5. How Does Hypertension Develop and What Does It Have to Do With a High Risk of Heart Attacks?

High blood pressure level (BP), cigarette smoking, diabetes mellitus, and lipid abnormalities are major modifiable risk factors for cardiovascular illness (CVD). Among these, loftier BP is associated with the strongest prove for causation and has a high prevalence of exposure. However, in that location is considerable show that a biologically normal level of BP in humans is considerably lower than what has been traditionally employed in clinical practice and research, leading to an underrepresentation of the role that BP plays equally a take a chance factor for CVD. We suggest the post-obit integrated theory for CVD causation that is supported by a robust body of coherent and consistent bear witness: CVD in humans is primarily acquired past a correct-sided shift in the distribution of BP.

Theories abound in the electric current era of social networks, but few fulfill the bones requirements for causality. Scientific theories are most apparent because they are structured and bailiwick to refutation past systematic ascertainment and experimental hypothesis testing.ⁱ Our theory fulfills virtually all of the criteria for causality proposed by Bradford Hill.²

Shift of BP Distribution in Humans: Uncovering a Option Bias

At the end of the 19th century, Osler³ did not mention the risks of high BP in his classic The Principles and Practice of Medicine textbook because, at that time, there was no practical fashion to measure BP using a noninvasive technique. Shortly afterwards the development^4,five and dissemination of noninvasive methods for BP measurement physicians and actuaries deduced that high BP could be a crusade of disease, peculiarly CVD events.^{half dozen,7} In 1913, Janeway⁷ study of 7872 patients led him to conclude that an average BP to a higher place 160 mm Hg was pathological.

Despite the merits of early BP-CVD association reports, they compared the risk of CVD in adults identified every bit having a very loftier level of BP with the corresponding take chances in counterparts with a lower just still high BP. The pioneers of BP measurement could non know that well-nigh all humans, including virtually of those in the lower BP category, had a level of BP to a higher place what is biologically normal and desirable. It took several decades before BP was measured in groups of humans with a true biologically normal BP because they were living in isolated unacculturated societies. Investigators discovered that most all of those studied had an average BP that was substantially lower than the corresponding levels noted in studies that had been conducted in acculturated societies.^eight–11

In that location are potentially confounding differences between people living in acculturated societies and their counterparts living in isolated unacculturated societies. Near of these misreckoning variables were, still, controlled in a seminal study of 2 Amazonian tribes who had a similar background and cultural habits, with the exception of a difference in sodium intake.⁸ The Mundurucus, whose lifestyle was influenced by the Franciscans, had incorporated salt into their diet as a means to preserve and flavor their food. In contrast, the Carajás had little contact with Westerners and consumed nearly no salt. Average BP during adult life increased with rising age in the Mundurucus but not in the Carajás (Figure 1), whose mean systolic BP (SBP) and diastolic BP (DBP) remained about 110 and threescore mm Hg, respectively, throughout their adult lifespan.

Figure 1. — **Figure one.** Blood pressure (BP) for men by age in Mundurucus and Carajás Indians, showing a rise with aging in the acculturated Mundurucus but not in the unacculturated Carajás. Reprinted from *The Lancet* (Lowenstein⁸) with permission. Copyright © 1961, Elsevier.

Another isolated lodge in Brazil, the Yanomamo Indians, with very limited access to common salt likewise demonstrated picayune if any rise in BP with aging.¹⁰ In addition to excreting very lilliputian sodium in their urine, they had high levels of plasma renin activity and aldosterone. These findings suggest biologically normal values of BP, renin activity, and aldosterone are very different compared with the relatively loftier levels of BP and low levels of plasma renin activity and aldosterone identified in acculturated societies, where at that place is exposure to high levels of dietary sodium. Animate being model studies, population studies, and clinical trials provide bear witness supporting the central role of excessive sodium consumption in causing age-related increases of BP.¹²

The consequences of 2 definitions for identification of an abnormally high BP are depicted in Figure 2. The left-hand panel depicts the rightward shift of SBP and DBP that occurs with acculturation. The shaded area in the distribution for unacculturated populations identifies high BP using a definition (SBP ≥120 mm Hg or DBP ≥70 mm Hg) is based on the BP distribution in observational studies. The respective shaded expanse in the distribution for acculturated populations is based on a definition of high BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg) that has traditionally been used in acculturated populations. The shaded areas in the right-hand console identifies high BP in acculturated societies using the SBP 120 mm Hg and DBP ≥70 mm Hg cut points.

Around 70% of those living in acculturated societies would exist at higher risk of developing CVD according these values. Using the cut points proposed for diagnosis of hypertension in the 2017 American College of Cardiology/American Heart Association BP guideline (SBP ≥130 mm Hg or DBP ≥80 mm Hg),¹³ around 63% of adults aged 45 to 75 years in the United States and 55% in People's republic of china have hypertension.¹⁴

In recent decades, a leftward shift in the distribution of BP has been identified in high-income countries.¹⁵ Equally expected, this downward shift in BP has been accompanied past a reduction in the incidence of CVD. The absolute number of individuals with hypertension in the world, notwithstanding, has increased due to a rightward shift in the distribution of BP in low- and middle-income countries.¹⁵

Evidence From Cohort Studies

In an early cohort study, Keith et al¹⁶ reported on BP-related risks, stratified by BP levels, symptoms, ECG abnormalities, albuminuria/hematuria, and optic fundi abnormalities. The bloodshed rate was proportional to severity of affliction, existence >fourscore% over 1 year for participants who had BP resistant to treatment, bad general condition, an abnormal ECG, albuminuria, hematuria, and optical edema (characterized every bit grade IV). Despite this and other observational reports published in the first one-half of the 20th century that suggested high BP caused CVD, many opinion leaders believed high BP was an inconsequential finding and use of the term beneficial essential hypertension was commonplace. White was in the group of influential leaders who believed high BP was a physiological compensatory machinery and should not exist manipulated by handling.¹⁷

In a series of seminal reports, the Prospective Studies Collaboration pooled data from many accomplice studies and accounted for the effects of regression dilution bias to generate precise estimates of the relationship between BP and CVD. Their most important report¹⁸ was based on feel in 61 cohort studies that provided 12.7 million person-years of risk experience (56 000 deaths from coronary heart illness [CHD] and stroke). The take a chance of CVD increased steadily with progressively higher levels of baseline SBP and DBP, above a usual SBP and DBP of 115 and 75 mm Hg, respectively. For a 20 mm Hg higher level of SBP and x mm Hg higher level of DBP the risk of CVD was 2-fold higher (Effigy three, left, with log-transformed vertical axis). The respective pattern for BP-related absolute chance of CVD (Figure 3, right), revealed an exponential association between increased BP and risk for CHD and stroke. It identified a relatively pocket-sized increment in absolute risk of CVD with increasing BP levels at lower BP values and at younger historic period, which likely explains why individual studies in young and middle-anile participants take only identified a CVD risk at higher values of BP.^nineteen

**Figure 3.** Log transformed (**left**) and untransformed (**right**) absolute risk of coronary heart disease or stroke in adults, by systolic and diastolic claret pressure, stratified past age. Reprinted from *The Lancet* (Lewington et al^xviii) with permission, copyright © 2002 Elsevier; and reprinted from Fuchs^xix with permission, copyright © 2018, Springer International Publishing.

Most of the early observational studies were focused on BP complications (stroke and CHD) which normally occur earlier than other BP clinical consequences and are especially prominent at higher levels of BP. At older age, stroke and CHD are accompanied past several complications that develop over a longer period of exposure to high BP, either because the target organs are more resistant or because more modest BP elevations have been present for a prolonged menses of time. The complications of high BP tin can exist classified as brusk- and long-term consequences (Table). Consequent observational evidence suggests high BP is the leading crusade of long-term consequences such as heart failure, with and without preserved ejection fraction,²⁰ atrial fibrillation,²¹ valvular heart disease,^22,23 peripheral arterial disease and aortic syndromes,²⁴ chronic kidney illness and stop phase renal disease,^25,26 dementia,^27,28 and Alzheimer Disease.²⁹ Diabetes mellitus,^thirty erectile dysfunction,³¹ and age-related macular degeneration³² are other conditions that likely have high BP as one of their causes.

**Tabular array.** Short-Term and Long-Term Consequences of Loftier BP
Short and long-term consequences
Stroke
Coronary heart disease
Heart failure
Cardiovascular expiry
Long-term consequences
Hypertensive cardiomyopathy
Center failure with preserved ejection fraction
Atrial fibrillation
Valvular heart illness
Aortic syndromes
Peripheral arterial disease
Chronic kidney disease
Dementias
Diabetes mellitus
Erectile dysfunction

Centenarians

The primary reason that centenarians achieve 100 years of age is an unusually low burden of CVD and cancer. CHD, stroke, dementia, and hypertension are less frequent in centenarians compared with individuals who die at a younger age³³ (Figure 4). Vascular crumbling is directly associated with level of BP and non inexorable. Prevention of age-related increases in BP would substantially reduce the vascular consequences usually attributed to crumbling. Individuals who develop hypertension late in life are non at increased risk for CVD earlier in life.³⁴ Centenarians may be resistant to dietary sodium loads having the power to excrete sodium in the absenteeism of high-pressure natriuresis.

Figure 4. — **Figure four.** Disease-gratuitous age survival for cardiovascular disease (CVD), dementia, stroke, and hypertension (HTN) in controls (individuals without a familial predisposition for exceptional longevity (blackness line), and centenarians (color lines), stratified by age in years at decease. The data demonstrate a consequent filibuster in onset of CVD, dementia, and stroke when HTN starts late in life. Reprinted from Andersen et al³³ with permission. Copyright © 2012, The Writer. Published by Oxford University Press on behalf of The Gerontological Society of America.

Cartesian Evidence

Experimental studies, the highest hierarchical method for demonstration of causality, provide stiff support for our theory of CVD causation. The 1967 Veterans Administration Cooperative Report Group on Antihypertensive Agents,³⁵ SHEP trial (Systolic Hypertension in the Elderly Program)³⁶ and SPRINT (Systolic Claret Pressure Intervention Trial)³⁷ are 3 of many randomized controlled trials (RCTs) that have provided strong testify regarding the effectiveness of BP lowering for prevention of CVD. Redefining the outcomes according a mod paradigm, the number needed to care for to forestall one major CVD event per year in the 1967 Veterans Administration trial was just 6 patients in those with a baseline DBP averaging 115 to 129 mm Hg.³⁸ Before publication of the SHEP results, many doctors believed isolated systolic hypertension was a natural and benign compensatory upshot of aging. The trial showed that chlorthalidone-based therapy reduced the incidence of stroke, the primary finish point, past 36% compared with placebo.³⁶ Sprint demonstrated that participants randomized to a SBP goal <120 mm Hg (intensive treatment) had an incidence of the main composite CVD cease point that was 25% lower compared with those randomized to a SBP goal <140 mm Hg (standard handling).³⁷ At that place were reductions of 43% in CVD mortality and 27% in all-cause mortality. A similar do good was demonstrated in the relatively large (N=2636) subgroup of participants 75 years or older at baseline, including those with frailty and reduced gait speed.³⁹

Loftier-quality meta-analyses take demonstrated the effectiveness of BP lowering for prevention of CVD. Additionally, studies accept compared the observed benefit of BP reduction in RCTs with the expected benefit based on BP as a risk cistron for CVD in observational studies.^xl–42 In a study that included 147 RCTs, Law et al⁴⁰ calculated the CVD risk reduction for the average active treatment versus command trial divergence in SBP (10 mm Hg) observed in their meta-analysis. As depicted in Effigy 5, the reductions in stroke and CHD incidence rates were similar to the benefits expected on the basis of a 10 mm Hg departure in SBP in the Prospective Studies Collaboration meta-analysis of observational studies. Benefit for the same difference in BP was greater for stroke, reflecting the higher risk of elevated BP for cognitive vessels compared with the coronary circulation.

Figure 5. — **Figure v.** Relative risk estimates of coronary heart disease (**height**) and stroke (**bottom**) for systolic blood pressure level (BP) reduction of 10 mm Hg or diastolic BP reduction of 5 mm Hg in clinical trials meta-assay and respective difference in meta-analysis of observational accomplice studies. CHD indicates coronary heart illness; CV, cardiovascular; and RR, relative risk. Reprinted from Law et al⁴⁰ with permission. Copyright © 2009, BMJ Publishing Group Ltd.

A similar benefit was observed in a network meta-analysis conducted past Bundy et al.⁴² In this report, the relative gamble reduction of major CVD events in trials where the participants had been treated to a SBP target between 120 and 124 mm Hg, compared with a respective target of 160 mm Hg or higher, was 64%, which is close to the hypothetical risk reduction of 75% for a 40 mm Hg SBP reduction in the Prospective Studies Collaboration meta-analysis.^xviii The similarity between risk predicted in cohort studies and benefit demonstrated in RCTs fulfills one of the postulates of Descartes,⁴³ that is, that the sum of the angles of any triangle equals 180 degrees (ii right angles). The shut approximation between the observed (clinical trials) and expected (observational cohort studies) benefits of BP lowering is impressive, since the expected guess is based on imperfect measurements of a biological parameter.

Scant experimental evidence exists for prevention of the longer term consequences of high BP. Designing trials for these finish points is challenging, considering they require a longer duration of treatment than is necessary to demonstrate CVD do good. Despite this, suggestive benefit of BP lowering in RCTs exists for some of these outcomes. For example, the composite result of mild cognitive damage and dementia was significantly less common during long-term follow-upward in the SPRINT study.^44,45

The central part of BP levels has besides been demonstrated by studies where BP has risen during treatment and resulted in CVD events. Examples come from studies using celecoxib,⁴⁶ sibutramine,⁴⁷ and torcetrapib.⁴⁸ In contrast, prevention of CVD events by inhibitors of sodium-glucose cotransporter 2 in adults with,^49,50 and without diabetes mellitus⁵¹ may be due, in part, to BP-lowering.

Attributable Risks

Estimation of the loftier BP contribution to causation of CVD has increased progressively every bit the definition of hypertension and analytic techniques have evolved. Early on estimates of attributable risk were 25% for CHD and 50% for stroke.⁵² Based on the risks identified past the Prospective Studies Collaboration,¹⁸ the owing take chances for BP equal or >115/75 mm Hg was estimated to be 49% for CHD and 62% for stroke.⁵³ However, these estimates virtually certainly understate the true contribution of high BP to evolution of CVD. In many of the cohort studies, residual bias in estimation is probable because the adventure estimates have been based on only a few BP measurements. Vascular, cardiac, and renal harm results from an excessively high vascular load of beat-to-trounce elevations in BP over long periods.¹⁹ Ane or 2 BP measurements provide an insufficient estimate of vascular load. Other CVD take a chance factors, such as smoking, dyslipidemia and backlog body weight, are subject area to measurement error, but their estimation is much more precise compared to BP readings. More than efficient methods for BP measurement, such every bit ambulatory BP measurement,⁵⁴ particularly at night,⁵⁵ home BP monitoring and automatic office BP measurement provide more than precise estimation of BP-CVD run a risk, including identification of risk at lower BP values compared to traditional office BP measurements.⁵⁴ Another reason for underestimation of BP-related adventure is inclusion of intermediate consequences of loftier BP every bit causes of CVD in multivariate explanatory equations.⁵⁶ This is especially true for analyses that take included left ventricular hypertrophy or vascular wall thickening, merely even overweight and obesity are CVD run a risk factors that are largely mediated by high BP.⁵⁷ Recognizing the potential for underestimation, other misreckoning risks increase concomitantly with BP, merely in clinical trials the absolute gamble reduction from BP-lowering accounts for nearly all of the predicted take a chance, leaving trivial residuum risk to be explained by the other concomitant risks.

What Is Missing?

In adults without CVD, a strong BP-CVD risk association has been identified at lower levels of SBP (120–139 mm Hg) and DBP (80–89 mm Hg).¹⁸ Individuals inside this BP range are at increased hazard for development of higher levels of BP over relatively curt periods of follow-upwardly^58,59 and already have evidence of target organ damage.^{threescore,61} Moreover, meta-analyses of event-based RCTs have shown the do good of antihypertensive handling in adults with CVD (secondary prevention) and an average BP within the same range.^forty,41 Trials take too shown that low-dose pharmacotherapy in adults without CVD and an average SBP of 130–139 mm Hg or DBP ≤89 mm Hg^62,63 and SBP 120–139 mm Hg or DBP 80–89 mm Hg⁶⁴ lowers BP and prevents incident hypertension (SBP ≥140 mm Hg or DBP ≥90 mm Hg). The PREVER-Prevention trial additionally demonstrated that low-dose diuretic therapy (chlorthalidone and amiloride) in adults with a SBP 120–139 mm Hg or DBP eighty–89 mm Hg prevented incident LVH estimated by ECG.⁶⁴

Nonetheless, no BP-lowering trial has demonstrated prevention of CVD events in adults without CVD who have a SBP <140 mm Hg or DBP <ninety mm Hg.

Despite strong testify of a BP-lowering benefit in clinical trials and meta-analyses, directly documentation of intensive BP-lowering benefit is lacking in adults with high BP who accept diabetes mellitus or a history of prior stroke. At least 2 event-based trials (one in Brazil and the other in China) are addressing this question in diabetics and ane trial (in Brazil) is existence conducted in stroke survivors.

Conclusions and Perspectives

Our proposal that CVD is predominantly caused by a rightward shift in the distribution of BP is supported by coherence and factual prove. As a theory, it is open to refutation and formulation of alternative proposals. Amid the existing theories, nonetheless, ours is the one that best meets Occam's razor premise, that is, it is the hypothesis with the fewest assumptions. Other take chances factors, including lipid abnormalities, cigarette smoking, physical inactivity, and dietary influences other than sodium play an important role in CVD causation. Although elevated BP has the greatest effect on population health, prevention of CVD is best achieved by a comprehensive approach aimed at improving CVD risk factors at all stages of life.

Regardless of its exact contribution, high BP is a major take chances gene for development of CVD. Prevention of the age-related increase in BP would substantially reduce the vascular consequences ordinarily attributed to aging. Information technology is time to focus greater attending on initiatives for prevention of the typical age-related increase in BP in addition to control of high BP in those with established hypertension. Even fractional improvement in the age-related increase in BP would eliminate a large proportion of the existing burden of BP-related CVD.

Sources of Funding

P.Grand. Whelton was supported by a Centers for Research Excellence grant from the National Institute of General Medical Sciences (P20GM109036).

Footnotes

Correspondence to Paul K. Whelton, 1440 Canal St, Room 2015, New Orleans, LA 70112. Email [email protected] com

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Source: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.119.14240

5. How Does Hypertension Develop and What Does It Have to Do With a High Risk of Heart Attacks?

Shift of BP Distribution in Humans: Uncovering a Option Bias

Evidence From Cohort Studies

Centenarians

Cartesian Evidence

Attributable Risks

What Is Missing?

Conclusions and Perspectives

Sources of Funding

Footnotes

References

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