension (according to JNC VII),¹⁸ with a range of 135-139 mm Hg in systolic pressure or 85-89 mm Hg diastolic pressure, can be classified as genuine hypertension in the context of a diabetic patient with liver disease. In addition, the TROPHY study noted that more than 50% of patients with normal high systemic blood pressure detected in ambulatory monitoring will become hypertensive over the course of a year.²⁶ 
3. Ambulatory blood pressure monitoring is a useful alternative for borderline cases or suspected white coat or reactive HT. Also, teaching patients self-measurement of blood pressure has proved to be useful; however, it can arouse anxiety and obsessive attitudes in some individuals.^27-29 In this consensus the authors emphasize the usefulness of this evaluation method.

 

Classification by blood pressure figures

The level of blood pressure is an important parameter for diagnosis and the therapeutic approach, as long as one takes into account the patient’s context. Table I demarcates the classification by level of blood pressure in mm Hg.

Optimal level

It is generally accepted that pressure figures < 120/80 mm Hg represent the lowest risk for developing cardiovascular complications, hence the term optimal. The prevalence of subjects with optimal figures reported in Mexico in the year 2000 was only 21%.^4,6 Does this mean that 79% of the population between 20 and 69 years should receive some kind of recommendation or therapeutic intervention? The most likely answer would be negative; however, one must insist that the patient be approached holistically. Thus, it is the individual’s context that will determine whether or not borderline figures represent any kind of risk. The term prehypertension should be used with great caution, but should never be underestimated. 

Normal-acceptable level

This is classified as normal when systolic pressure ranges from 120 to 129 or diastolic pressure between 80 and 84.

Borderline-pre-elevated level

This category is recognized in the United States as prehypertension, and it includes individuals with systolic pressure between 130 and 139 mm Hg, or diastolic pressure 85 to 89 mm Hg. This group has special importance, because if diabetes is associated with proteinuria or incipient kidney damage, the patient should be considered as equivalent to hypertensive stage I, and they require drug treatment. Figures consistently greater than 140 mm Hg systolic pressure or 90 mm Hg diastolic pressure establish the diagnosis of HT.

Exaggerated hypertensive response to moderate physical effort

It is not so uncommon for young subjects who come to the clinic for a checkup to awake a hypertensive response within minutes of beginning to exercise, even when their resting numbers were normal or even optimal. Although there is little information, some authors^30,31 have classified this response as abnormal and have even associated it with the likelihood of developing hypertension in the next decade. Our group suggests that these patients, especially if they have other risk factors, should get follow-up more frequently and at the slightest suspicion of target organ damage; proteinuria or ventricular hypertrophy should be monitored or medicated if deemed necessary. This generally (if not contraindicated) responds to low doses of beta-blockers. This response is also prevalent among overweight or obese patients who do not exercise, and simple weight loss and change in the sedentary lifestyle can normalize this hyperreactive response. Do not forget that some chromaffin cell tumors (pheochromocytoma or paraganglioma) may even precede the hypertensive crisis of hypotension. Moreover, in the case of a patient who comes because they were told that their systemic blood pressure was very high, and that when we take it turns out normal or optimal, one should not rule out HT by simply thinking that whoever took it did it went wrong or used an uncalibrated device; although this is the most common, a stress test or a series of samples can be a timely measure.

Classification of hypertension by stages

The classification by stages is based on systemic blood pressure figures in mm Hg recorded in both systolic and diastolic pressure. If a person who is hypertensive according to the pressure figures detected falls into one category with systolic and another with diastolic, they should be classified according to the highest of the two values. The stages are shown in Table II.

HT Stage I

A patient will be cataloged as hypertensive stage I when systolic pressure is between 140 and 159 mm Hg or diastolic blood pressure is between 90 and 99 mm Hg. However, if the patient has diabetes or kidney damage with proteinuria, they should be classified as hypertensive stage II, and there is a formal indication of required drug treatment with ACE inhibitors or angiotensin receptor blockers (ARBs), alone or in combination with other drugs (including diuretics or calcium antagonists) achieve optimal blood pressure numbers (< 130/80 mm Hg).

HT Stage II

This stage contains patients whose systolic pressure is greater than 160 mm Hg or diastolic pressure greater than 100 mm Hg. In general, this group hardly responds to a single drug, so the initial therapy may be combined treatment, and a thiazide diuretic at usual doses is recommended in those over 55 years, or a calcium channel blocker, especially in young subjects. It should be noted that if the patient is also diabetic, has proteinuria, or there is evidence of kidney or other target organ damage, they are to be considered at greater risk.

HT Stage III (extremely high blood pressure)

This group of patients deserves special attention because it is rare for a hypertensive individual to begin or to attend a visit with systolic pressure > 180 mm Hg or diastolic pressure greater than 110 mm Hg, especially if they are under 54, not older patients.⁷ The person warrants special tests and should be evaluated by a specialist. Usually they barely respond to a single drug, and it is not uncommon to need the combination of more than two drugs.

In subjects who suddenly change their hypertension pattern from level I or II to a very hard to control hypertension, the possibility of an endocrine, metabolic, or structural factor, such as stenotic renal arteries from atherosclerosis, should always be kept in mind. Therefore, rather than continuing to add antihypertensives, an aggregate component should be ruled out.

HT classification according to systolic or diastolic pressure and pulse pressure^32-35

Either of the figures, systolic or diastolic, that reach or exceed the figures given as limits (140/90 mm Hg), is sufficient to establish the diagnosis; that is, both do not necessarily need to be high. Thus, one can speak of hypertension with diastolic predominance, or even pure isolated diastolic hypertension (values over 90 mm Hg with normal systolic pressure); one can also talk about hypertension with systolic predominance or even pure isolated systolic hypertension (values ​​over 140 mm Hg with normal diastolic pressure). The term systolic-diastolic hypertension should be reserved for cases where both figures are high. The importance of this classification is related to the underlying pathophysiological mechanisms, which are different and could at any given time determine the type of antihypertensive treatment. Age is a factor that is associated with the systolic or diastolic predominance of hypertension. Thus, the prevalence of diastolic predominance is higher in subjects over age 50. In Mexico, due to its population distribution characteristics, where most of the population between 20 and 69 is still made up of subjects under age 50 (pyramidal distribution), the highest prevalence of HT is of diastolic predominance. Thus, unlike in developed countries, whose distribution by age group shows a predominance of subjects older than 50 years, the prevalence of the isolated systolic type is more common (more than 30% of all hypertensive patients).

In recent years the simple direct relationship of cardiovascular risk with systolic and diastolic pressure has become more complex from the fact that the patient should be seen in their full context of comorbidity, not only their numerical figures; pulse pressure (systolic minus diastolic) has also shown to be a determining prognostic.^35,36

Initial diagnostic evaluation

Diagnostic procedures should be aimed at establishing pressure levels; identifying possible causes of secondary HT; and assessing total cardiovascular risk by investigating other risk factors, target organ damage, concomitant diseases, or accompanying clinical conditions.

Diagnostic procedures involve repeated blood pressure measurements, medical history, physical examination, and laboratory and imaging tests, some of which should be considered routine for every person with high blood pressure.

Measuring blood pressure

Blood pressure is characterized by large variations within or between days.^18,22,36 Therefore, the diagnosis of HT should be based on several measurements made on separate occasions. If blood pressure is only slightly elevated, occasionally, it is recommended to establish a more frequent follow-up system (biannually). We must not forget, however, that 40% of these people will become genuinely hypertensive in a period not exceeding 5 years, especially if other risk factors are not modified.

Health professionals taking blood pressure measurements need adequate initial training and periodic review of its functioning.²³

Equipment providers must ensure that the devices for measuring blood pressure are properly validated, maintained, and regularly re-calibrated according to the manufacturer’s instructions and with authorization from the Secretaría de Salud.

Where possible, standardize the environment when measuring blood pressure: provide a relaxed, temperate atmosphere with the patient seated and their arm resting comfortably (note that the principles of correct good technique for measuring blood pressure are key. If the first measurement exceeds 140/90 mm Hg, take a second confirmatory reading at the end of the visit).

Measure blood pressure in both the patient’s arms, identifying the arm with the highest value for future reference. Patients whose blood pressure drops when standing, i.e. those with hypotension (drop in systolic blood pressure by 20 mm Hg or more when standing) and symptoms (fall or postural vertigo) should be referred to a specialist (Table III).

Unexpected values

Refer patients with accelerated HT to a specialist immediately (pressure more than 180/110 mm Hg with suspected papilledema or retinal hemorrhage), or those with a suspected secondary cause, such as pheochromocytoma or renovascular hypertension.²²

Defining a subject as hypertensive

To define a subject as a carrier of hypertension (persistent high blood pressure above 140/90 mm Hg), ask the patient to return for at least two subsequent visits to determine blood pressure from two readings in conditions that are better and more favorable for sampling.

Time intervals to measure the response

Measurements should normally be done at monthly intervals. However, patients with more severe hypertension (Stage II or III) should be reevaluated earlier.

Ambulatory monitoring

The routine use of home or ambulatory blood pressure monitoring with the devices used in primary care is currently recommended because its value has been properly established; however, the patient should be well chosen (cooperative and not anxious). The proper use of the devices in primary care remains a subject for further research.

Consider the need to review research on patients with unusual records or symptoms, or when the variations are very wide between samples on different days and circumstances.

Pressure measurement by medical personnel³⁷

This should preferably use a mercury sphygmomanometer or the digital or electronic equivalent, in good condition, validated and calibrated. Or, an aneroid manometer validated with a mercury manometer, preferably every six months; that is, these devices must meet the requirements of standardization protocols. The blood pressure measurement procedures to be done by the medical personnel are listed in Table III.

Ambulatory blood pressure measurement (ABPM)²⁸

Many devices (mostly oscillometric) are available and allow automatic pressure monitoring while the person does their usual activities. These systems provide information on the profile over 24 hours, or for more restricted periods, such as day, night, and morning hours. Although this information should not replace measurement in the office, many studies have shown that the determination of pressure in the office has little relation to that recorded over 24 hours.²⁸ These studies have also shown that ambulatory blood pressure a) correlates with target organ damage better than pressure from the office, b) predicts cardiovascular risk better, and c) measures the reduction in blood pressure due to treatment more accurately.

As a result, ambulatory blood pressure helps eliminate the "white coat" and placebo phenomena, plus it has a high reproducibility over time.^36,37

When measuring blood pressure over 24 hours, one must be careful to:

• Use only validated devices standardized with international protocols.
• Use appropriately sized cuffs, comparing the first measure obtained with the office sphygmomanometer measure, and checking that the difference is not greater than 6 mm Hg.
• Schedule readings at intervals not exceeding 60 minutes to obtain an adequate number of values ​​and have more representative hours, taking into account the readings that will be rejected for being obsolete.
• Instruct the individual under study to do their normal activities but to refrain from strenuous exercise and to keep the arm extended during the reading.
• Obtain another ambulatory record if the first determination was less than 70% of the expected values ​​due to a high number of artifacts.
• Remember that ambulatory blood pressure is usually lower than that obtained in the office.³⁷

As shown in Table IV, systemic blood pressure in the non-hypertensive population, office values ​​of 140/90 mmHg correspond to average values of about 125/80 mm Hg ​​for average ambulatory pressure over 24 hours.

Measuring blood pressure at home

Self-monitoring of blood pressure at home, while they do not provide the extensive information of 24-hour ambulatory monitoring (recordings during work and at night) can provide values ​​for different days in conditions in very close to daily normal life. When these values ​​are averaged, they share some of the advantages of ambulatory monitoring (such as eliminating the "white coat" effect); they are also reproducible and predictive of the presence of target organ damage, more than the pressure recorded in the office.³⁷ Therefore, home blood pressure measurements for reasonable periods of time (a few weeks) before and during treatment can also be recommended because of its low cost and encouraging greater adherence to treatment. The disadvantage could be attributed to the time taken (weeks), compared to monitoring for only 24 hours. When choosing self-measurement at home, one must take into account the following considerations:

• Use only internationally validated devices and instruct the patient (or the person who is going to take the measurement) to keep the arm extended at the time of reading. No device has been validated for the wrist.
• Recommend semiautomatic devices for people with hearing problems.
• Instruct them to sit for several minutes before making the first reading and inform them that measurements may differ due to spontaneous variations in blood pressure.
• Avoid them taking multiple measurements, and explain that some should be taken before taking the antihypertensive medicine, which will provide the doctor with information on the duration of the pharmacological effect of the drug.
• As with measuring ambulatory blood pressure, point out that home measurements may be lower than those recorded in the office.
• Give the patient clear instructions on the need to provide the doctor with accurate information, which will prevent self-inflicted alterations in treatment regimens.

White coat or office hypertension

Sometimes blood pressure recorded in the office can be found to be persistently high during the day, while the 24-hour monitoring values are normal. This condition is widely known as white coat hypertension.³⁷ Approximately 10% of the general population may suffer from this condition; there is evidence that the cardiovascular risk is higher in this population. However, many, but not all, studies have reported that this condition may be associated with target organ damage and metabolic abnormalities, which may suggest that this is not an entirely innocent phenomenon.

Physicians should diagnose isolated reactive HT (Table V), provided that they register pressure ≥ 140/90 mm Hg on several doctors’ visits, while in 24-hour ambulatory monitoring the pressure is ≤ 125/80 mm Hg. Medical treatment should be instituted if there is evidence of target organ damage or if there is a cardiovascular risk profile. Lifestyle changes and close monitoring should be done in people with isolated reactive HT, in whom it is decided not to start pharmacological treatment.

Less common is finding individuals with normal pressure in the office, but with 24-hour ambulatory monitoring that is positive for HT (masked hypertension). However, a higher than normal prevalence of target organ damage has been found in this group of patients.

Comprehensive clinical approach

Family history should be collected with special attention to HT and associated diseases like diabetes, dyslipidemia, premature coronary heart disease, cerebrovascular disease, and kidney disease. The history should include the following:

1. Duration and previous levels of hypertension.
2. Data suggesting secondary causes of HT, as well as consumption of drugs or substances that can raise blood pressure (alcohol, cocaine, amphetamines, steroids, oral contraceptives, nonsteroidal anti-inflammatory drugs, erythropoietin, and cyclosporine).
3. Lifestyles, e.g. dietary excess (animal fat), salt, alcohol, tobacco; whether the patient does physical activity; whether they are overweight, plus if they have a sedentary lifestyle and if there are any changes in their work activities.
4. Past or current history of coronary disease, heart failure, peripheral vascular or cerebral disease, renal disease, diabetes mellitus, gout, dyslipidemia, bronchospasm, and drugs used to treat these conditions.
5. Previous antihypertensive therapy, results, and adverse effects.
6. Personal or environmental factors that may influence blood pressure, cardiovascular risk, course, and treatment outcome.

Physical examination

In addition to clinical history, physical examination should be undertaken to investigate evidence of additional risk factors (particularly abdominal obesity, waist > 90 cm in men and > 85 cm in women, Figure 5), signs of secondary HT (with possible known cause), and target organ damage (Table VI).

An interesting aspect is that when analyzing different waist measurement cutoffs for Mexican men and women to determine the prevalence of hypertension and diabetes, a very interesting behavior is established, because although the cutoffs are useful for epidemiological issues, in clinical practice one should consider other aspects such as the presence or absence of associated comorbidities (diabetes, dyslipidemia, atherosclerosis, kidney disease, and others), as the impact that central obesity can have is often different. Therefore, our recommendation is not to take the internationally mentioned cutoff points dogmatically, plus it should be more useful to use risk ranges. Thus, waistlines below 80 in both sexes are associated with low prevalence, and waists 85 and up increase the likelihood of having other chronic non-communicable diseases; if they exceed 90 cm in both sexes, the probability grows significantly; however, the impact is less young women than in those post-menopausal (Figure 5A, 4B, C, D). Another notable aspect is that very large waists (> 140) bear no proportion to serum glucose levels, and many do not have hypertension; genetic aspects are likely involved in this, because having morbid obesity requires a significant pancreatic reserve.

Laboratory tests

Laboratory tests (Table VII) are aimed at finding evidence of additional risk factors, HT secondary to a possible known cause, and determining if there is target organ damage. The minimum tests required is a matter of debate; however, there is a consensus that one should go from the simplest to the most sophisticated. The younger the person under study, the higher the pressure and the faster development; therefore, the more detailed the diagnostic work should be.  

In general, routine examinations should include glucose, urea, creatinine, sodium, potassium, complete blood count, total cholesterol, high and low density cholesterol, triglycerides, calcium, phosphorus, uric acid, urinalysis with examination of the sediment, an electrocardiogram, and a chest X-ray. If the patient is diabetic, one should request a review of glycated hemoglobin. Moreover, and based on recent epidemiological evidence, it is suggested to include, if possible, the determination of high-sensitivity C-reactive protein as part of primary prevention.^38,39 This should be measured particularly in patients with metabolic syndrome.⁴⁰ Recently the use of cardiological bioimpedance has begun to give useful evidence in monitoring.

Comprehensive systematic evaluation

This should be reserved for complex refractory or complicated cases, in which the specialist can do specific studies according to clinical suspicion of an underlying disorder.

Target organ damage

Because of the importance of target organ damage in cardiovascular risk, evidence of organ damage should be carefully investigated.^41,42 Recent studies have shown the usefulness of echocardiogram (ventricular hypertrophy) and carotid ultrasound⁴³ (wall or plate thickening) to properly classify cardiovascular risk; otherwise, up to 50% of hypertensive people may have been wrongly classified as low or intermediate risk. Therefore, when the resource is there, both echocardiography and carotid ultrasound studies are useful and should be performed. The search for albuminuria (macro or micro) is essential because it is very sensitive to determine organ damage, not only in diabetes but also in HT.⁴⁴

Heart

Chest x-rays should always be included in routine diagnostic evaluation, giving information about the cardiac silhouette and pulmonary arteries. The electrocardiogram (ECG) should be part of routine patient study of all hypertensive patients, in order to detect myocardial ischemia, conduction disorders, hypertrophy, and arrhythmias. Although the ECG’s sensitivity to detect ventricular hypertrophy is suboptimal, its specificity is high. Thus, when the Sokolow-Lyon index is positive (Sv1 + Rv5, v6 > 38 mm) or the Cornell index is modified (> 2440 mm*ms), its importance is such that it has been shown to be an independent risk factor for major cardiovascular events.⁴⁵ Echocardiography undoubtedly has greater sensitivity for detecting left ventricular hypertrophy and predicting cardiovascular risk;⁴⁶ unfortunately, is not a study that is as easy to access in rural areas.

Echocardiographic evaluation should include measurements of interventricular septum and posterior wall thickness, diastolic diameter, as well as the calculation of ventricular mass. Although the relationship between ventricular mass index and cardiovascular risk is continuous, the threshold of 125 g/m² for men and 110 g/m² for women is widely used for conservative estimates of left ventricular hypertrophy. The classification of concentric or eccentric hypertrophy, and concentric remodeling, using the parietal thickness/radio index of the cavity (values > 0.45 define a concentric pattern) have also been shown to have predictive risk value.⁴⁷ In addition, echocardiography allows one to find ventricular systolic function, including the circumferential shortening fraction, which have been proposed as predictors of cardiovascular events. Ventricular diastolic compliance (diastolic function) can also be determined by measuring the ratio between the E wave and the A wave of the Doppler transmitral flow, as well as early diastolic relaxation, evaluating pulmonary venous flow patterns within the left atrium.^47,48 There is current interest in whether the so-called "diastolic dysfunction" patterns can predict the onset of dyspnea and poor exercise tolerance without evidence of systolic dysfunction, which often occurs in young adults with hypertension and older adults.⁴⁸

Regarding heart failure with preserved ejection fraction (HFpEF),⁴⁹ today there is enough evidence to define it. Hypertension is the most common risk factor associated with this failure, although it is not exclusive. Beyond being defined as diastolic heart failure, current evidence confirms that this concept is much more complex and includes nested systolic dysfunction. Finally, echocardiography can provide information about changes in regional ventricular contraction due to ischemia or previous infarction. Other diagnostic cardiac procedures, such as nuclear myocardial perfusion, magnetic resonance imaging, stress testing, and coronary angiography are reserved for specific situations (coronary heart disease, cardiomyopathy, etc.).

Blood vessels

The examination of the carotid arteries by ultrasound, measuring the thickness of the intima and the media, and the detection of plaques,⁵⁰ has shown that it predicts both atherothrombotic brain disease and myocardial infarction. The relationship between the arterial thickness of the carotid intima-media and cardiovascular events is linear. A threshold > 0.9 mm should be taken as a significant alteration.⁵⁰

The increasing interest in systolic blood pressure and pulse wave pressure as predictors of cardiovascular events, which has been stimulated by evidence in various publications regarding the beneficial effects of lowering blood pressure in the elderly and in controlling isolated systolic hypertension, has encouraged the development of different techniques for measuring arterial distensibility.⁴⁸ Major and important pathophysiological, pharmacological, and therapeutic information has been accrued.⁵¹ Two of these techniques have been developed for possible use as a diagnosis procedure: measurement of the pulse rate and the rate of increase. Both are of interest and may be different from what is usually measured in the arm, as it has different predictive values ​​can be affected by different antihypertensive drugs. Endothelial dysfunction has been found as an early marker of cardiovascular damage.⁵² The techniques used to investigate endothelial dysfunction are very laborious, and consume time and resources for the clinical evaluation of the hypertensive patient. However, recent studies on circulating markers of endothelial activity (nitric oxide and its metabolites, endothelin, cytokines, adhesion molecules, etc.) may soon offer very simple tests of endothelial dysfunction,⁵³ as is currently the case with C-reactive protein.⁴¹ For now these studies are not available routinely in most health centers in our country. However, as already mentioned, it should not be forgotten that other clinical elements remain valid and very useful in risk stratification for the hypertensive individual (age, personal history and inherited family history, weight, waist, gender, diabetes, hyperuricemia, smoking, etc.).

Kidney

Hypertension secondary to kidney damage is based on the finding of elevated serum urea and creatinine, decreased creatinine clearance, and proteinuria. It is important to note that the relationship between serum creatinine and the extent of kidney damage is such that small elevations in serum creatinine level translate to significant kidney damage; thus, creatinine levels at or above 1.5 mg/dL serum correspond to significant renal damage associated with clearance numbers below 40 or 60 mL/min. It should be recalled that in patients with HT and kidney damage, elevations in serum creatinine and urate can be observed after having instituted or intensified antihypertensive treatment, which should not necessarily be considered a sign of progression of kidney damage (as long as it's not over 20% of baseline). Moderate renal impairment has recently been defined by detecting serum creatinine values ≥ 1.5 ​​mg/dL in men and ≥ 1.4 mg/dL in women,⁵⁴ or with values ​​< 60-70 mL/min of estimated creatinine clearance. An estimate of creatinine clearance in the absence of 24-hour urine collection can be obtained based on equations corrected for age, gender, height, and bodyweight.⁵⁵ Slight elevations in serum creatinine and urate may be observed after instituting or intensifying antihypertensive treatment. This should not be taken as a sign of progressive renal damage. Hyperuricemia (defined as urate level above 5.5 mg/dL) can frequently be seen in patients with untreated HT and has also been correlated with the existence of nephrosclerosis.^56-58

Finding deterioration of renal function in a hypertensive individual is a potent predictor of future cardiovascular events and death. Therefore, in all hypertensive patients it is essential to determine serum creatinine, creatinine clearance, serum urate, and proteinuria. In all diabetic patients with HT, with or without the diabetic condition, the presence of microalbuminuria must be looked for. Meanwhile, an elevation of serum creatinine indicates reduction in the glomerular filtration rate, and increased urinary albumin or protein excretion speaks of an impaired glomerular filtration barrier.⁵⁹ Microalbuminuria has shown to be predictive for the development of diabetic nephropathy, both type 1 and 2; however, the presence of proteinuria generally indicates the existence of well-established renal parenchymal damage.⁶⁰ In nondiabetic hypertensive patients, microalbuminuria, even below the current threshold values, has proven to be predictive of cardiovascular events. 

Cardiorenal syndrome has been defined as the simultaneous dysfunction of heart and kidney. Hypertension can lead not only to impaired cardiac function but also to impaired renal function. This worsening in patients with acute heart failure has been classified as type 1 cardiorenal syndrome.

In this context, worsening renal function is frequent and occurs as a result of complex multifactorial pathophysiological processes that are not well known, which include hemodynamic factors (renal artery hypoperfusion and renal venous congestion) as well as non-hemodynamic factors. Traditionally, worsening renal function has been associated with poor prognosis; however, some observations have revealed diverse and heterogeneous results, which may suggest that the same phenotype can correspond to various pathophysiological and clinical situations. The interpretation of the magnitude and timing of renal disorders, together with baseline renal function, the state of fluid overload, and clinical response to treatment may be useful to establish the clinical significance of changes in renal function that occur during an episode of decompensated heart failure.

Eyes

In contrast to the assertions of 1930’s, when Keith, Wagener, and Baker classified ocular changes in HT into four degrees,⁶¹ it is now rare to find patients with hemorrhage (grade 3) and papilledema (grade 4). Grades 1 and 2, consisting of arteriolar changes, are seen often, but there is no evidence that these changes have prognostic value. Therefore, grades 1 and 2 cannot be used as evidence of target organ damage; however, grades 3 and 4 are certainly markers of severe complications.

Proteinuria and retinopathy, underestimated risk markers?

The kidney has a unique filtration mechanism that allows the glomerulus to discriminate such small molecules (about 40 angstroms). Albumin is filtered only slightly, and the minimum amount that gets through is reabsorbed, such that it is almost impossible for a conventional reactive strip for urine protein to detect it. That is, if proteins are detected in a simple conventional reactive strip, the amount being filtered now exceeds 200 mg/dL. Unless there is an obvious reason (infection, pollution, expired strip, etc.), the presence of proteinuria, however slight, is an indirect sing of microcirculation damage, and should alert the physician to the need to optimize or even change antihypertensive treatment. The search for proteinuria is mandatory in any patient with HT, especially if the patient has diabetes or glucose intolerance. If they also have nitrogen retention or if proteinuria is significant, the patient should be referred to a specialist. Another very important clinical window in the evaluation of patients with HT is the study of the fundus. The presence of microhemorrhages should warn that there may be damage to microcirculation, and although its prognostic value has been overlooked, is as valuable as proteinuria can be.^61,62

Brain

In patients who have suffered from cerebral vascular disease, the imaging techniques that we have today can improve diagnosis, nature, and location of the injury.^63,64 Cranial computed tomography is the procedure of choice for the diagnosis of a cerebrovascular attack, but except for the early recognition of an intracranial hemorrhage, MRI has been slowly replacing the scan. This has even led to changes in therapeutic decision-making.^62,63 MRI is superior to tomography in identifying silent brain infarctions, the large majority of which are small and deep (lacunar infarctions). MRI can identify infarctions with a diameter of more than 3 mm. Despite the clinical relevance that this entails, the time and cost of MRI do not yet allow its widespread use.

Pathophysiology: topics in HT

Importance of the renin-angiotensin-aldosterone system^65-67

Regardless of the advances in knowledge of the renin-angiotensin-aldosterone system (RAAS) for the treatment of patients with HT, as well as many other factors, it is very important for any physician who is in contact with hypertensive patients to know the basic principles of this system, which is why we expand this section in summary.

Classically, angiotensin II (Ang II), the central product of the renin-angiotensin system (RAS) (Figure 6), is well-known as being responsible for vasoconstrictive effects, by influencing the renal tubules to retain sodium and water, as well as the release of aldosterone from the adrenal gland, besides participating in the regulation of the thirst center.

Regarding vascular tone homeostasis, these properties have made accumulated evidence supporting the perception that the renin-angiotensin system not only plays a central role in the etiopathogenesis of hypertension, but is involved in the mechanisms of production of myocardial hypertrophy and vascular remodeling. The recent recognition that angiotensin II has mitogenic properties capable of inducing intracellular signaling cascades that culminate in the modification and regulation of protein synthesis in cells with angiotensin receptors, has undoubtedly revolutionized the understanding of the mechanisms producing hypertrophy, fibrosis, and synthesis of the extracellular matrix. 

Thus, in the last 10 years major advances have occurred in the recognition of new functions of Ang II. These advances have proven that it is capable of directly inducing cell growth, regulating gene expression of various bioactive substances (vasoactive hormones, growth factors, components of the extracellular matrix, cytokines, activation of multiple intracellular signaling cascades), modifying cell activity (such as monocytes and platelets), and even participating in the modulation of immune function and coagulation.

As such there is more and more evidence supporting the hypothesis that Ang II is capable of inducing cardiovascular and kidney disease under certain circumstances, regardless of its functions on the regulation of blood pressure.

Recent observations have focused on the possible role of the renin-angiotensin system as a modulator of atherogenesis mechanisms that occur in the arterial wall.

This review aims to update the concepts of molecular and cellular mechanisms of the renin-angiotensin system responsible for cardiovascular disease, and to specifically analyze the possible mechanisms involved in the development of the atherogenic process.

Classic mechanisms and alternative pathways in Ang II synthesis

The cascade starts with the cutting of a large polypeptide known as angiotensinogen, whose main synthesis occurs in the liver, but which can be synthesized by the endothelium. Through renin (an enzyme produced in the liver and endothelium), a first degradation product consisting of 10 amino acids is separated, which is inactive and is known as angiotensin I. It is of interest that angiotensin I is not only produced through renin, but alternative pathways have been detected. Angiotensin I, then through the angiotensin-converting enzyme-1, is converted to a highly active octapeptide already mentioned, angiotensin II. Initially it was thought that angiotensin-converting enzyme type 1 is mainly found in the lungs, but today it is known that the entire endothelium has the ability to produce this enzyme. Recently, alternative routes for angiotensin II synthesis from angiotensin I have also been discovered, which are not mediated by ACE (angiotensin converting enzyme). These are tonin, trypsin, cathepsin, and chymase. These alternative routes could explain why, despite using one ACE inhibitor chronically, plasma concentrations of Ang II are not completely suppressed, rather, on the contrary, there is a trend for this to recover its serum levels.

ACE has well-recognized kininase functions. Thus, it is known that it is able to participate in the degradation of substances such as bradykinin, such that its inhibition allows its serum accumulation, which would in theory contribute to the observed hypotensive effects when an ACE inhibitor is administered. Accumulation in the lungs allows fluid extravasation and the stimulation of the receptors responsible for, among other things, the not uncommon side effect: a cough. As shown in Figure 7, the degradation of angiotensin continues.

Thus, Ang II is degraded to what has been called as "the other angiotensins", comprising angiotensin IV to Ang 1-7, to Ang-III, whose biological functions have begun to be seen.⁶⁸

Role of endopeptidase 24.11 (neprilysin) and Ang II

Neprilysin is an endogenous endopeptidase that promotes the synthesis of angiotensin 1-7, which is considered the true counter-regulator of Ang II. Angiotensin 1-7 has the advantage that it is also synthesized by ACE-2 (Figure 7). Furthermore, neprilysin is capable of catalyzing the natriuretic peptides, so its inhibition to increase levels of natriuretic peptides is a promising target. However, the greatest use has resulted when combined with a type 1 Ang II receptor blocker, such as valsartan, whose molecule has been made to bond to the neprilysin inhibitor, sacubitril, giving rise to a new concept of molecules known by the acronym RNAi. The drug LZC696 has proven to have high impact for heart failure with reduced ejection fraction, and expectations remain regarding HFpEF and HT.

Non-hemodynamic effect of Ang II

It has been shown that regardless of blood pressure, stimulation with Ang II was capable of causing ventricular hypertrophy and accumulation of the extracellular matrix, as well as increase in the middle layer of the vessels. It has also been shown that continuous endothelium stimulation with Ang II causes the expression of adhesion molecules such as P- and E-selectin. Thus, the facilitation of adhesion and activation of blood cells and platelets mediated by the endothelium is feasible, and Ang II is involved in this signaling traffic. An increase in the synthesis of chemokines (cell traffic regulatory proteins) can be stimulated by Ang II. One aspect of interest is that the plasminogen activator inhibitor (PAI) factor can be stimulated by angiotensin IV, so RAAS’s participation in coagulation has been demonstrated. Another very novel and interesting aspect is the participation of Ang II in atherogenesis. It is known that Ang II not only promotes the adhesion and migration of monocytes to the endothelium, but upon being attracted by a chemoattractant gradient to the subendothelial space, its contact with substances such as oxidized LDL requires the expression of the macrophage membrane and receptors, known as scavengers. Ang II promotes its expression. In a recent study in monkeys that were fed a high-fat diet, they were divided into two groups: one group was given an RAS blocker, and the second group was not given the blocker. Surprisingly, the monkeys who did not receive the drug developed atherosclerotic plaques, while those who received the drug did not develop atherosclerosis. This confirms that the RAS, if not the only factor, does in some way participate in the development of aterosclerosis.⁶⁶

Angiotensin-converting enzyme type 267

Recently, a homologue of ACE, termed ACE type 2, or ACE-2, has been identified; this is predominantly expressed in vascular endothelial cells of the heart and kidney. Unlike ACE, ACE-2 functions as a carboxypeptidase, which separates a single amino acid into angiotensin I, generating a residue of 9 amino acids, called angiotensin 1-9. Moreover, it is able to act directly on Ang II, also removing its last amino acid and giving rise to angiotensin 1-7 (Figure 7). The gene maps of ACE-2 and its relationship with hypertension are already known, and it is further recognized that Ang 1-7 has an important role in the pathophysiology of hypertension. In mouse models it is known that a downregulation of its expression occurs when there is hypertension. The hearts of mice with induced ACE-2 mutation develop dilated heart chambers and heart failure. Since ACE-2 theoretically competes with ACE for its substrate, and angiotensin I degrades into Ang II, the absence of ACE-2 is thought to cause an increase in circulating levels of Ang II. 

The increased levels of Ang II stimulates endopeptidases and ACE-2 itself to promote the synthesis of angiotensin 1-7. Moreover, one more receiver this angiotensin, the receptor AT-1, exerts opposite effects to what Ang II does.

Angiotensin II and kidney damage

Despite the large accumulation of basic information, it was not until the mid-eighties that a randomized clinical trial managed to demonstrate that, in patients diagnosed with diabetes mellitus and proteinuria, treatment with ACE inhibitors significantly reduced the likelihood of progression to terminal renal failure in over 40% of cases followed over five years. Despite the great initial criticism, the nephroprotection mechanism was unclear, since it was able to show that Ang II levels increased after two weeks of treatment. Subsequent studies demonstrated that the kidney has an intrinsic regulation system in the production of Ang II. More recent studies using specific AT-1 receptor blockers have confirmed that the Ang II damage mechanism happens through its receptor, since it was possible to significantly reduce the progression of glomerular damage in patients under treatment with AT-1 blockers. The great advantage of current controlled clinical trials is that their population is more securely selected, and although the type of design and follow-up time showed no significant differences in terms of mortality, the nephroprotection was clearly demonstrated (RENAL, IRMA studies)^69,70 More recent studies suggest that if treatment is administered early when proteinuria is beginning, the glomerular damage may even be reversible. In addition, in studies of rats’ kidneys that removed 4/5 of the kidney to force the residual nephrons into a state of hyperfunction, it was noted that the progression of damage and the development of hypertension can be prevented by giving an AT-1 blocker.

Angiotensin and ventricular hypertrophy⁴⁴

Left ventricular hypertrophy is a marker of target organ damage secondary to hypertension, which has been recognized for many years; however and nevertheless, strong measures to control and reverse this have been controversial because there was no well-structured controlled clinical trial aimed at this goal. Thus, ventricular hypertrophy has an estimated prevalence of 10 to 40% of the hypertensive population, and it is higher with age. If we consider that more than half of the world population with HT does not know that they have it, that of those who already know less than half properly take their treatment, and also that of those who take treatment, less than half have well-controlled HT, then we should not be surprised that it is estimated that the ventricular hypertrophy figures in hypertensive patients over 50 may be more than 90%. The presence of ventricular hypertrophy triples the risk of stroke, doubles the risk of heart attack, and increases the risk of sudden death and cardiovascular death in general.

Hypertension and sodium sensitivity

A term often used, but of which little is known, is the sodium sensitivity developed in a great number of hypertensive patients. Recent evidence suggests that the older an individual, the greater their risk of developing HT, among other reasons because the kidney develops subtle progressive damage that is secondary to multiple factors, including oxidative stress and genetic predisposition.⁷¹

Thus, whenever the imbalance between Ang II regulation and sodium excretion is reached, the increased sodium sensitivity determines the relative but sufficient increase in intravascular volume, a mechanism contributing to elevated blood pressure. That is, what at an early stage is a defense mechanism to increase natriuresis, can eventually become harmful.

Moreover, it is worth mentioning that not all patients respond to restriction of dietary sodium, for which reason some authors note that more than 40% are not sodium-sensitive, especially in early stages. This could have a big impact for the young hypertensive population, such as in Mexico. Unfortunately, the vast majority of hypertensive patients are detected as late (when they are more than 40 years old), and until the epidemiological mechanisms exist to detect this earlier, more than 75% will already have developed sodium hypersensitivity when they go the doctor, so, in general, it is better to recommend a low-sodium diet than to look for who is or is not sodium-sensitive.

Insulin resistance and hyperinsulinemia in HT

Although there is substantial evidence that patients with HT have a higher proportion of insulin resistance (IR)/hyperinsulinemia compared to normotensive individuals,^72-78 some epidemiological studies have failed to discern a significant relationship between insulin resistance and hyperinsulinemia.^79,80 In an effort to resolve these apparently conflicting results, the European Group for the Study of Insulin Resistance examined the relationship between a specific measure of glucose uptake mediated by insulin, fasting insulin concentration, and blood pressure in 333 normotensive individuals studied in 20 different clinical research centers.⁸⁰ The results indicated that systemic blood pressure was directly related to both IR and insulin concentration. In addition, these relationships were independent of differences in age, gender, and degree of obesity.

The size of the European study, besides the use of a direct measure of insulin action, as proposed, in contrast to the surrogate estimates, provides evidence that there is a relationship between insulin resistance, hyperinsulinemia, and systemic arterial pressure; however, it does not necessarily establish a direct cause-effect relationship.

For example, it is arguable that HT leads to IR/hyperinsulinemia. Thus, at the simplest level, the percentage of IR does not increase in patients with HT as the identified cause.⁷⁹ In addition, IR/hyperinsulinemia exists in normotensive first-degree relatives of individuals with essential hypertension.^81-85 Significant correlations were also found based on the results of several previous studies in which hyperinsulinemia has been used as a surrogate marker to infer insulin resistance under the idea that hyperinsulinemia is linked to the development of essential HT.^86-90  

The study that appears to be the most relevant in this matter was conducted by Skarfors et al.,⁸⁹ who evaluated the risk factors for the development of HT in 2130 men observed over a period 10 years. It was found that baseline blood pressure was the strongest predictor of developing hypertension. In addition, the baseline characteristics of normotensive men who developed HT were compared with those of individuals who remained normotensive. The analysis showed that individuals who subsequently developed HT were those who were more obese, had higher plasma insulin (fasting and after intravenous glucose), and high triglycerides (TG). When basal systemic blood pressure was excluded from multivariate analysis, independent predictors of progression to hypertension were obesity (as estimated by body mass index -BMI), fasting plasma insulin levels, and abnormal glucose tolerance tests, as well as family history of HT.

The predictive capacity of insulin for changes in systemic blood pressure over time has also been shown in children and Finnish adolescents.^89,90 The ages of the study population were three to 18 years, and the individuals under study were followed for an average of 16 years. The results of this study indicated that fasting insulin concentrations "appear to regulate the actual blood pressure within the normal range and predict future systemic blood pressure."

Despite the above-cited evidence regarding the role that hyperinsulinemia and insulin resistance in the pathogenesis of HT, interpretations of the results of statistical analyses of population studies continue to question the existence of this association. More specifically, when the statistical technique called factorial analysis¹⁷ is used to evaluate the relationship between insulin resistance and related conditions, blood pressure appears to be an independent factor associated with both insulin resistance and hyperinsulinemia.⁹¹ Although these results are usually interpreted as evidence against an independent relationship between IR/hyperinsulinemia, the etiological and clinical heterogeneity of patients with essential HT provides a more obvious reason for this conclusion. Resistance to glucose uptake mediated by insulin and compensatory hyperinsulinemia are continuous, not dichotomous, variables;⁹² thus there are no easy means to designate a person as insulin resistant or sensitive.

The observation that only 50% of patients with HT have IR/hyperinsulinemia explains why the controversy continues. At the simplest level, it is not surprising that studies based on large populations (in which surrogate markers of insulin resistance are applied mostly to normotensive individuals) had difficulty discerning a relationship between insulin resistance and blood pressure. However, these results do not talk about the 50% of HT patients who do have IR/hyperinsulinemia, and in these individuals the abnormality in the arrangement of insulin-mediated glucose and the consequences of this defect are very likely to play an important role in the genesis of increased blood pressure and the clinical outcome of patients with HT.

It must be also remembered that the results of population studies that conclude that insulin resistance is not related to the development of essential HT do not deny the following observations:

1. The prevalence of IR/hyperinsulinemia increases in patients with essential HT.
2. These changes can be seen in normotensive first-degree relatives of patients with HT.
3. IR/hyperinsulinemia, as demonstrated in previous studies, is an independent predictor of the development of essential hypertension. The isolated fact that IR/hyperinsulinemia does not contribute to the etiology of essential hypertension in some individuals should not obscure the conclusion that it is involved in underlying pathophysiological mechanisms that are relevant. Moreover, and perhaps most importantly, the subset of patients with hypertension and insulin resistance are largely at increased risk of developing severe cardiovascular disease.^92-95

Although indiscriminately, the terms cardio-metabolic syndrome, metabolic syndrome, insulin resistance and glucose intolerance, hypertriglyceridemia with low HDL levels, and metabolic hyperuricemia may appear deep down to refer to the same thing; it is important to note that it is not so.

Hypertension and metabolic syndrome

The extraordinary coincidence in the prevalence and interaction between these metabolic events, initially known by Gerald Reaven as metabolic syndrome X,^92,96 or later the "death quartet" by R. Kaplan, and then the "death quintet" etc., did lay the foundations for a common underlying metabolic component. While it is undeniable that the insulin resistance frequently accompanied by "compensatory" hyperinsulinemia is an independent risk factor for cardiovascular events, not all patients with HT are resistant to insulin.

However, according to the method of conjunctive consolidation,¹⁷ if a person enters the medical office and is female, is overweight or obese, is more than 50 years old, and has borderline or HT figures detected, their chance of being diabetic it is close to 30%, but the likelihood of insulin resistance is greater than 75% (Table VIII).

Table VIII Classification of cardiorenal syndrome (CRS)
Types of CRS	Characteristics	Clinical scenarios
CRS type1 (Acute CRS)	Rapid deterioration of cardiac function, leading to AKF	Acute decompensated HF, MI with cardiogenic shock, acute valvular insufficiency
CRS type 2 (Chronic CRS)	Chronic disorders in cardiac function causing chronic progressive renal disease	ICC (RAAS and SNS activation; chronic hypoperfusion, long-term)
CRS type 31 (acute cardiorenal syndrome)	Primary worsening of renal function leading to acute cardiac dysfunction. Fluid overload, electrolyte disorders, myocardial depressant factor accumulation, neurohormonal activation, and systemic inflammation have been postulated to lead to cardiac dysfunction	Acute kidney injury (uremia, causing deterioration of contractility, arrhythmia due to hyperkalemia and volume overload, causing pulmonary edema)
CRS type 41 (chronic cardiorenal syndrome)	Chronic kidney failure (CKF) is the main factor contributing to the deterioration of cardiac function and an increase in cardiovascular events	CKF leads to diastolic dysfunction, LVH, and coronary heart disease
CRS type 51 (Secondary CRS)	It is SCR 5 if the presence of concomitant cardiac and renal dysfunction is due to acute or chronic systemic diseases	Diabetes mellitus, vasculitis, amyloidosis, sepsis, and cardiogenic shock
AKF = acute kidney failure; HF = heart failure; MI = myocardial infarction; RAAS = Renin-angiotensin-aldosterone system; SNS = sympathetic nervous system; LVH = left ventricular hypertrophy

Thus, because a manifestation very often associated with insulin resistance syndrome is hypertriglyceridemia with low HDL levels, this should make us think that simple physical examination and interview are the most powerful tools that the doctor has for the detection and study of KCDA. There are no items 100% proving that insulin resistance is the cause of high blood pressure, but no doubt it is more frequent in hypertensive individuals, and the existence of IR should alert us because the risk of developing a cardiovascular event is greater that in hypertensive patients without insulin resistance.

The ENSANUT 2014,^4,15,16 (like other reports in the literature worldwide) showed that type 2 diabetes can significantly promote the development of HT. Thus, about half of patients with DM2 are carriers of HT, and generally more than 75% of patients with DM2 after age 60 will be hypertensive. In turn, HT doubles the risk of developing type 2 diabetes. Multiple studies are new being developed to demonstrate that treatment with type 1 Ang II receptor antagonists can reduce the risk of developing type 2 diabetes.

Hypertension and central obesity

Two observations have been derived from our analysis. First, there is a clear correlation between BMI and waist circumference; second, short stature is an independent risk factor and, third, the cutoffs for waistlines published by the World Health Organization do not apply in our country. The International Diabetes Federation recently published that Mexicans must build on the Asian criteria for abdominal circumference; well, there is nothing more wrong than that.

The correct way to measure the waist is with the patient standing and leaning slightly on a wall to allow them to be as erect as possible, without resistance from the rectus abdominis muscles; this way, the average height between the lowest costal margin and the ipsilateral iliac crest is measured without pressure. Sometimes in the very obese patient it is difficult to palpitate the lowest costal margin. In these cases they may be asked to flex their body slightly sideways to the opposite side from that being palpated, and any time the costal margin is felt, they are asked to return to their fully upright position, thus demarcating the point sought. Subsequently, the iliac crest is palpitated, and just in the central part of the distance from both points is where the tape goes. The same procedure is performed on the opposite side. Illustrative videos can be viewed on the Internet.  

Table IX describes the prevalence of abdominal circumference in Mexico according to the 2000 ENSANUT. The major differences with Europeans, Asians, and Aglo-Saxons are again emphasized. The same table shows significant differences by age group and gender with respect to international standards. We also observe how the waistline of 102 cm in men gives a very low percentage that underestimates the prevalence of diseases such as HT and DM2 in Mexico (Table IX, Figure 5A-D).

Importance of uric acid in HT

Uric acid is a product of purine degradation and is primarily degraded by a hepatic enzyme, urate oxidase. In subjects with obesity, insulin resistance, and dyslipidemia (metabolic syndrome), hyperuricemia frequently occurs because insulin stimulates reabsorption of not only sodium but also uric acid. It is estimated that up to 25% of the untreated hypertensive population, 50% of the population treated with diuretics, and 75% of those with so-called malignant hypertension have hyperuricemia. Hyperuricemia is associated with HT, vascular disease, kidney disease, and cardiovascular events. Although the pathophysiological mechanism is beginning to be elucidated, it is important to consider its role, as we often forget to measure their levels on a regular basis (biannually), especially in the context of the hypertensive patient. In addition to the potential direct damage caused by the elevation of uric acid, hyperuricemia is a possible marker of inflammatory activity, cell membrane damage, and increased production of oxygen free radicals. Recent studies suggest that hyperuricemia treatment (diagnosed with over 7 mg/dL in men and over 6 mg/dL in women) contributes significantly to good control of patients with HT. In addition, as an important element to remember, after menopause women often have increased levels of uric acid, a situation that in clinical practice is often not given the importance it deserves; however, we now know it should be recognized as a critical cardiovascular risk factor. So, one should not ignore this aspect in any patient in whom a thiazide diuretic is chosen as monotherapy.^56,57

Genetics and hypertension⁹⁷

The genetic variants that contribute to human hypertension have been preserved by natural selection (and the process that is genetically derived), but it is highly unlikely that there are genes for hypertension in an evolutionary context. Thus, it is likely that hypertension is a result of genetic variants preserved for other functions, and it is possible that these functions can yield insights into the genes that contribute to elevated blood pressure.⁹⁸

Since the functions that contribute to hypertension are complex, it is not surprising that essential hypertension is also a complex genetic and proteomic entity (there are many genes that interact in unpredictable ways). Currently, even the general nature of gene-gene and protein-protein interactions and how they relate to polygenic disease are poorly understood, hence the understandable desire to reduce the complexity of the problem, limiting attention to single gene variants.⁹⁸

Finding individual variants with a major defect on systemic blood pressure has proven difficult, because, although expected, sustained elevation of blood pressure (HT) is a complex polygenic disease. However, as we detect variations in more and more genes, we can now understand how new interconnections of these genes and their proteins cooperate in the biological pathways underlying HT.

Currently, studies of the genetics of HT are dominated by reductionist approaches that are often thoughts pointing to isolated biochemical or cellular aspects that are targeted at the mechanisms that promote hypertension. Suitable methods for the study of human hypertension, therefore, belong to the discipline of systems biology.

So, while animal models have been of unquestionable importance for understanding the biochemistry and physiology of HT, such models are not as effective in the discovery of the gene or genes involved, because while innate hypertensive tensions mimic essential hypertension, they fail as true models (simplified representations of complex systems). However, although genetic studies are more difficult in humans than in animals, we must focus increasingly on humans when looking for genetic determinants of HT.^99,100

Finally, hypertension results from the interaction of genes and environment. While it is commonly stated that about 40% of HT is attributable to genes, it is really impossible to separate genetic and environmental components.

Genes involved in hypertension

Blood pressure is a quantitative trait with continuous variation from low to high values ​​without an obvious tiebreaker point in the population distribution. Such quantitative traits are usually polygenic (the product of many genes). In fact, when the heritability of HT was established in comparisons of blood pressure values ​​in identical and non-identical twins, patterns of transmission of blood pressure in extended families, and the transversely sectioned measurements of blood pressure in adopted and biological children within families, they were the most consistent with polygenic inheritance. Estimates of the contribution of genetic factors derived from such studies suggest that less than half of the variation in population blood pressure can be attributed to genes; however, as already mentioned, understanding the phenotypic variation in genetic and environmental components can be done only on a particular set of environmental circumstances, because all hypertension is the result of gene-environment interactions.^100-103 Genes contribute to hypertension if they have allelic variants leading to increased systemic blood pressure. The standard model holds that the effects of these multiple alleles are additive; each genetic variant can contribute either a small increase or decrease in the level of systemic blood pressure. The situation is undoubtedly more complex, with interactions in genomics, gene expression, post-translation, and protein levels. Even after these factors are understood, as noted above, the results of the genetic complex of hypertension help understand certain differences affecting the integrated functions of cardiovascular and renal regulation of systemic blood pressure.

Gene-environment interactions¹⁰³

George Rose first said that when a disease is defined by an arbitrary threshold value (for example, 140 mm Hg of systolic BP for hypertension), the prevalence of hypertension is a function of the population average, with perhaps an additional contribution skewing the population distribution. Populations include individuals with differing genetic complements, and as these expose a population of individuals to a common system of environmental influences, some respond more vigorously than others based on how their gene systems interact with the environment.

This is known as a norm of reaction. In large populations, if most individuals have at least some response, the distribution of the entire population shifts to another of higher complexity. If only some individuals respond, the distribution is separated and skews. In any case, universal exposures result in an increase in the proportion of individuals with hypertension. Ecological differences in the environment of the populations that differentiate the phenotype of hypertension may suggest causal factors; the best-studied ecological factors associated with hypertension are the result of obesity and mechanisms of dietary sodium. Environmental factors can also be suggested by exposure studies of intrapopulation individuals to factors that continue with the phenotype of interest; alcohol use is one example for hypertension.

Below we explain some examples of the previous assertion. GNB3 (G protein of beta-3, allele 825 of subunit T) shows a latitudinal gradient particularly of the pulse, and with data from 35 populations in the international study of sodium, potassium, and blood pressure (INTERSALT), and the genotypes of human genome diversity, a very strong association of the allele GNB3 825T with hypertension is projected. So GNB3 is a likely gene for which the natural selection of an allele that promotes sodium conservation and vasoconstriction in our ancestors now promotes susceptibility to hypertension in the modern environment. Since GBN3 825T is only one of several genes known to have adapted alleles, the impact of progressively colder environments with migration away from the Equator may be one of the most important forces that form a genetic predisposition to hypertension.

Role of genetic variation in the genesis of HT^102-105

The cardiovascular system is complex and integrated; HT is an unexpected effect of the entire system. Using a variety of experimental models, Guyton et al. developed a model of circulatory physiology that describes the relationship of the product of sodium and water on the regulation of systemic blood pressure. In this model, the many mechanisms affecting systemic blood pressure, the volume, and the long-term homeostasis of blood pressure are achieved by the natriuresis and diuresis carried out by the kidney. Natriuresis induced by blood pressure is a classic negative regeneration or compensation system. When systemic blood pressure rises, renal excretion of sodium and water occurs and continues until blood pressure is restored to a point where the volume of product and output are matched. Thus, without a change in the setpoint of renal natriuresis of pressure, there should not be a sustained increase in systemic blood pressure. 

There are a number of ways to change the pressure-natriuresis setpoint; the most obvious is a change in kidney function (e.g. decreased glomerular filtration rate). Lowering the glomerular filtration rate as a result of disease or normal senescence compromises the kidney’s ability to excrete normal amounts of sodium, and adapts the system to continue operating at a higher point of blood pressure.

Besides mutations causing monogenic forms of hypertension, there are a number of other genes with alleles related to HT. The example of GNB3 is described above. Thus, a sodium retention allele affecting the angiotensinogen (AGT) promoter gene shows a similar latitudinal domain. The ancestral allele (which is present in our African ancestor) is associated with the sodium sensitivity of blood pressure, and, as is the case for the variants AGT and GBN3, there is a striking latitudinal gradient for the alleles of CYP 3A5, so equatorial populations have a high prevalence of the functional allele while northern populations have a high prevalence of the derivative and non-functional form. In addition, there is a strong correlation of these alleles of CYP 3A5 and AGT which promotes sodium sensitivity, suggesting that both alleles responded to the same selective forces created by migration to the northern latitudes. 

Finally, several reports have observed an association of variants of the beta-2 adrenergic receptor with aspects of hypertension, including sodium sensitivity. Other candidate genes that may affect renal sodium direction may affect the distal tubular epithelial sodium channel. In conclusion, all these genetic findings strongly support the hypothesis that genes contributing to differences in the renal tubular sodium direction are intimately involved in predisposition to essential hypertension.^106-110

Resistant hypertension¹¹¹

Resistant hypertension or hypertension uncontrolled by three or more antihypertensive drugs is increasingly common in clinical practice. Physicians should exclude pseudo-resistant hypertension resulting from non-adherence to medications or high blood pressure related to white coat syndrome. In patients with truly resistant hypertension, thiazide diuretics, particularly chlorthalidone, can be considered one of the initial agents. The other two agents should be included, calcium antagonists and ACE inhibitors for cardiovascular protection. A growing body of evidence has suggested benefits of mineralocorticoid receptor antagonists, such as spironolactone eplerenone, to improve control of blood pressure in patients with resistant hypertension, regardless of circulating aldosterone levels. So one should consider this class of drugs for patients whose blood pressure remains elevated after treatment with a three-drug regimen to maximum or near maximum doses. Resistant hypertension may be associated with secondary causes of hypertension, such as obstructive sleep apnea or primary aldosteronism. The treatment of these disorders can significantly improve blood pressure beyond medical treatment alone. The role of renal artery device therapy to treat the typical patient with hypertension resistant is still unclear.^112-114

Secondary forms of hypertension

The diagnostic and therapeutic approach of known etiologies of HT is not the goal of this consensus. However, one should always keep in mind this possibility, although only 5 to 7% of all hypertension patients have an underlying cause. Table X lists some of the most common causes of secondary hypertension. A secondary cause should always be ruled out when HT behavior is unusual (paroxysmal hypertensive crisis, severe occurrence in very young subjects, change in the pattern of behavior becoming very rebellious to treatment - bilateral atherosclerotic stenosis of renal arteries), or when the patient’s phenotype suggests to us any chance of congenital malformation (coarctation, Marfan’s syndrome, Williams syndrome, etc.). A deterioration of renal function after reducing blood pressure to optimal figures might suggest the presence of renal arterial stenosis. Before considering HT to be refractory, the most common causes of treatment failure should be ruled out, including nonadherence or administration of suboptimal doses or manipulation by the patient. In addition there are some substances that can contribute to or cause elevated blood pressure, such as anabolic steroids, caffeine, cocaine, ethanol, nicotine, sympathomimetic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), chlorpromazine, corticosteroids, cyclosporine, erythropoietin, monoamine oxidase inhibitors, oral contraceptives, and tricyclic antidepressants.¹¹⁵

Renal parenchymal disease is a common cause of secondary hypertension. A thorough interview about intercurrent urinary infections or palpitation of masses in the renal fossa should indicate an ultrasound to rule out morphological abnormalities and disorders of the cortical-subcortical relationship. The presence of cylinders in the urinary sediment, erythrocytes, or abundant leukocytes should point towards the infectious problem or parenchyma.

Renovascular hypertension¹¹³

Although its prevalence is estimated around 2% of all secondary causes of HT, the deliberate search has reached 25%, especially in young, difficult to control subjects. Fibromuscular dysplasia of the renal arteries is the most common root cause, but in adult subjects with risk factors for atherosclerosis who begin to treat their HT with difficult control, suspected renal artery atherosclerosis should be considered. Renal ultrasound is useful as a screening study, since differences of 1.5 cm between kidneys suggests renal artery stenosis in up to 70% of cases. Magnetic resonance angiography with gadolinium is the most widely used diagnostic procedure today. Another support maneuver for the suspected diagnosis is impairment of renal function with the use of ACE inhibitors or ARBs, especially in cases of bilateral renal artery stenosis; an increase greater than 0.7 in serum creatinine within a week of use should make us suspect renal artery stenosis bilateral. Treatment must be individualized according to the anatomical state and can range from intervention, surgery, or medical treatment when the anatomy cannot be addressed. 

Pheochromocytoma^113-120

It is estimated that pheochromocytoma has an incidence of two to eight cases per million inhabitants. It may have a genetic or acquired background. Hypertension generally has a stable beginning but in about 70% paroxysms appear characterized by sudden onset headache, sweating, and pallor. The diagnosis requires great clinical meticulousness, because the only way to know if there is pheochromocytoma is by keeping in mind the possibility of its existence. Diagnosis is usually established with the quantification of serum catecholamines and urinary metabolites (metanephrines). Stimulation or suppression tests with glucagon or clonidine are used less and less. Ambulatory blood pressure monitoring is useful for detecting hypertensive peaks. Whenever suspicion increases with laboratory studies, imaging studies (ultrasound or CT) are required. Magnetic resonance imaging has come to replace other studies because of its high sensitivity and specificity in detecting small tumors. When there is a family history or multiple locations, the possibility of multiple endocrine neoplasia should be considered. One should not forget that 10 to 20% of pheochromocytomas are not in the adrenal glands and are called paragangliomas.

Primary aldosteronism^121,122

This has become of interest in this entity in recent decades, as it often does not manifest as a single tumor, and it has been shown that there may be multiple implants in the adrenal gland; thus, reported prevalences of 1% in the past have increased to 11% in some studies. The most important thing is to always remain alert to changes in the behavior of patient pressure already known as hypertension, the presence of hypokalemia of unknown cause however mild, HT behavior resistant to treatment, or the need to considerably increase the dose or combinations to achieve goals. When suspected, the patient should be sent to secondary or tertiary care for study. The test of aldosterone suppression with fludrocortisone and renin and aldosterone measurement at baseline are tests that help greatly to confirm the diagnosis. It was recently suggested to use the aldosterone/renin ratio but the controversy continues, as some authors point out that the results are not so reliable in elderly people or black people. Spironolactone or eplerenone can be used while the surgical procedure is planned in the case of adenoma. Laparoscopic surgery has been successful.

Coarctation of aorta¹²³

Coarctation of the aorta is a rare form of hypertension and is usually detected in childhood; however, it is not uncommon, especially in emerging countries, the diagnosis is established in adolescence or young adulthood. The presence of precordial and dorsal murmur, and a differential systolic pressure above 10 mm Hg between the upper and lower extremities should alert the clinician to perform relevant imaging studies. MRI and CT angiography today offer great accuracy in their anatomical characteristics. The use of angioplasty with STENT offers very encouraging results, especially in aortic coarctation of the diaphragmatic type. One aspect that the clinician should not forget is that it is not uncommon for patients to remain hypertensive, mostly when treated at older ages.¹²³  

Cushing’s syndrome¹²⁴

It is estimated that less than 1% of the total population suffers from Cushing's syndrome. This means that in Mexico around one million people are carriers of this disease and probably a large percentage of them are undiagnosed. Hypertension is present in 80% of cases, but its prevalence can be as low as 50%, especially in children and adolescents. The external habitus (obesity, full moon face, hirsutism, abdominal striae, alterations in carbohydrate metabolism) requires a determination in 24-hour urine cortisol; if its value exceeds 110 mmol, the suspected diagnosis is highly suggestive. Some authors suggest that nocturnal cortisol determination or in saliva may be more practical and useful strategies for screening.¹²⁴

Sleep apnea and hypertension

The increase in the prevalence of obesity has also been reflected in a marked increase in the prevalence of sleep apnea. This entity causes nocturnal desaturation that causes varying degrees adrenergic activity reflected in increases in blood pressure, especially at night. Often those who suffer from apnea wake up with headache and tinnitus. Morning recording or ambulatory monitoring studies are useful for analyzing the impact of obstructive sleep apnea on the control of systemic blood pressure. It is not uncommon for the number and doses of antihypertensive drugs to be reduced considerably when a good control of sleep apnea is achieved.¹²⁵

Malignant hypertension

The term malignant HT was described by Volhard and Fahr in 1914. It was defined as a hypertensive entity of rapid progression with high mortality in which 99% of the carriers of this disease die within five years after their diagnosis with hypertension. However, the advent of dialysis and transplantation has managed to reduce mortality to less than 25% at five years. This kind of HT usually occurs with very high and difficult to control numbers, commonly with retinal hemorrhage and exudates; they may also have papilledema, but its absence does not rule it out; microangiopathy and progressive renal damage are common. Severe disorders in the regulation of intrarenal angiotensin and other vasoactive peptides have been linked to the pathogenesis of this disease. More recently other inflammatory components have been described as mediators or triggers of malignant HT.¹²⁶  

Unlike essential HT, in which the symptoms are often very insidious, in the accelerated or malignant type, there are usually symptoms. Headache and visual symptoms are the most common. Headaches often occur in the morning. The differential diagnosis of hypertension of renovascular origin is needed. Histological studies show myxoid arteriolar thickening, predominantly on smooth muscle cells. In patients with aggressive behavior of target organ damage, the need to use more than three drugs to achieve control should cause suspicion of this entity.¹⁰⁶ It is always advisable for these patients to be evaluated by a specialist.

Because HT is unfortunately unknown for 50% of its carriers, hypertensive emergencies remain a major health problem in Mexico; even patients known to be carriers of HT are admitted on average four times per year to some kind of emergency service in clinics and hospitals. 

Drug-induced hypertension¹¹²

Often we minimize the possibility that HT is associated with anxiety or a critical existential crisis. We grant the HT diagnosis regardless of the reactive component; although these patients over time often become hypertensive, follow-up and the use of ambulatory monitoring are extremely useful. Some substances that have been associated with increased blood pressure are the indiscriminate intake of alcohol, oral contraceptives, cocaine, amphetamines, erythropoietin, cyclosporine, tacrolimus, and thyroid hormones.

Risk stratification of patients with HT

The multi-categorical analysis by the method of conjunctive consolidation,¹⁵ used in the ENSANUT 2000,⁴ objectively showed the different percentage gradients of change in the prevalence of KCDA, depending on various circumstances.

Thus, for hypertension it is important to consider the initial clinical characteristics in each patient, as that can help us estimate the prevalence. Although there are many attempts to achieve a practical, simple, and easy to apply risk stratification, none replaces the clinician’s judgment. This should be based on the fact that being a carrier of hypertension is itself a risk to cardiovascular health. Morbidity and mortality will increase in the measure that more cardiovascular risk factors such as obesity, insulin resistance, diabetes, dyslipidemia, age, gender, family history, and the environment of each case are added. A patient may reduce or increase their probability of having a major cardiovascular event to the extent that an assessment of total cardiovascular risk considers all elements. Our HTM classification system (Hypertension System of Mexico) aims like many other classification systems to help with a quick and simple classification of the clinical environment of the patient with hypertension; it is based on national surveys and uses worldwide published literature as a framework.

Institutional system for the classification of risk groups

Age, diabetes, metabolic syndrome, obesity, target organ damage, and the degree of systemic blood pressure elevation are undoubtedly the main factors that greatly determine the likelihood of developing a cardiovascular event. The combination of the above factors can classify more than 85% of all hypertensive individuals and may also guide the therapeutic approach.

The combination of the factors listed in Table XI gave rise to a classification proposal called “HTM Classification" to indicate that it is a classification system for HT that combines the presence of other commonly associated cardiovascular risk factors. This classification may be useful for countries with

similar demographic characteristics to Mexico. The classification was designed with the idea of ​​having a simple and practical clinical stratification system that would permit a diagnostic and therapeutic approach upon first contact with the adult patient, which was simple and easy to apply. However, this classification proposal should not be taken as dogma or a coercive paradigm. 

The classification has two large groups: 1) HTM-1 designates hypertensive patients without evidence of metabolic syndrome or type 2 diabetes, and 2) HTM-2 classifies hypertensive carriers of metabolic syndrome or type 2 diabetes. In this regard, the reader will note that HTM-2 is unfortunately the most frequent presence in Mexico because of the high prevalence of metabolic syndrome.

The HTM classification system takes into account five basic indicators that allow the clinician to quickly find out the context of the hypertensive patient they are facing, for whom they need to design a work plan and therapeutic goals. In addition, due to the strong results of the AS-COT-BPLA study,¹²⁷ the association of a statin for the strict control of atherogenic dyslipidemia contributes to better control of blood pressure, so the individual and overall management of the hypertensive patient should always be kept in mind. Good control of comorbid cardiovascular risk factors often helps better control of the hypertensive patient and vice versa.

The HTM classification system proposed by our working group allowed us to build recommendations for pharmacological and non-pharmacological treatment. These recommendations appear in Table XII and Figures 8a, 9, and 10.

Consensus before the patient with systemic blood pressure, borderline, or prehypertension

When the term prehypertension appeared in the JNC-VII classification, instead of normal high blood pressure as defined by the Europeans, there were many controversies and publications in newspapers and magazines in popular circulation. Time has proven that not everything was bad, not even a single note of sensationalism. We clinicians know that hypertension has a whole pathophysiological continuum, and when it reaches the limit of 140/90 mm Hg, countless alterations in endothelial, neurohormonal, and kidney function may already have occurred. The TROPHY study¹²⁸ came to us to demonstrate the undisputed role of the renin-angiotensin-aldosterone system in etiopathogenesis, at the same time letting us see that treating those with high normal blood pressure with ARBs may delay its appearance in the clinical horizon, but that it is by no means a panacea, and in the absence of target organ damage it is not an indication. The TROPHY study came to us to remind us of the dynamics of the underlying pathophysiological processes and the need to monitor these patients more closely and to establish preventive measures on weight and diet, as more than 40% of those who received no treatment and had discreetly altered their 24-hour ambulatory monitoring formally became hypertensive at 12 months follow-up.

Non-pharmacological treatment in HT

Diet modification plays a key role in the management of HT. Several dietary guidelines provide scientifically-based advice to promote health and reduce the risk of major chronic diseases through diet and physical activity. In the United States, the leading causes of morbidity and mortality are related to poor diet and sedentary lifestyle. Some specific diseases related to poor diet and physical inactivity include cardiovascular disease, type 2 diabetes, hypertension, osteoporosis, and certain cancers. In addition, poor diet and physical inactivity, which result in an energy imbalance (more calories consumed than are expended), are the most important factors contributing to the increase in overweight and obesity in this country’s population. A diet that does not provide excess calories, following the recommendations of this document, combined with physical activity, should improve the health of most people.

Dietary recommendations

An important component of each five-year review of the dietary guidelines is the analysis of new scientific information by the Dietary Guidelines Advisory Committee (CASGA). This is the main resource used by departments to develop the report on the guidelines. The 2005 CASGA Report is a detailed scientific analysis that was used to develop dietary guidelines jointly between the two departments, and it forms the basis of the recommendations that the Food and Drug Administration (FDA) of the United States will use in the development of its programs and policies. Therefore, this publication is aimed at those who develop the policies, those responsible for nutrition education, nutritionists, and health care providers rather than the general public, as with previous versions of the dietary guidelines. It also contains more technical information.^129,130 

The intent of the dietary guidelines is to summarize and synthesize knowledge regarding individual nutrients and food components into recommendations for an eating pattern that the public can adopt. In this publication, the key recommendations are grouped under nine areas of related interest. The recommendations are based on the preponderance of scientific evidence for reducing the risk of chronic disease and health promotion. It is important to remember that they are integrated messages that should be implemented as a whole. Taken together, they encourage most Americans to eat fewer calories, to be more active, and to choose their food more wisely.

A basic premise of the dietary guidelines is that nutrient needs should be met primarily through food consumption. Food provides a set of nutrients and other components that may have beneficial health effects. In some cases, fortified foods and nutritional supplements can be useful sources of one or more nutrients that otherwise would be consumed in less than the recommended amounts. However, nutritional supplements, while recommended in some cases, do not replace a healthy diet.

The DASH Eating Plan (Dietary Approaches to Stop Hypertension,)¹³¹ used in the United States, is designed to incorporate nutritional recommendations for healthy eating habits for most people. These eating patterns are not weight loss diets but illustrative examples of how to eat according to the dietary guidelines. Eating patterns are built through a range of calorie levels to meet the needs of various age and gender groups. For the dietary guidelines, estimates regarding the nutrient content for each food group and subgroup are based on the population-weighted food intake. Estimates of nutrient content for the DASH Eating Plan are based on selected foods that are chosen for a sample seven-day menu. Although originally developed to study the effects of an eating pattern on prevention and treatment of hypertension, DASH is an example of a balanced eating plan consistent with the 2005 Dietary Guidelines. In most of this publication, examples use a 2,000-calorie reference level in order to match the nutritional facts table. Although this level is used as reference, the recommended calorie intake will differ for people depending on their age, gender, and activity level. At each level of calories, it is possible for people who consume nutrient-dense foods to meet their recommended nutrient intake without using all the assigned calories. The remaining calories, i.e., the amount of discretionary calories, give people the flexibility to consume some foods and beverages that may contain added fats, added sugars, and alcohol.

The Dietary Guidelines recommendations are for people over two years. It is important to incorporate the food preferences of different racial/ethnic groups, vegetarians, and other diets when planning and developing educational programs and materials. The DASH Eating Plan is flexible enough to include a range of food and culinary preferences.

Below is a list of dietary guidelines by chapters.

Key recommendations

• Eat a variety of foods and drinks with high nutrient density within the basic food groups while choosing foods that limit the intake of saturated and trans fats, cholesterol, added sugars, salt, and alcohol.
• Comply with the recommended intake within caloric needs by adopting balanced eating habits.
• Key recommendations for specific population groups
• People over 50 years: consume vitamin B12 in crystalline form (i.e., fortified foods or supplements).
• Women of childbearing age who may become pregnant: eat foods high in heme iron or iron-rich plant foods or iron-fortified foods with an iron-absorption enhancer, as well as foods rich in vitamin C.
• Women of childbearing age who may become pregnant and women in the first trimester of pregnancy: eat an adequate amount of synthetic folic acid (from fortified foods or supplements) in addition to food forms of folate, following a varied diet.
• Older adults, people with dark skin, and people exposed to insufficient ultraviolet radiation (i.e., sunlight): consume extra vitamin D in vitamin D-fortified foods or supplements.

Weight management

To keep body weight in a healthy range, balance calories in the form of food and beverages with calories expended. To prevent gradual weight gain over time, slowly decrease calories consumed in foods and beverages, and increase physical activity.

Key recommendations for specific population groups

• People who need to lose weight: Aim to lose weight slowly but steadily through decreased caloric intake; also maintain adequate nutrient intake and increase physical activity.
• Overweight children: reduce the rate of body weight increase without interfering with growth and development. Consult a health care provider before indicating a weight loss diet to a child.
• Pregnant women: be sure to have appropriate weight gain, as indicated by a health care provider.
• Breastfeeding women: moderate weight reduction is safe and does not compromise the weight gain of the breast-feeding baby.

Physical activity

Get regular physical activity and reduce sedentary activities to promote health, psychological well-being, and a healthy body weight.

1. To reduce the risk of chronic diseases in adulthood, most days of the week, get at least 30 minutes of moderate intensity physical activity, in addition to your usual activity at work or at home.
2. Most people can get more health benefits by doing harder or more prolonged physical activity.
3. To help manage body weight and prevent gradual unhealthy bodyweight increase in adulthood, get about 60 minutes of moderate to vigorous activity most days of the week, and at the same time do not exceed your caloric intake requirements.
4. To keep the weight off after weight loss in adulthood, do moderate-intensity physical activity 60 to 90 minutes a day at least, while not exceeding caloric intake requirements. It is possible that some people should consult a healthcare provider before participating in this level of activity.
5. Achieve physical fitness by including cardiovascular conditioning, stretching exercises for greater flexibility, and resistance exercises or calisthenics for muscle strength and endurance.

Key recommendations for specific population groups

• Children and adolescents: get at least 60 minutes of physical activity most days of the week or preferably every day.
• Pregnant women: if there are no medical or obstetric complications, do 30 minutes or more of moderate intensity physical activity most days of the week or preferably every day. Avoid activities that involve a high risk of falling or abdominal trauma.
• Breastfeeding women: know that neither acute exercise nor regular exercise affect the mother’s ability to give her baby a good breastfeeding.
• Older adults: do regular physical activity to reduce functional decline associated with aging and to achieve the other benefits of physical activity identified for all adults.

Consumption of food groups

Consumption to be encouraged

• Fruits and vegetables, but stay within the framework of caloric needs. For an intake of 2,000 calories taken as a reference, two cups of fruit and two cups of vegetables per day are recommended, and the amounts will be higher or lower depending on the calorie level. Choose a variety of fruits and vegetables each day. In particular, select from all five vegetable subgroups (dark green, orange, legumes, starchy vegetables, and other vegetables) several times a week.
• Three or more ounces of whole-grain products per day, and the rest from recommended enriched grains or whole grain products. In general, at least half the grains should come from whole grains.
• Three cups per day of skim or lowfat milk or equivalent dairy products.

Fats

• Consume less than 10% of calories from saturated fatty acids and less than 300 mg a day of cholesterol, and keep trans fatty acid consumption as low as possible.
• Keep total fat intake at a level ranging between 20 and 35% of calories, with most fats coming from polyunsaturated and monounsaturated sources of fatty acids, such as fish, nuts, and vegetable oils.
• When selecting and preparing meat, poultry, vegetables, milk, or milk products, choose products that are lean, low-fat, or fat-free.
• Limit intake of fats and oils high in saturated or trans fatty acids, and choose products low in these fats and oils.

Carbohydrates

Often choose fruits, vegetables, and whole grains rich in fiber. Choose and prepare foods and beverages with little added sugars or caloric sweeteners, such as the amounts suggested by the USDA Food Guide and the DASH Eating Plan. Reduce the incidence of dental cavities by practicing good oral hygiene and consuming foods and drinks that contain sugar and starch less often.

 

Sodium and potassium

Consume less than 2,300 mg of sodium (about one teaspoon of salt) per day. Choose and prepare foods with little salt. At the same time, consume potassium-rich foods, such as fruits and vegetables.

People with hypertension, black people, and middle-aged and older adults should consume no more than 1,500 mg of sodium per day and comply with the recommendation potassium intake (4700 mg daily) in food.

Alcoholic drinks

Those who choose to drink alcoholic beverages should do so sensibly and in moderation, which is defined as the consumption of up to one drink per day for women and up to two drinks per day for men.

Some people should not drink alcoholic beverages, including those who cannot restrict their alcohol intake, women of childbearing age who may become pregnant, pregnant women, and breastfeeding women, children and teens, people taking medications that interact with alcohol, and those with specific medical conditions.

People performing activities that require attention, skill, or coordination, such as driving or operating machinery, should avoid alcohol.

Overall nutritional support recommendations

 

• Use many spices instead of salt. When cooking or at the table, season foods with herbs, spices, lemon, lime, vinegar, or seasoning mixes that contain no salt.
• Eat fresh chicken, fish, and lean meat instead of consuming canned, smoked, or processed meats.
• Serve yourself moderate portions and when you snack, eat fruit, vegetables, or popcorn without salt or butter.
• When eating so-called convenience foods, choose ones that are low in sodium. Try not to eat many frozen meals or prepared dishes, such as pizza, packaged mixes, canned soups or broths, and salad dressings (as they are generally high in sodium).
• Start your day with breakfast cereal with low salt and sodium.
• Cook rice, pasta, and hot cereals without salt; try not to eat rice, pasta, or cereal mixes that are instant or flavored, because they often contain salt.
• Buy fresh, frozen, or canned vegetables "with no salt added."
• Drink water instead of drinking soft drinks with high sugar content.
• When you go out to eat, remove the salt shaker from the table. Decrease the amount of condiments such as ketchup, pickles, and sauces that have ingredients high in salt.
• Try not to eat processed or fast food high in salt and sodium.

Medication treatment

National consensus (expert advice)

Most important thing in the treatment of HT is the reduction in pressure values. The results of the guiding questions used for national consensus established that...

1. The threshold for initiation of medication treatment in blood pressure for the general population is 140/90 mm Hg. It is suggested to consider medication treatment if the patient presents with longstanding diabetes or there is already target organ damage with figures > 135/85 mm Hg. 
2. A comprehensive approach should always be established when considering the specific circumstances of the patient being treated and with a model of goals to be achieved.
3. In the general population treatment should always be initiated if systolic blood pressure is > 140 mm Hg, maintaining a goal of < 140 mm Hg.
4. In the general population medication treatment should always be initiated if diastolic blood pressure is > 90 mm Hg, maintaining it at < 90 mm Hg.
5. Renin-angiotensin system blocking is the cornerstone in the diabetic population or those with renal damage at any stage.
6. Combination therapy may be administered as first-line, especially with extreme elevations in blood pressure or established target organ damage.
7. In the population over age 18 with renal impairment, the goal that must be considered is ≤ 130/85 mm Hg. The primary drug is an ACE inhibitor or ARB II, combined with a diuretic or a calcium antagonist.
8. In the population under age 60 suffering from ischemic heart disease with a hyperreactive component, first-line beta-blockers must be considered with a goal of < 140/90 mm Hg.
9. Treatment with beta-blocker is first-line in patients with ischemic heart disease or heart failure if there is no contraindication. Except for cases of vasospastic angina, in which the clear indication is a calcium antagonist.
10. In the general population if the goal is not reached in a month of treatment, the dose should be increased, or a second drug added (thiazide diuretics, dihydropyridine calcium channel blocker, an ACE inhibitor or ARB II.
11. In the general population with HT that misses the preset goals with two drugs within three weeks, one must add a third drug.
12. The combination of an ARB II with an ACE inhibitor demonstrated no benefit and some risks, so we do not recommend their combined use.
13. The use of a diuretic alone as first-line therapy should be recommended in subjects without an associated metabolic disorder, especially insulin resistance or diabetes; monitoring is also recommended.
14. For the general population of over age 70 with stage II, hypertension should be made to gradually decline (eight weeks); if there is no comorbidity seek to justify stricter goals, a goal of < 150/90 mm Hg is recommended.
15. The initial therapy for hypertensive patients with heart failure (HF) with reduced ejection fraction is ACE inhibitor or ARB II and a thiazide diuretic.
16. The recommended treatment for the hypertensive with HF with normal ejection fraction is an ACE inhibitor or an ARB II with thiazide diuretic.

However, the first-line drug is always subject of discussion. Our proposal is first to stratify the characteristics of the hypertensive patient to be treated, based on the HTM classification and the goal sought in mm Hg.

Types of drugs

As an attempted summary, some of the characteristics of the main antihypertensives are described.

 

Diuretics

Diuretics are sometimes called "water pills" because they work in the kidney and remove water and sodium. The side effect of loop diuretics is that the elimination of potassium can cause hypokalemia. The most commonly used is thiazide diuretic at natriuretic doses more than diuretic doses. In Mexico the most commonly-used drugs are chlorthalidone and hydrochlorothiazide. The latter is often combined with some antihypertensive drugs in doses ranging from 12.5 to 25 mg. Hydrochlorothiazide is not recommended as first-line treatment, except in cases of stage I isolated systolic hypertension, which responds to low doses. To use it, there must be the absence of obesity, insulin resistance, or diabetes. These drugs are very useful in patients with evidence of left ventricular failure. Monitoring of serum electrolytes is recommended, as some elderly patients show hypersensitivity and these drugs can cause hyponatremia.

Beta-blockers

Beta-blockers reduce the stimulation of beta-adrenergic receptors in the heart and vessels. This causes the heart to decrease its heart rate and to beat with less force. Most current antihypertensives of this family act more selectively on beta-1 receptors, which has reduced the incidence of undesirable effects. It is advised as first-line antihypertensive therapy in patients without contraindication (lung disease with bronchial reactivity), preferably young, non-obese, or with waistlines < 90 cm and no evidence of carbohydrate metabolism disorders. Its use is sometimes more because there is another reason for it, such as the existence of associated ischemic heart disease. In older adults, or in obese subjects, if there is no clear indication, its use should be restricted. Diuretic use is not recommended unless there is significant cardiac or renal failure with severe fluid retention. 

 

Angiotensin-converting enzyme inhibitors (ACEI)

ACE inhibitors are drugs that act directly by blocking the enzyme that converts the decapeptide called angiotensin I into a hormone of eight amino acids called angiotensin II (we abbreviated it as Ang II above in this paper), which has an extraordinary power as a vasoconstrictor and also stimulates harmful remodeling processes in the vessels and heart. It is a mitogenic hormone and promotes the processes of fibrosis, atherogenesis, ventricular hypertrophy, and kidney damage. ACE inhibitors are first-line drugs for hypertension with target organ damage, especially if there is kidney damage. Its main limitation is that patients have cough as a side effect in a range from 15 to 25%. This effect disappears after discontinuing the drug. If used in a patient with micro- or macroalbuminuria and they do not reach adequate numbers, it can be combined with an ARB II or a calcium antagonist.

Angiotensin II receptor type 1 blockers (ARB II)

Today it is recognized that the harmful effect of excess angiotensin II is due to stimulation of its type I receptor. The discovery of ARB IIs proved this theory, and their use in clinical practice is gaining ground. The evidence accumulated over the last 20 years positioned as first-line drug in the treatment of hypertension when there is evidence of target organ damage, especially ventricular hypertrophy or renal damage manifested by proteinuria (micro- or macroalbuminuria). Although there is a class effect, evidence of nephro- and cardioprotection in large clinical trials suggests differences that should be taken into account. The half-life, doses, and interaction with medications or food should be considered when choosing one. However, it should not be forgotten that in about 75% of patients with target organ damage, the use of combination therapy is very common; in fact, a combination of an ARB II and an ACE inhibitor or an ARB II and a calcium antagonist with or without thiazide diuretic are very commonly used, as the therapeutic goal is much stricter in patients with target organ damage who hope to achieve figures under 125/80 mm Hg. 

Remember! Renin-angiotensin system blocking is the cornerstone in the first-line treatment in all patients with HT with target organ damage or diabetes.

Calcium channel blockers (CCBs)

Because of the popularity of renin-angiotensin-aldosterone system blockers, the use of calcium channel blockers (dihydropyridine) was thought to be decreasing. Nothing is more false than this. Its antihypertensive power is fully demonstrated, and, although comparative studies with ACE inhibitors or ARB IIs demonstrate their antihypertensive similarity, their antiproliferative effects and as protection from kidney damage and regression of hypertrophy are still under discussion; however, when the therapeutic goal in mm Hg has not been achieved with an ACE inhibitor or an ARB II in patients with complicated HT, the combined use with a calcium antagonist is highly recommended. Calcium antagonists can be a first-line treatment in young patients, the obese, and those without evidence of target organ damage. They are also very useful in patients who also present with pulmonary hypertension, or as co-therapy in selected cases of ischemic heart disease. Due to the high prevalence of target organ damage in our country, use in combination with a renin-angiotensin system blocker is becoming more frequent. Keep in mind: the goal in patients with target organ damage, especially ventricular hypertrophy, or kidney damage or diabetes should be < 125/80 mm Hg. Nondihydropyridine CCBs, such as verapamil or diltiazem, should be reserved for special cases, especially those without arteriovenous conduction disorders and those who aim to modulate their heart rate.

Alpha-blockers

Arterial vessels are rich in alpha-receptors 1 and 2. Hence, drugs that block these receptors produce a vasodilator effect favoring decreasing peripheral vascular resistance and thus decreasing blood pressure, which facilitates emptying cardiac output. Its main side effect is orthostatic hypotension and tachycardia.

Alpha-beta blockers

These drugs cause peripheral vasodilatation and reap the benefits of beta-blockers in the heart. They are good antihypertensive drugs, but their use should be reserved for selected cases.

Direct vasodilators

Some medications such as hydralazine have a direct vasodilator effect and have been classified separately. Their use in practice continues, but should be reserved for very special cases, such as carriers of pulmonary hypertension, or in some cases of HT in pregnancy.

Direct nervous system inhibitors

Although some drugs with central effects on the brain are still on the market (clonidine), their undesirable effects and the existence of other drugs of similar efficacy have limited their use to a very specific group of patients, such as those with refractory HT.

ACE-2 inhibitors and endothelin receptor blockers

The existence has recently been described of a type 2 angiotensin converting enzyme (ACE-2) which converts Ang II to angiotensin 1-9 and can promote the formation of angiotensin 1-7; its blockade and the impact in the clinic is increasingly evident. Thus, it is thought today that the true natural balancer of Ang II is angiotensin 1-7, whose proto-oncogenic receptor is already recognized, called mas. This line of research opens new therapeutic opportunities. Meanwhile, endothelin receptor type 1 inhibitors have similar effects to ARB II; however, its use in clinical practice is under study and the results have not been encouraging.

Renin blockers

Some new combinations, or drugs with different mechanisms of action, such as aliskerin (renin blocker) give encouraging results; however, the management of hypertensive patients should be individualized, and novel drugs need further Phase III study and to stand the test of time. It should be noted that the FDA has already approved aliskerin.

New data and results to consider¹³²

As already noted, the present work was undertaken to take account of the American and European guidelines, including the National Collaborating Centre for Chronic Conditions, based at the Royal College of Physicians of London (2006), with two goals: to incorporate new evidence at the The National Institute for Health and Care Excellence (NICE) and to collaborate with the British Hypertension Society (BHS) to produce the new common advice for primary care prescribers in the NHS. In general it can be said that the British have withdrawn beta-blockers as first-line therapy. We, on the contrary, think that we must be cautious because young subjects without obesity or carbohydrate disorders may be suitable candidates for the use of beta-blockers, especially if there is a strong component of anxiety and hyperreactivity. In addition, as noted above, the division of the HTM classification system into two groups (types 1 and 2) is done in relation to the presence or absence of metabolic syndrome or diabetes. Thus, current evidence suggests that the higher prevalence of target organ damage occurs in the group HTM-2. Therefore, blood pressure level is not the only factor determining the initial medication treatment behavior. For example, a patient between 20 and 34 years without evidence of associated risk factors without obesity can be treated with beta-blocker at first with or without a diuretic or a calcium antagonist, depending on the goal they seek to achieve in mm Hg; however, in an individual of similar age but with metabolic syndrome or evidence of renal damage, first-line therapy should be an ACE inhibitor or an ARB II, with or without a diuretic or a calcium antagonist, depending on the therapeutic goal they seek to achieve.  

That is, two aspects should always be noted: (1) the corresponding HTM classification type and (2) the mm Hg goal sought to be reached in each case. Therefore the general HTM type helps us determine the first-line pharmacological treatment. Moreover, the mm Hg goal sought to be reached determines the need and the characteristics of the combination therapy to be used. Thiazide diuretic is the most commonly-used combination drug; however, in younger subjects whose rate of sodium-sensitive hypertension is lower, a calcium antagonist is a useful alternative. 

Obesity being the main catalyst of the KCDA, lifestyle and diet changes are definitely cornerstones for hypertensive patients.

It is also important to note that in Mexico, as in other countries, obesity is the main trigger of metabolic syndrome and insulin resistance, a situation that often limits the use of beta-blockers as first line drug; in the absence of target organ damage, a calcium antagonist offers a good alternative as an initial drug.

However, as detailed in Table XII, the hypertensive patient with evidence of target organ damage should always start with a renin-angiotensin system blocker (ARB IIs or ACE inhibitors), regardless of weight.

Therefore, the deliberate search for proteinuria (micro- or macroalbuminuria) or left ventricular hypertrophy is necessary before deciding on the most appropriate initial drug. Moreover, due to under-diagnosis or late diagnosis of HT, most patients receive care only when they have already developed some degree of target organ damage. While this would represent the need for more renin-angiotensin system blockers in daily practice, it is common to see the need to involve more than one drug to achieve the ideal goal in mm Hg.

The association of ACE inhibitors or ARB IIs with a diuretic or a calcium antagonist is very common practice. The possibility of associating ACE inhibitors with ARB IIs should not be dismissed, especially in the context of hypertensive patients with diabetes in whom the optimal reduction of proteinuria has not been reached.

Final thoughts

Then, as a pre-conclusion, we offer some final considerations for this consensus:

1. In Mexico in 2015, the epidemiological picture of HT is presented as a real public health challenge. An average prevalence of 31%, leading to a growing trend, requires special attention.
2. The population distribution of HT in our country is set apart from global patterns of detection, diagnosis, treatment, and prevention. The great bulk of our Mexican population is composed of people under 50 years of age, determining a large proportion of hypertension with diastolic prevalence. Other intrinsic characteristics of our population, such as ethnicity, genomics, and phenomics, give very particular features to the various forms of HT in Mexico, necessitating strategies of special attention.
3. The partial or total concurrence with elements of metabolic syndrome (insulin resistance-diabetes mellitus type 2, overweight-obesity, high triglycerides, low HDL cholesterol), and other factors such as microalbuminuria, hyperuricemia, and proinflammatory and procoagulant states, points towards the concept of a pathogenic chain. While exploring whether there is a relationship of shared pathophysiology in this pathogenetic chain, it is advisable to take into consideration the opinion of the Conjunctive Consolidation Analysis applied to the 2000 ENSANUT data. A patient with HT will have a higher risk of diabetes and this probability will grow if they are overweight or obese, and even more if they are male and older than 50.
4. The concept derived from the Conjunctive Consolidation Analysis provides sufficient elements to simply stratify hypertensive individuals, and it has led to the proposed classification system (HTM). The first step is to define the presence or absence of metabolic syndrome. In our country, metabolic syndrome is present in the vast majority of hypertensive patients. Once this stratification is done, factors are added such as age, body mass index, stage of hypertension, and presence of kidney or other target organ damage. This procedure is key to the approach/therapeutic diagnosis of first contact. 
5. An optimal medication treatment is the choice of drugs that potentially offer the greatest benefit to patients and their budget, in harmony with the stratification of their condition. The arsenal of antihypertensive drugs is very varied in their mechanisms of action and indications. The key features of HT in Mexico, with its association with metabolic syndrome and the frequent occurrence of target organ damage such as heart, kidney, and brain circulation, usually require the application of two or more drugs and necessarily indicate lifestyle changes.
6. The renin-angiotensin system’s participation in the genesis of HT and target organ damage has led to the successful use of ACE inhibitors and ARB IIs. These groups of drugs occupy a special place in the treatment of HT associated with metabolic syndrome and the prevention and containment of the progression of target organ damage, evidenced by left ventricular hypertrophy, congestive heart failure, left ventricular dysfunction, and diabetic nephropathy.
7. The participation of calcium ions (Ca ++) in the final pathway of a part of the pathophysiological mechanism of hypertension has placed L-type calcium channel blockers (calcium antagonists) in a place of importance for the treatment of this disease. Calcium antagonists have shown a high degree of efficacy in older adults and in isolated systolic hypertension, in association with hypertension, angina pectoris, peripheral vascular disease, carotid atherosclerosis, and in women even in the presence of pregnancy.
8. Blocking beta adrenergic receptors is key in hypertensive states associated with intense adrenergic influence, such as hypertension or diastolic predominance or in forms of hypertension associated with angina pectoris or myocardial infarction treatment. One should also consider the use of some drugs of this group in HT associated with congestive heart failure, tachyarrhythmia, and pregnancy.
9. Diuretics, with the three most common subgroups (thiazide, loop, and aldosterone), acting as antihypertensives, have particular indications. Thiazide diuretics are useful in HT associated with congestive heart failure and HT occurring in older adults, the isolated systolic variety, and in ethnic groups of African origin. Loop diuretics are also useful in hypertension associated with congestive heart failure, and even more if so there is renal failure. Aldosterone antagonists, meanwhile, are beneficial in hypertension and are associated with myocardial infarction treatment, and in the presence of congestive heart failure. Diuretics also have a special synergistic quality that favors most antihypertensive drugs. 
10. HT treatment has brought forth an interesting evolution towards preventing and reducing the risk of cardiovascular, renal, and neuronal damage, achieved through the development of more sophisticated and not always affordable pharmacological resources every day in our area. However, the primary goal remains lowering high blood pressure to levels considered normal, and keeping it there. Sustained blood pressure control, achieved through a rational therapeutic strategy, will itself bring the benefit of preventing and reducing the risk of target organ damage (Figures 7, 8, and 9).

Is a consensus on HT needed in the context of health policies in Mexico?

The evolution of knowledge and the recognition of gene-environment interactions and the spectrum and variability of response to drugs and lifestyle changes has created a revolution in one of the most common risk factors: HT. In fact, HT is recognized as the risk factor that, when adequately addressed, potentially represents a key strategy as the primary prevention of cardiovascular disease. The urgent need to update the guidelines and recommendations of the National Institute for Health and Clinical Excellence (NICE) in collaboration with the British Hypertension Society is a clear example.

Thus, there was need to review the role of beta-blockers in light of new information, relegating them as non-initial therapy, as they proved to be less effective in preventing vascular events, especially strokes. In addition, some studies have suggested the possibility of increasing the risk of developing diabetes, especially in combination with a diuretic. However, it should not be overlooked that the vast majority of the accumulated evidence has been used in a population over age 55, and more experience is needed with young adults.

The use of ACE inhibitors and ARB IIs alone or in combination with low doses of a thiazide diuretics has been sufficiently demonstrated, especially with target organ damage. However, at this stage of the natural history of HT, it is common to use more than one antihypertensive, and calcium antagonists seem to be a good alternative for combination; in fact, they can be used together to begin treatment if BP is in an advanced stage. So, when studies like ADVANCE^133,134 show that good blood pressure control with fixed perindopril and indapamide combination therapy reduces mortality in diabetic patients, the ACCORD study warns that the aggressive reduction of glucose levels in the diabetic population could increase the risk of mortality. Since the study also looked at the aggressive treatment of blood pressure and triglycerides, many controversies have emerged. The study continues and the aggressive treatment of glucose was modified; final results are expected between 2015 and 2020 and it will be interesting to learn their conclusions.^135,136

When the patient develops hypertensive heart disease in the dilated phase, it is curious that the use of beta-blockers is considered anew. Also, when ischemic heart disease makes its appearance, the use of beta-blockers is often indicated, whether or not patients are diabetic, or in low doses for patients with heart failure. SNS modulation should not be left aside, as new molecules are in development and others such as ivabradine are beginning to gain approval to modulate heart rate. The main message is that one must stop dichotomizing risk factors, and one must stop talking about overall cardiovascular risk. Every hypertensive patient has a context of genetics, environment, and comorbidity. We must not forget that some polymorphisms or disorders in protein processing within the cell (proteomics) and its proper function outside constitute a complex mechanism recognized as the physiome. It is no coincidence that the US has made the launch of the European guidelines public in 2013 and of the new JNC-8 guidelines in 2014, with a comprehensive approach to the hypertensive patient clearly stated in these recommendations.

Acknowledgments

The authors wish to thank all secondary medical specialists (79) and family physicians (54) from different parts of the republic who, by random sampling, were included in the national survey of hypertension. A recognition to all those who made this manuscript possible and who were given the task to review it independently.

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