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Clinical sequelae of hypertension include heart failure, arrhythmias, and ischemic events, especially myocardial infarction and stroke. Recognizing the hypertensive heart has both diagnostic as well as prognostic implications. Current imaging techniques offer noninvasive approaches to detecting myocardial fibrosis, ischemia, hypertrophy, and disordered metabolism that form the substrate for hypertensive heart disease. In addition, recognition of aortopathy and atrial myopathy as contributors to myocardial disease warrant incorporation of aortic and atrial functional measurements into a comprehensive understanding of the hypertensive heart.
Investigators of hypertensive heart disease (HHD) have traditionally studied elements of its pathophysiology from distinct perspectives – hypertrophy, hemodynamic models, genetic influences and neurohormonal pathways to name a few. One is reminded of the allegory of the blind men who walk into a forest and encounter an elephant, an animal unknown to them. Each unseeing man trying to understand what stands before him explores what is closest – the man feeling the stout leg labels it a tree, while another brushed by the tail thinks it a rope. Ultimately, none ‘see’ the elephant for what it is without composing these disparate perspectives into one. Such an aggregation of viewpoints is similarly required to better diagnose and treat HHD.
The ongoing need for coherence in comprehension is evident when one finds that that hypertensive patients’ risk of heart failure has changed little since its recognition by large population-based studies over the past decades(1). Also apparent is the link between HHD and atrial fibrillation, whose likelihood increases by 40–50% in the presence of hypertension(2). Ventricular arrhythmias occur more frequently in hypertensive patients(3), with QTc dispersion increasing directly with left ventricular (LV) mass(4). Increased susceptibility to ischemic heart disease rounds out the cardiovascular sequelae of HHD, with 6-fold higher risk of myocardial infarction in hypertensive patients compared to normotensive individuals(1).
Cardiomyocyte hypertrophy is but one of many structural alterations in HHD(5). Fibroblasts undergo hyperplasia and conversion to myofibroblasts, along with hypertrophy of vascular smooth muscle cells. Noncellular elements central to myocardial remodeling in HHD include expansion of interstitial and perivascular collagen that make up the extracellular matrix. Changes in intramyocardial capillary density and arteriolar thickening compound ischemia in the hearts of patients with hypertension. These remodeling events are orchestrated via effects of biomechanical stress on the extracellular matrix that, in turn, signals stretch-activated ion channels leading to intracellular transmission of signals to the nucleus, upregulating hypertrophic gene expression. Similar transduction occurs from cytokine signaling via intracellular calcium handling to myocardial transformation(6).
Is there a benefit to myocardial hypertrophy? In the short-term, increasing wall thickness in proportion to increased pressure helps to normalize myocardial stress; hemodynamic studies have shown that the pressure-overloaded LV has reduced wall stress compared to the volume-overloaded ventricle(7). However, long-term outcomes clearly worsen with progressive hypertrophy, with increasing LV mass index translating to commensurate increases in adverse cardiovascular events and all-cause mortality(8). Conversely, regression of hypertrophy by either electrocardiographic measures or echocardiography confers lower rates of cardiovascular death, myocardial infarction, stroke and all-cause mortality(9–11).
This underscores the need to measure LV mass with care, as it informs not only diagnosis but also prognosis in HHD. Reliance on the electrocardiogram alone has limitations in both sensitivity and specificity of voltage-based criteria, an understanding made possible with the advent of cardiac imaging(12). Particularly prone to error is the diagnosis of LVH in young males using conventional electrocardiographic criteria(13). Echocardiography performs well in detection of concentric hypertrophy given an adequate acoustic window; asymmetric and milder forms of hypertrophy may benefit from alternate imaging approaches. Reproducibility of LV mass measurement using cardiac magnetic resonance (CMR) is well-established(14), making it the standard when evaluating newer techniques such as three-dimensional echocardiography(15). Cardiac computed tomography also allows precise measurement of LV mass(16,17), requiring less radiation exposure with progressive technological advances. High reproducibility is relevant to clinical practice as it affords (1) cost-effective sample size design in clinical trials of therapeutics targeting LVH, (2) quantitative investigation of rare diseases and (3) precise detection of serial changes in individual patients.
A common endpoint of many cellular and noncellular pathologic processes in HHD is myocardial fibrosis. Fibrosis quantification in endomyocardial samples obtained via transjugular biopsy showed significantly greater collagen volume fraction in patients with hypertension compared with normotensive controls(18). Various imaging techniques have emerged to quantify myocardial fibrosis noninvasively. Echocardiography with integrated backscatter show good correlation with collagen volume fraction, recognizing that slightly less than half of patients may have suitable backscatter signal for analysis(19). A more robust approach for visualization of myocardial fibrosis is late gadolinium enhancement (LGE-CMR). This technique shows enhancement in regions of fibrosis with appropriate T1-weighted techniques 10–15 minutes after intravenous administration gadolinium-based contrast because of (1) expanded extravascular volume in fibrotic myocardium that is occupied by this extracellular contrast agent and (2) impaired efflux of gadolinium-based contrast due to vascular changes in fibrotic myocardium. A recent European study showed that approximately half of patients with LVH due to arterial hypertension manifested patchy enhancement on LGE imaging(20); this pattern is clearly distinguishable from the subendocardial enhancement of infarcted myocardium. Our group has shown that severity of diastolic dysfunction increases with extent of fibrosis by LGE(21). This suggests a potential noninvasive metric for trials of novel agents to treat heart failure with preserved ejection fraction (HFpEF), an all too common outcome in hypertensive patients with diastolic dysfunction.
In other populations with cardiomyopathy, myocardial enhancement by LGE-CMR has been shown to identify substrate for ventricular arrhythmias and sudden cardiac death(22,23). Similar prospective studies in patients with hypertrophy due to hypertension are needed before ascribing arrhythmia risk to the patchy enhancement seen in HHD.
Visibly enhanced myocardial regions by LGE-CMR may be absent in HHD even in the presence of diffuse interstitial fibrosis. This has prompted the development of T1 mapping, a technique that may be applied to the entire myocardium allowing quantification of differences in T1 relaxation, an intrinsic property of spins or protons, of fibrotic vs. normal myocardium. These differences are further exaggerated after gadolinium administration, which showed good correlation with collagen volume fraction in a small study of post-orthotopic heart transplant patients (Figure 1)(24). Brilla and colleagues used endomyocardial biopsy in patients with hypertension and diastolic dysfunction to show that treatment with an angiotensin converting enzyme (ACE) inhibitor produced measureable reduction in collagen volume fraction and improved diastolic function, neither of which were achieved with diuretic therapy despite similar improvement in blood pressure control(25). One could envision similar studies using T1 mapping as an endpoint for future therapeutic trials targeting fibrosis in HHD, precluding the need for serial invasive myocardial sampling.
Microvascular disease and endothelial dysfunction are apparent in hypertensive heart disease. A study of African-American men with hypertension showed progressive impairment of flow-mediated vasodilatation as LV mass increased(26), consistent with the previously described ultrastructural remodeling of myocardial microvessels. Looking directly at myocardial perfusion with vasodilator stress CMR, Pilz and colleagues showed increased frequency of hypertension in patients with chest pain, angiographically-normal coronary arteries and subendocardial ischemia on perfusion imaging(27). Of course, hypertensive patients may also have myocardial ischemia due to epicardial coronary stenosis that can be detected noninvasively using stress perfusion scintigraphy(28) or coronary computed tomography(29).
At the macrovascular level, increased arterial stiffness often seen in long-standing hypertension accelerates aortic pulse wave velocity (PWV)(30). This, in turn, results in earlier return of the wave reflected at the iliac bifurcation in systole, increasing LV afterload and central pulse pressure. The concomitant fall in central diastolic blood pressure decreases coronary perfusion, further contributing to myocardial ischemia. PWV measurement, either with CMR velocity-encoded imaging or multi-station arterial tonometry, provides an assessment of aortic function. Ahimastos and colleagues applied the latter in showing that ACE inhibition effected its benefit on aortic remodeling via lowering of aortic PWV, further mediated by changes in matrix metalloproteinases and transforming growth factor-β that are known to degrade aortic integrity(31). Aortic distensibility, albeit a load-dependent measure of aortic function, can be readily quantified using high temporal resolution cine CMR techniques. With this approach, Hundley et al. showed a progressive decline in aortic distensibility with age that was lower still in patients with diastolic heart failure(32). These aortic changes paralleled reduction in peak oxygen consumption, an important metric of functional capacity that further illuminates how the aorta contributes to clinical sequelae of hypertension (Figure 2).
Several other mechanisms warrant consideration in completing our current understanding of hypertension and the heart. Altered myocardial energy utilization in HHD has been studied by Lamb et al. using phosphorus magnetic resonance spectroscopy (P-MRS) during pharmacologic stress(33). Because of the critical role of adenosine triphosphate (ATP) and creatine cycling in supplying myocytes with the energy needed for normal function, changes in the ratio of phosphocreatine (PCr) to ATP that can be measured noninvasively with P-MRS allow noninvasive quantification of myocardial metabolism. With prolonged dobutamine and atropine infusion to allow sufficient time to collect the P-MRS signal, patients with hypertension had measurably lower PCr:ATP during stress compared to healthy controls, indicating impaired myocardial energetics. Recognizing the systemic vasculature’s integrated role in energy utilization and blood flow may require consideration of not only myocardium but also skeletal muscle in HHD, facilitated by imaging techniques such as MRS(34) and positron emission tomography with 15-oxygen labeled water(35).
Finally, no discussion of hypertensive heart disease would be complete without appreciating the role of the left atrium. As witness to chronically-elevated LV filling pressures, left atrial enlargement is a reliable marker of diastolic dysfunction in the absence of mitral valve disease. The correlation between left atrial volume and brain natriuretic peptide levels further underscores its role as a sentinel in HFpEF(36). Beyond passive expansion, Kurt and colleagues have recently shown that changes in active left atrial strain by tissue Doppler may distinguish between asymptomatic patients with diastolic dysfunction and those with diastolic heart failure(37), something not feasible with traditional echo-Doppler measures such as E/E’ ratio. Thus, left atrial myopathy warrants inclusion in our coalescent understanding of hypertensive heart disease.
Increasing recognition of genetic factors that produce variable therapeutic response among patients with hypertension(38,39) should motivate better understanding of the structural and functional differences that mediate this heterogeneity. Imaging attuned to the multiple aspects of HHD (Figure 3), by quantifying the degree to which specific elements predict variability in disease development and progression, can provide specific phenotypic evidence to guide development of novel therapeutics.
The clinical burden of hypertensive heart disease is great, as is the opportunity to develop new treatment options for patients with HFpEF that so often results from unchecked hypertension. Innovation will require investigations that consider hypertrophy, fibrosis, ischemia, altered metabolism, aortopathy and atrial myopathy as interconnected mechanisms along the HHD spectrum. Contemporary noninvasive imaging facilitates such an understanding, and warrant incorporation into preclinical research and therapeutic trials to improve the lives of patients with hypertensive heart disease.
Sources of Funding
Dr. Raman is supported in part by HL095563 (National Heart Lung and Blood Institute, NIH).
Dr. Raman receives research support from Siemens Medical Solutions.
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