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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Am Coll Cardiol. Author manuscript; available in PMC 2011 January 12.
Published in final edited form as:
PMCID: PMC2853718

The Hypertensive Heart: An Integrated Understanding Informed by Imaging

Subha V. Raman, M.D., M.S.E.E., F.A.C.C.


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.

Keywords: hypertension, left ventricular hypertrophy, diastolic heart failure, imaging, hypertensive heart disease, pathophysiology

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).

Structural Remodeling

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(911).

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.

Myocardial Fibrosis

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.

Figure 1
Magnetic Resonance T1 Mapping for Myocardial Fibrosis Quantification

Vascular and Other Changes in Hypertensive Myocardial Disease

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).

Figure 2
Aortic Distensibility and Diastolic Heart Failure

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.

Future Directions

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.

Figure 3
The Many Aspects of Hypertensive Heart Disease


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).


hypertensive heart disease
left ventricle/ventricular
cardiovascular magnetic resonance
late gadolinium enhancement
heart failure with preserved ejection fraction
angiotensin converting enzyme
pulse wave velocity
adenosine triphosphate
phosphorus magnetic resonance spectroscopy



Dr. Raman receives research support from Siemens Medical Solutions.

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1. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557–62. [PubMed]
2. Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N–9N. [PubMed]
3. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med. 1987;317:787–92. [PubMed]
4. Dimopoulos S, Nicosia F, Donati P, et al. QT dispersion and left ventricular hypertrophy in elderly hypertensive and normotensive patients. Angiology. 2008;59:605–12. [PubMed]
5. Diez J, Gonzalez A, Lopez B, Querejeta R. Mechanisms of disease: pathologic structural remodeling is more than adaptive hypertrophy in hypertensive heart disease. Nat Clin Pract Cardiovasc Med. 2005;2:209–16. [PubMed]
6. Berenji K, Drazner MH, Rothermel BA, Hill JA. Does load-induced ventricular hypertrophy progress to systolic heart failure? Am J Physiol Heart Circ Physiol. 2005;289:H8–H16. [PubMed]
7. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest. 1975;56:56–64. [PMC free article] [PubMed]
8. Schillaci G, Verdecchia P, Porcellati C, Cuccurullo O, Cosco C, Perticone F. Continuous relation between left ventricular mass and cardiovascular risk in essential hypertension. Hypertension. 2000;35:580–6. [PubMed]
9. Devereux RB, Dahlof B, Gerdts E, et al. Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial. Circulation. 2004;110:1456–62. [PubMed]
10. Okin PM, Devereux RB, Jern S, et al. Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. JAMA. 2004;292:2343–9. [PubMed]
11. Verdecchia P, Angeli F, Gattobigio R, Sardone M, Pede S, Reboldi GP. Regression of left ventricular hypertrophy and prevention of stroke in hypertensive subjects. Am J Hypertens. 2006;19:493–9. [PubMed]
12. Devereux RB, Reichek N. Repolarization abnormalities of left ventricular hypertrophy. Clinical, echocardiographic and hemodynamic correlates. J Electrocardiol. 1982;15:47–53. [PubMed]
13. Sohaib SM, Payne JR, Shukla R, World M, Pennell DJ, Montgomery HE. Electrocardiographic (ECG) criteria for determining left ventricular mass in young healthy men; data from the LARGE Heart study. J Cardiovasc Magn Reson. 2009;11:2. [PMC free article] [PubMed]
14. Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. Am J Cardiol. 2002;90:29–34. [PubMed]
15. Soliman OI, Kirschbaum SW, van Dalen BM, et al. Accuracy and reproducibility of quantitation of left ventricular function by real-time three-dimensional echocardiography versus cardiac magnetic resonance. Am J Cardiol. 2008;102:778–83. [PubMed]
16. Raman SV, Shah M, McCarthy B, Garcia A, Ferketich AK. Multi-detector row cardiac computed tomography accurately quantifies right and left ventricular size and function compared with cardiac magnetic resonance. Am Heart J. 2006;151:736–44. [PubMed]
17. Lin FY, Devereux RB, Roman MJ, et al. Cardiac chamber volumes, function, and mass as determined by 64-multidetector row computed tomography: mean values among healthy adults free of hypertension and obesity. JACC Cardiovasc Imaging. 2008;1:782–6. [PubMed]
18. Querejeta R, Varo N, Lopez B, et al. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation. 2000;101:1729–35. [PubMed]
19. Mizuno R, Fujimoto S, Saito Y, Nakamura S. Non-invasive quantitation of myocardial fibrosis using combined tissue harmonic imaging and integrated backscatter analysis in dilated cardiomyopathy. Cardiology. 2007;108:11–7. [PubMed]
20. Rudolph A, Abdel-Aty H, Bohl S, et al. Noninvasive detection of fibrosis applying contrast-enhanced cardiac magnetic resonance in different forms of left ventricular hypertrophy relation to remodeling. J Am Coll Cardiol. 2009;53:284–91. [PubMed]
21. Moreo A, Ambrosio G, Chiara BD, et al. Influence of myocardial fibrosis on left ventricular diastolic function: noninvasive assessment by CMR and echo. Circ Imaging. 2009;2(6):437–43. [PMC free article] [PubMed]
22. Adabag AS, Maron BJ, Appelbaum E, et al. Occurrence and frequency of arrhythmias in hypertrophic cardiomyopathy in relation to delayed enhancement on cardiovascular magnetic resonance. J Am Coll Cardiol. 2008;51:1369–74. [PubMed]
23. Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy. J Am Coll Cardiol. 2006;48:1977–85. [PubMed]
24. Iles L, Pfluger H, Phrommintikul A, et al. Evaluation of diffuse myocardial fibrosis in heart failure with cardiac magnetic resonance contrast-enhanced T1 mapping. J Am Coll Cardiol. 2008;52:1574–80. [PubMed]
25. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000;102:1388–93. [PubMed]
26. Lapu-Bula R, Ofili E. From hypertension to heart failure: role of nitric oxide-mediated endothelial dysfunction and emerging insights from myocardial contrast echocardiography. Am J Cardiol. 2007;99:7D–14D. [PubMed]
27. Pilz G, Klos M, Ali E, Hoefling B, Scheck R, Bernhardt P. Angiographic correlations of patients with small vessel disease diagnosed by adenosine-stress cardiac magnetic resonance imaging. J Cardiovasc Magn Reson. 2008;10:8. [PMC free article] [PubMed]
28. Bigi R, Bestetti A, Strinchini A, et al. Combined assessment of left ventricular perfusion and function by gated single-photon emission computed tomography for the risk stratification of high-risk hypertensive patients. J Hypertens. 2006;24:767–73. [PubMed]
29. Schuijf JD, Bax JJ, Jukema JW, et al. Noninvasive evaluation of the coronary arteries with multislice computed tomography in hypertensive patients. Hypertension. 2005;45:227–32. [PubMed]
30. London GM, Guerin AP. Influence of arterial pulse and reflected waves on blood pressure and cardiac function. Am Heart J. 1999;138:220–4. [PubMed]
31. Ahimastos AA, Aggarwal A, D’Orsa KM, et al. Effect of perindopril on large artery stiffness and aortic root diameter in patients with Marfan syndrome: a randomized controlled trial. JAMA. 2007;298:1539–47. [PubMed]
32. Hundley WG, Kitzman DW, Morgan TM, et al. Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol. 2001;38:796–802. [PubMed]
33. Lamb HJ, Beyerbacht HP, van der Laarse A, et al. Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism. Circulation. 1999;99:2261–7. [PubMed]
34. Khong TK, McIntyre DJ, Sagnella GA, et al. In-vivo intracellular pH at rest and during exercise in patients with essential hypertension. J Hypertens. 2001;19:1595–600. [PubMed]
35. Laine H, Knuuti MJ, Ruotsalainen U, et al. Preserved relative dispersion but blunted stimulation of mean flow, absolute dispersion, and blood volume by insulin in skeletal muscle of patients with essential hypertension. Circulation. 1998;97:2146–53. [PubMed]
36. Kim H, Jun DW, Cho YK, et al. The correlation of left atrial volume index to the level of N-terminal pro-BNP in heart failure with a preserved ejection fraction. Echocardiography. 2008;25:961–7. [PubMed]
37. Kurt M, Wang J, Torre-Amione G, Nagueh SF. Left atrial function in diastolic heart failure. Circulation: Cardiovascular Imaging. 2009;2:10–15. [PubMed]
38. Yang Z, Huang X, Jiang H, et al. Short telomeres and prognosis of hypertension in a chinese population. Hypertension. 2009;53:639–45. [PMC free article] [PubMed]
39. Turner ST, Bailey KR, Fridley BL, et al. Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic. Hypertension. 2008;52:359–65. [PMC free article] [PubMed]