Cardiac Target Organ Damage in Hypertension: Insights from Epidemiology

Introduction

Given the magnitude of cardiac risk associated with hypertension, and its wide prevalence in the community at large, hypertension remains among the most important modifiable risk factors for cardiac disease. Specifically, hypertension significantly augments risk for major morbid and common cardiac conditions such as coronary atherosclerosis, heart failure, and atrial fibrillation. Globally, it is estimated that 7. 6 million premature deaths and 92 million disability-adjusted life years are attributed to elevated blood pressure (BP). 1 As the world population ages, the prevalence of hypertension and its end-organ sequelae will only continue to increase VSports注册入口. Decades of epidemiologic investigations have helped to identify key determinants of hypertension-related cardiac disease and, in turn, highlighted treatment opportunities. Herein, we will review the insights that epidemiologic observations have provided to date regarding the progression from hypertension to subclinical and eventual clinical cardiac disease.

Precursors to Hypertension

Numerous risk factors for hypertension are also risk factors for cardiac disease, suggesting shared pathophysiology (Figure 1). It is well known that clinical traits such as older age, male sex, greater body mass index, parental history of hypertension, and cigarette smoking are all associated with increased risk for both incident hypertension and developing an adverse cardiac event. 2 Several emerging biomarkers have also been associated with both hypertension and overt cardiac disease, underscoring mechanistic common ground. Specifically, biomarker investigations have implicated pathways of inflammation (C-reactive protein), thrombosis (fibrinogen), fibrinolytic potential (plasminogen activator inhibitor-1), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide [BNP], and N-terminal proatrial natriuretic peptide), and oxidative stress (homocysteine) in association with both subsequent hypertension3 and heart failure;4 many of these same biomarkers have been shown to predict a first major cardiovascular event and death V体育官网入口. 5.

Epidemiologic investigations into the origins of hypertension and associated cardiac disease have also identified common genetic traits that may precede and possibly manifest as detectable variations in pathway biomarkers V体育2025版. Intriguingly, certain conserved DNA variants that are associated with the development of hypertension are also associated with several overt cardiac conditions, including left ventricular hypertrophy (LVH) and coronary atherosclerosis. 6–8 Notably, these variants include polymorphisms at distinct loci encoding for natriuretic peptides, subunits of soluble guanylate cyclase, and adrenomedullin in addition to several other proteins with biologically plausible effects on BP regulation. Hence, the pathway to cardiac disease in many individuals with hypertension likely begins well before the onset of elevated BP.

Progression from Hypertension to Subclinical Cardiac Disease

The progression from chronically elevated BP, once established, towards overt cardiac disease often involves initially asymptomatic alterations in cardiac structure and function. Subclinical abnormalities in cardiac structure are associated with abnormalities at the cellular level, including cardiomyocyte hypertrophy, dropout, and replacement fibrosis. Gross morphologic manifestations include the development of left ventricular remodeling, with or without an increase in LV mass VSports. Longitudinal cohort data indicate that age-related cardiac remodeling over the adult life course includes a progressive increase in LV wall thickness (concentric remodeling) and a concomitant decrease in LV dimensions (cavity shrinkage). 9,10 Elevations in BP are also associated with these structural abnormalities and, in addition to augmenting so-called age-related cardiac remodeling, promote the development of concentric hypertrophy in particular. 10,11 Thus, the most well-recognized structural phenotype of hypertensive heart disease is LVH, defined as an increase in LV mass, and involving more often an increase in wall thickness than an increase in LV cavity size. 12.

Interestingly, the development of LVH can occur very early in life, even in adolescence13 and prior to a clinical diagnosis of hypertension. 14 Mechanistic contributors to both hypertension and LVH may involve angiotensin II,15 endothelin,16–18 the circulating catecholamines (norepinephrine and epinephrine), and increased sympathetic tone involving both peripheral and cardiac efferents. 19,20 Genetic traits that predispose to both hypertension and LVH have also been identified, including deletion polymorphisms in genes such as the angiotensin-converting enzyme (ACE) and the bradykinin 2 receptor (B2BKR 2). 21,22 Conventional and novel biomarkers of cardiac stress have been associated with LVH as well as LV systolic dysfunction; these biomarkers include growth differentiation factor-15 (GDF-15) and BNP, both of which have also been related to arterial remodeling and dysfunction. 23–25 Clinical factors substantially influence the relationship between hypertension and LVH. For example, hypertensive women exhibit a greater prevalence of LVH than men for a similar degree of BP elevation, and less regression of LVH with antihypertensive therapy;26 this finding is also observed in blacks compared to whites VSports app下载. 27–29.

Hypertension is related not only to subclinical abnormalities in cardiac structure but also function V体育官网. Although chronically elevated BP may eventually lead to a reduced LV ejection fraction (LVEF),30 often in the setting of eccentric hypertrophy, the more common and much earlier manifestations of BP-related cardiac dysfunction include abnormalities in LV diastolic function, ventricular-vascular coupling, and myocardial strain – all typically in the presence of a preserved LVEF. Asymptomatic diastolic dysfunction is prevalent in up to 25% of adults in the community, especially in the setting of hypertension and particularly in the setting of elevated systolic BP. 31–33 Mechanistically, abnormal vascular stiffness has been observed in association with reduced ventricular elastance (the substrate for diastolic dysfunction) with an apparent predilection for older adults and women. 34,35 This interactive coupling of ventricular-vascular abnormalities may be especially relevant for individuals predisposed to HF with preserved LVEF. 36 Several studies have demonstrated that elevated BP is associated with abnormalities in LV strain,37,38 reflecting alterations in myocardial systolic deformation even in the setting of a normal LVEF. Notably, abnormalities in subclinical LV global and regional strain as well as synchrony have been associated specifically with LVH in addition to hypertension. 39,40.

Progression from Subclinical to Clinical Cardiac Disease

Among individuals with asymptomatic hypertensive heart disease, many will go on to develop the familiar cardiac sequelae of hypertension including coronary artery disease (CAD), heart failure (HF) with and without a preserved LVEF, and common arrhythmias such as atrial fibrillation. The progression from subclinical to clinical cardiac disease may be influenced by multiple factors including the type of BP elevation (e.g. isolated systolic, isolated diastolic, or combined hypertension), severity of BP elevation, duration of BP elevation, presence of concomitant risk factors, and treatment exposure.

The most common clinical cardiac disease that occurs in hypertensive individuals is atherosclerotic CAD, with elevated BP contributing to almost half of all coronary events.¹ Large, mainly population-based studies have clearly identified hypertension as an independent risk factor for CAD.^41–50 A meta-analysis of observational studies involving one million hypertensive individuals, representing 12.7 million person-years at risk, showed that BP elevations above a threshold as low as 115/75 mmHg were associated CAD.⁵¹ The investigators reported that between ages 40 to 69 years of age, each systolic BP difference of 20 mm Hg or diastolic BP difference of 10 mm Hg was associated with a twofold increase in the mortality rates from CAD as well as from other vascular causes. These associations are even more pronounced in older adults.⁵² Interestingly, CAD has been observed as the first cardiovascular event to occur after hypertension onset in men, whereas stroke tends to be the first event after hypertension onset in women.⁵³ The various hemodynamic loading conditions manifesting as different forms of hypertension may also play a role, as data from some cohorts suggest that systolic BP may be a particularly important determinant of CAD risk when compared to diastolic or mean BP.⁵⁴ Mechanistically, chronically elevated BP of any type is believed to increase the rate at which atherogenic lipid molecules are taken up into vascular plaque due to increases in transmural pressure in arterial vessels and an increase in mechanical stress and endothelial permeability.⁵⁵ Abnormal endothelial function and abnormal nitric oxide signaling may also play a role.^56,57 Importantly, BP lowering therapy is efficacious in both the primary and secondary prevention of CAD.⁵⁸ In a meta-analysis of nearly 464,000 participants from 147 clinical trials, there was a 22% reduction in coronary events for a systolic BP reduction of 10 mm Hg or diastolic of 5 mm Hg,⁵⁸ mirroring data from observational studies that had previously indicated equivalent BP reductions in association with a 25% decrease in CAD risk.⁵¹

Whereas CAD is the most common cardiac disease that occurs in hypertensives, hypertension is by far the most prevalent major risk factor among individuals who develop HF.⁵⁹ Indeed, the coexistence of hypertension and CAD markedly increases HF risk, likely through neurohormonal activation and promotion of early ventricular remodeling.⁶⁰ Nonetheless, while CAD is also a well-recognized risk factor for HF, CAD is not a part of the causal pathway between hypertension and HF in a majority of cases. Early evidence suggested that the hypertension coinciding with CAD tends to lead to HF with reduced EF (HFREF), whereas the hypertension existing in the absence of CAD tends to lead to HF with preserved EF (HFPEF). However, more recent population-based data indicate that this distinction is not so clear, and that hypertension likely plays an important role in increasing risk for both these types of HF.^61,62 Duration of BP exposure likely impacts the overall risk for HF, and the timing of hypertension onset (i.e. during mid-life) also appears to be important.⁶³ Data from several studies indicate that hypertension after age 40 years doubles the risk of incident systolic HF, and even mild elevations in BP are associated with increased risk overall.^59,64–66 Cohort data also suggest that elevations in systolic BP and pulse pressure may be more hemodynamically important determinants of systolic HF than elevations in diastolic or mean BP.⁶⁷ These findings coincide with physiologic studies indicating that interactive coupling of arterial and LV stiffness may play a particularly important role in the development of HFPEF as well as HFREF.^36,68 In addition to arterial stiffness,⁶⁹ the intermediate phenotypes of subclinical cardiac disease that are commonly associated with hypertension, including LVH and conventionally defined asymptomatic LV systolic as well as diastolic dysfunction, have all been shown to increase HF risk in the community.^30,70–72

Notwithstanding CAD and HF, hypertension is also the most important modifiable risk factor for the most common cardiac arrhythmia, non-valvular atrial fibrillation (AF).^73–76 Data from large cohort studies indicate that hypertension increases the risk of AF by 40–50%.^77,78 Population-based studies also suggest that the risk of incident AF among patients treated for hypertension differs by the degree of BP control, with declining rates of incident AF among those hypertensive patients treated closer to a pre-specified target.⁷⁹ Anti-hypertensive therapies that target the renin-angiotensin-aldosterone axis may have particular utility.⁷⁶ Mechanistically, the cardiac structural and functional abnormalities that accompany hypertension – LVH, impaired ventricular filling, left atrial enlargement – are associated with a slowing of atrial conduction velocity, which favors the development of atrial fibrillation.^74,80

"V体育安卓版" Conclusions

Epidemiologic studies to date indicate that the transition from hypertension to heart disease is a process that typically progresses over the life course – and that the pathogenesis likely begins very early in life. The classic paradigm is that, in vulnerable individuals, hypertension initially leads to subclinical disease that can manifest with abnormalities in imaging as well as non-imaging biomarkers of cardiac stress and end-organ damage, prior to the onset of clinically overt outcomes. However, this pattern of progression proves not always to be the case. Hypertension is, in fact, a heterogeneous disorder and modifying exposures are not always captured. In addition, many forms of subclinical cardiac disease are not completely detected using conventional methods and assays, which may have limited sensitivity for detecting subtle incremental changes. Moreover, even among individuals with obvious subclinical cardiac remodeling and dysfunction, not all will go on to develop symptomatic disease. Further research is needed to clarify why it is that many people with hypertension go on to develop events and, equally as important, why many people with hypertension do not – with or without the chronic administration of conventional BP lowering therapies. Given the wide and growing prevalence of hypertension in the community at large, investigating the precursor and preclinical determinants of hypertensive heart disease remains an important area of ongoing research.