Hypertensive-Heart-Failure

S Ramakrishnan, SS Kothari, VK Bahl

Department of Cardiology, All India Institute of Medical Sciences, New Delhi

Heart failure is being increasingly recognized the world over. Hypertension and ischemic heart disease are the two cardinal causes of heart failure.1,2 Over the years, a voluminous amount of literature has accumulated regarding various facets of hypertensive heart failure. Despite this, the risk and mechanisms of heart failure in patients with hypertension is not completely understood. Further, due to the common coexistence of coronary artery disease (CAD) and hypertension in the population, the relative contributions of CAD and hypertension to heart failure have been difficult to disentangle. This article provides an overview of the salient aspects of hypertensive heart failure (HHF) from a clinical standpoint.

Epidemiology

The data on the prevalence of hypertension in patients with heart failure are rather discordant. In the Framingham Heart Study cohort,3 hypertension antedated the development of congestive heart failure (CHF) in 91% of cases and was associated with a two- to three-fold risk of development of CHF after adjusting for age and other risk factors. Hypertension also had a high populationattributable risk (the percentage of heart failure cases that can be attributed to hypertension) for CHF, viz. 39% in men and 59% in women in the Framingham study. In contrast, hypertension was found to be the primary factor in only 17% of hospitalized heart failure patients.4 Moreover, hypertension was reported to be the primary etiological factor in only 4% of heart failure patients in an overview of 31 studies.5

Recent data from two population-based studies indicate that hypertension is responsible for CHF in 4%–20% of patients. In a Swedish study of 7500 patients followed up for 27 years,6 the identified etiological factors for CHF were hypertension in 20.3%, and CAD either alone or in combination with hypertension in 58.8%. Fox et al.7 have reported hypertension to be the primary attributable factor for CHF in only 4.4% of incident cases of CHF examined prospectively. This study emphasized the fact that associated CAD might be clinically underestimated if coronary angiography is not routinely performed. However, the contribution of hypertension to heart failure in patients with significant CAD was not analyzed in the study. Myocardial infarction (MI) is associated with a five- to sixfold increase in the risk of heart failure in hypertensive patients.3 Antecedent hypertension interacts with neurohumoral activation, and thereby adversely modifies early ventricular remodeling to increase the risk of heart failure after MI.8 Taken together, these data suggest that while hypertension clearly causes or contributes to heart failure, the absolute risk of heart failure in an individual remains low in the absence of other factors.

Individual Risk Assessment

In addition to CAD, several other patient-related risk factors influence the risk of heart failure. These include age, gender, race, diabetes, valvular heart disease, obesity, severity of hypertension, left ventricular hypertrophy (LVH), and alcoholism. An Italian study9 suggests that in a 60-yearold asymptomatic man with a systolic blood pressure (BP) of 160 mmHg, the risk of developing heart failure is 0.37% per year in the absence of LVH, which increases to 0.9% per year in the presence of hypertrophy. If ischemic heart disease, valvular heart disease, and diabetes coexist in the same subject, then the risk of heart failure rises to 5.1% and 9.5% in the absence and presence of LVH, respectively.

In humans, what degree and duration of hypertension would cause LVH or heart failure has not been determined. No threshold of BP has been observed for a substantive change in risk for heart failure,3,10 yet 70%–80% of patients with heart failure and hypertension have a BP >160/100 mmHg.3 The incidence of CHF is clearly greater at increasing levels of blood pressure and lower with lesser systolic BP.3,10 The etiology of hypertension could also influence the risk of CHF. Renovascular hypertension is associated with more target organ damage,11 and possibly more CHF.

The incidence of heart failure increases as a function of age.3 In the young and middle-aged, the incidence of heart failure correlates with diastolic and mean pressures.12 However, in the elderly, both these measures correlate poorly with heart failure. Instead, pulse pressure, a measure of pulsatile load, is a powerful and independent predictor of heart failure.13 A wide pulse pressure is either an indicator or a consequence of aortic stiffness, which increases the systolic BP and lowers the diastolic BP by a variety of mechanisms. An increase in the systolic BP increases the load, and lower diastolic BP reduces the coronary perfusion pressure, thereby increasing the vulnerability of the heart to failure.13 Both hypertension and LVH are stronger risk factors for CHF in women as compared to men. However, women have a lower prevalence of LVH than men for any given level of blood pressure.14 In obese hypertensive patients, varying combinations of pressure and volume overload are seen, resulting in a mixed eccentric–concentric form of LVH.15 Moreover, obesity is an important independent predictor of left ventricular (LV) mass, and the effects of hypertension and obesity are additive.16

Diabetes is emerging as an important precursor of heart failure.3 In the United Kingdom Prospective Diabetic Study (UKPDS),10 the incidence of heart failure in 4801 white men with type 2 diabetes was 2.4 per 1000 person-years’ follow-up in patients with a systolic BP in the range of 120–129 mmHg, and rose to 7.0 in patients with a systolic BP >160 mmHg. However, no threshold of BP was seen for the occurrence of heart failure.

Left Ventricular Hypertrophy

Left ventricular hypertrophy represents the major biological adaptation to increased pressure load and its limitations. Thus, understanding ventricular remodeling influences the entire issue of heart failure in hypertension and its therapy. Although cardiac failure would possibly occur earlier in the absence of LVH, LVH is clearly a double-edged sword. Hypertensive LVH has repeatedly been shown to be an independent marker of cardiac failure, accelerated atherosclerosis of the coronary arteries, lethal cardiac arrhythmias, and sudden death.17 The increased risk of sudden death can be explained at least in part by the repolarization abnormalities described in patients with hypertensive LVH. Graded prolongation of the QT interval occurs with increasing LV mass index, and measures of QT dispersion are also related to the LV mass.18 Abnormalities of the QT interval occur irrespective of the geometry of LVH.18 Each 50 g/m2 increase in LV mass is associated with a 1.49 increase in the relative risk of cardiovascular disease for men and a 1.57 increase for women.16 However, individuals differ in their response of LVH to a given pressure load. Only 15%–20% of hypertensive patients show echocardiographic evidence of LVH16 and, in hypertensive patients, it is estimated that approximately 40% of the variance in LV mass is accounted for by the total LV load.19 Further, LVH occurs in the absence of hypertension and, in some cases, precedes its development (cardiogenic hypertension).20 Old age, male sex, obesity, diabetes in women, black race, and certain genetic influences such as angiotensin-converting enzyme (ACE) polymorphisms lead to a greater LVH for a given BP.21 The geometric pattern of LVH in hypertension also influences the risk. The 10-year incidence of cardiovascular events is reported to be 30% in those with concentric LVH, 25% in those with eccentric LVH, 15% in those with concentric remodeling (increased relative wall thickness with a normal LV mass), and 9% in those with a normal LV mass.22

Cellular Mechanisms of Left Ventricular Hypertrophy and Heart-Failure

Mechanical forces are thought to be the principal determinants of cardiac hypertrophy. The principal mechanical contributor that promotes LVH in early hypertension is sustained increase in systemic vascular resistance.19 The molecular mechanisms that translate increased wall stress to cellular hypertrophy are beginning to be elucidated.23 Increased wall stress activates a stretch receptor that releases intracellular calcium and activates calcineurin, which, acting through a series of subcellular events, activates fetal cardiac and growth genes, such as cmyc and c-jun, to upregulate protein synthesis.24 The mechanical forces work in tandem with potent neurohumoral mediators such as angiotensin II, norepinephrine, and insulin.23

The hypertrophy that occurs in hypertensive heart disease (HHD) is not homogeneous. In contrast to the hypertrophy seen in athletes, in HHD it is disproportionate, and predominantly involves noncardiomyocytes. Thus, it is not the quantity but the quality of the myocardium that distinguishes HHD from the adaptive hypertrophy of the athlete.25 In certain disease states such as chronic anemia, small arteriovenous fistula, atrial septal defect, or hyperthyroidism, cardiac hypertrophy occurs with preserved homogenecity. These conditions are not associated with activation of the circulating renin–angiotensin system.26 Several attempts have been made to differentiate physiologic and pathologic hypertrophy by noninvasive means. It has been shown that the long-axis mean annular velocities measured by tissue Doppler are significantly decreased in HHD as compared to athletes.27

Fibrosis, an integral feature of the adverse structural remodeling of the heart seen in HHD, appears in two morphologically distinct forms: a reactive form expressed as a perivascular/interstitial fibrosis, and a reparative fibrosis represented by microscopic scars that replace necrotic myocytes.26 Adverse accumulation of extracellular matrix initially increases myocardial stiffness, and its continued accumulation impairs contractile behavior. Early evidence suggests that the measurement of serum concentrations of procollagen type I C-terminal propeptide (a peptide that is cleaved from procollagen type I during the synthesis of fibril-forming collagen type I) may provide indirect information on the extent of myocardial fibrosis.28 Gadolinium-DTPA delayed-enhancement magnetic resonance imaging (de-MRI) is accurate in assessing regional fibrosis noninvasively.29

Imaging studies using 111In-labeled monoclonal antimyosin antibodies30 have shown that cell damage occurs early in HHD, and abnormally stimulated apoptosis of cardiomyocytes and noncardiomyocytes could be responsible for such cell damage.31 Local factors that may trigger apoptosis include mechanical forces, oxidative stress, hypoxia, and an unbalanced presence of growth factors and cytokines (e.g. angiotensin II) or neurotransmitters (e.g. norepinephrine).32 Since signals that potentially mediate hypertrophy are largely the ones proposed to mediate apoptosis also, it has been proposed that when growth signals persist chronically in terminally differentiated cells, they produce a contradictory genetic demand and trigger the apoptosis.32 The absence of a clear association between cardiomyocyte apoptosis and absolute BP values indicate that nonhemodynamic factors, especially angiotensin, may be more important.32

Clinical Transition to Heart-Failure

In humans, HHD leads to three recognizable stages in evolution of heart failure: LVH, diastolic dysfunction, and systolic dysfunction, not necessarily in the same order.

Abnormalities of LV diastolic filling are observed in various forms of hypertension in adults as well as children,21 and the prevalence may be as high as 22% in asymptomatic hypertensive patients with a BP of >140/90 mmHg.33 Diastolic filling abnormalities have been shown to generally correlate with LV mass,34 and BP.33 However, diastolic dysfunction could precede the onset of hypertension in the young male offspring of hypertensive parents.33

In hypertensive patients, diastolic heart failure is increasingly being recognized as a cause of CHF. However, the incidence is not clear, as establishing a definite diagnosis is difficult. In previous published studies on unselected heart failure populations, the reported prevalence of patients having preserved systolic function varied widely, from 13% to 74%.35 Each 1 mmHg increase in pulmonary capillary wedge pressure, a measure of diastolic dysfunction, is shown to be associated with a 23% increase in the risk of all-cause mortality, and a 13% increase in the risk of cardiovascular events in the 174 patients of uncomplicated hypertension followed up for 10 years.36

In the absence of MI, hypertensive patients with LVH commonly have supernormal ejection phase indices on echocardiography, and a significant decrease in LV ejection fraction occurs very late in the course of HHD.37 Yet, normalcy of these ejection indices may not imply normal systolic function in hypertension. When indices such as mid-wall fractional shortening are used, up to 16% of hypertensive patients were found to have depressed LV systolic function.38 Hypertensive patients also have a depressed end-systolic stress relationship. Furthermore, hypertension may lead to exercise-induced systolic LV dysfunction even though the resting LV function may be normal.39

Acute heart failure (pulmonary edema) in a hypertensive patient could be due to transient systolic dysfunction, diastolic dysfunction, ischemia, or mitral regurgitation. However, nearly 40% of hypertensive patients have a normal LV ejection fraction indicating diastolic dysfunction as the cause.40 Normally, the left ventricle compensates for an increase in systolic load by increasing end-diastolic volume (i.e., using preload reserve). In a patient with diastolic dysfunction, this small increase in left ventricular end-diastolic volume may be associated with a marked elevation in diastolic pressure, because of the reduced distensibility of the left ventricle, thereby precipitating pulmonary edema.41 Common precipitants of overt heart failure in patients with diastolic dysfunction include old age, tachycardia, sudden severe increase in overload such as a hypertensive crisis, and loss of atrial kick.42 The relative contribution of significant ischemia due to epicardial obstructive CAD in the causation of pulmonary edema is difficult to quantify. More than 60% of hypertensive patients presenting with flash pulmonary edema had epicardial obstructive CAD in one study.43 Interestingly, however, the flash pulmonary edema recurred in half the patients even after revascularization.43

The diagnosis of CAD in patients suspected of having HHF is difficult. The sensitivity and specificity of noninvasive stress tests are altered by both heart failure and hypertension. In heart failure patients, noninvasive stress tests can be less sensitive due to the low level of stress obtainable, and less specific due to doubtful echocardiographic pictures and perfusion images of dilated, hypokinetic ventricles. The baseline electrocardiogram also often shows intraventricular conduction delays and altered repolarization at rest. Hence, it has been suggested that in heart failure patients the coronary angiogram may be the sole determining test for excluding obstructive epicardial CAD.44 However, to assign ischemia as the etiology of heart failure in the presence of hypertension, the anatomic disease should be associated with regional wall motion abnormalities, perfusion abnormalities, or ischemic valvular dysfunction. It has been suggested that in HHF patients with a preserved LV ejection fraction, two groups could be identified based on LV mass. If there was a high degree of reactive hypertrophy, the patients had a lower chance of a positive stress test, whereas patients with only moderate hypertrophy have a high rate of epicardial obstructive CAD.45

Recently, tissue Doppler measurement of the cyclic variation index of the backscatter signal at the septum level have shown significant alterations in hypertensive patients, and it correlates with the LV mass and geometry of LVH. The alterations could be reversed with antihypertensive treatment.46 Hence, ultrasonic tissue characterization has the potential to identify early those hypertensive patients at risk of adverse remodeling.

Impact of Treatment

The reported median survival following the diagnosis of heart failure in hypertensive subjects is 1.37 years in men and 2.48 years in women. The 5-year survival rates are reported to be 24% in men and 31% in women.3 The prognosis may be better for patients with diastolic dysfunction. For example, in heart failure patients with preserved systolic function, the annual mortality was reported to be 8.7% v. 3.0% for matched controls, and in patients with LV systolic dysfunction, the annual mortality was 18.9% v. 4.1% for matched controls in the Framingham cohort.47 Hence, treatment is required before the onset of clinical heart failure.

The efficacy of antihypertensive medications in reducing the incidence of heart failure in diastolic48,49 as well as isolated systolic hypertension50 has been well documented. Meta-analysis of long-term hypertension has also shown that sustained lowering of blood pressure is effective in preventing LVH and CHF, regardless of the agent used,51 a finding not corroborated by a recent meta-analysis.52 Currently, there is no clear evidence that one class of antihypertensive agent is more effective than the other in retarding the progression of HHD; however, there, is some evidence that calcium-channel blockers may be less effective. In the recently reported ALLHAT study,53 the amlodipine group had a 38% higher risk of heart failure, and a 35% higher risk of hospitalized/fatal heart failure as compared to chlorthalidone. The recent meta-analysis has also shown that the risk of heart failure was 15% higher with calcium-channel blockers as compared to betablockers, and 18% higher as compared to ACE inhibitors.52  The relative superiority of ACE inhibitors and diuretics is not clear, as two recent large trials53,54 have yielded conflicting results. In the ALLHAT study,53 the lisinopril group had a 19% increased risk of heart failure as compared to patients treated with chlorthalidone, whereas in the second Australian national blood pressure study,54 the incidence of heart failure was not significantly different between ACE inhibitor- and diuretic-treated patients.

Management of hypertension should not focus merely on a reduction in BP, but must also target the adverse structural remodeling that begets HHD. Such approaches target diastolic dysfunction, adverse remodeling, apoptosis, fibrosis, and neurohumoral mediators. Drugs that are shown to be reparative include ACE inhibitors, angiotensin-1 receptor antagonists, endothelin antagonists, and aldosterone receptor antagonists.25 Two approaches that influence apoptosis include inhibition of apoptotic signals that trigger the process, and direct blockade of the intracellular apoptotic mechanisms. Drugs shown to be effective antiapoptotics include ACE inhibitors, losartan, alfa-blockers, and calcium-channel blockers. Hydralazine and diuretics have been shown to have no effect on apoptosis.32 Gene therapy, targeting abnormalities of ion handling, cellular signaling, neurohormonal control, and apoptosis, hold promise in retarding the progression to heart failure.55 ACE inhibitors have been shown to cause regression in fibrosis, leading to improvement in diastolic dysfunction as compared to diuretics.56 Further progress on specific therapy is awaited.

Conclusions

The data on the prevalence of hypertension in heart failure are rather discordant. The duration and severity of hypertension critical to cause heart failure is not known. For the same degree of hypertension, several patient-related factors modify the occurrence of heart failure. In patients with HHF, CAD needs to be carefully evaluated. Mechanisms of hypertrophy and remodeling that contribute to systolic and diastolic dysfunction are beginning to be understood. Antihypertensive treatment reduces the risk of HHF (possibly with some differences among various antihypertensive drugs). Specific therapies targeting adverse cardiac remodeling are under development.

Correspondence:

Professor VK Bahl,
Department of Cardiology,
All India Institute of Medical Sciences,
New Delhi 110029.
e-mail: vkbahl2002@yahoo.com

References

  1. Gillum RF. Epidemiology of heart failure in the United States. Am Heart J 1993; 126: 1042–1047

  2. Mckee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: The Framingham study. N Engl J Med 1971; 285: 1441–1446

  3. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA 1996; 275: 1557–1562

  4. Andersson B, Waagstein F. Spectrum and outcome of congestive heart failure in a hospitalized population. Am Heart J 1993; 126: 632–640

  5. Teerlink JR, Goldhaber SZ, Pfeffer MA. An overview of contemporary etiologies of congestive heart failure. Am Heart J 1991; 121: 1852–1853

  6. Wilhelmsen L, Rosengren A, Eriksson H, Lappas G. Heart failure in the general population of men—morbidity, risk factors and prognosis. J Intern Med 2001; 249: 253–261

  7. Fox KF, Cowie MR, Wood DA, Coats AJS, Gibbs JS, Underwood SR, et al. Coronary artery disease as the cause of incident heart failure in the population. Eur Heart J 2001; 22: 228–236

  8. Richards AM, Nicholls MG, Troughton RW, Lainchbury JG, Elliott J, Frampton C, et al. Antecedent hypertension and heart failure after myocardial infarction. J Am Coll Cardiol 2002; 39: 1182–1188

  9. Verdecchia P. [Cardiac failure in hypertensive cardiopathy] [Article in Italian]. Ital Heart J 2000; 1 (Suppl): 72–77

  10. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36):prospective observational study. BMJ 2000; 321: 412–419

  11. Losito A, Fagugli RM, Zampi I, Parente B, de Rango P, Giordano G, et al. Comparison of target organ damage in renovascular and essential hypertension. Am J Hypertens 1996; 9: 1062–1067

  12. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham study. Am J Cardiol 1971; 27: 335–346

  13. Vaccarino V, Holford TR, Krumholz HM. Pulse pressure and risk for myocardial infarction and heart failure in the elderly. J Am Coll Cardiol 2000; 36: 130–138

  14. Agabiti-Rosei E, Muiesan ML. Left ventricular hypertrophy and heart failure in women. J Hypertens 2002; 20 (Suppl): S34–S38

  15. Thakur V, Richards R, Reisin E. Obesity, hypertension, and the heart. Am J Med Sci 2001; 321: 242–248

  16. Levy D, Anderson KM, Savage DD, Kannel WB, Christiansen JC, Castelli WP. Echocardiographically detected left ventricular hypertrophy: prevalence and risk factors. The Framingham Heart Study. Ann Intern Med 1988; 108: 7–13

  17. Frohlich ED. Fibrosis and ischemia: the real risks in hypertensive heart disease. Am J Hypertens 2001; 14: 194S–199S

  18. Oikarinen L, Nieminen MS, Viitasalo M, Toivonen L, Wachtell K, Papademetriou V, et al. Relation of QT interval and QT dispersion to echocardiographic left ventricular hypertrophy and geometric pattern in hypertensive patients. The LIFE study. The Losartan Intervention For Endpoint Reduction. J Hypertens 2001; 19: 1883–1891

  19. Ganau A, Devereux RB, Pickering TG, Roman MJ, Schnall PL, Santucci S, et al. Relation of left ventricular hemodynamic load and contractile performance of left ventricular mass in hypertension. Circulation 1990; 81: 25–36

  20. Post WS, Larson MG, Levy D. Impact of left ventricular structure on the incidence of hypertension. The Framingham Heart Study. Circulation 1994; 90: 179–185

  21. Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure—a clinical mechanistic overview. Arch Intern Med 1996; 156: 1789–1796

  22. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991; 114: 345–352

  23. Morgan HE, Baker KM. Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation 1991; 83: 13–25

  24. Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 1998; 93: 215–228

  25. Weber KT. Cardioreparation in hypertensive heart disease. Hypertension 2001; 38: 588–591

  26. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin–angiotensin–aldosterone system. Circulation 1991; 83: 1849–1865

  27. Vinereanu D, Florescu N, Sculthorpe N, Tweddel AC, Stephens MR, Fraser AG. Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes. Am J Cardiol 2001; 88: 53–58

  28. Lopez B, Gonzalez A, Varo N, Laviades C, Querejeta R, Diez J. Biochemical assessment of myocardial fibrosis in hypertensive heart disease. Hypertension 2001; 38: 1222–1226

  29. Wilson JM, Villareal RP, Hariharan R, Massumi A, Muthupillai R, Flamm SD. Magnetic resonance imaging of myocardial fibrosis in hypertrophic cardiomyopathy. Tex Heart Inst J 2002; 29: 176–180

  30. Pons-Llado G, Ballester M, Borras X, Carreras F, Carrio I, Lopez-Contreras J, et al. Myocardial cell damage in human hypertension. J Am Coll Cardiol 2000; 36: 2198–2203

  31. González A, López B, Ravassa S, Querejeta R, Larman M, Díez J, et al. Stimulation of cardiac apoptosis in essential hypertension: potential role of angiotensin II. Hypertension 2002; 39: 75–80

  32. Fortuño MA, Ravassa S, Fortuño A, Zalba G, Díez J. Cardiomyocyte apoptotic cell death in arterial hypertension: mechanisms and potential management. Hypertension 2001; 38: 1406-1412

  33. Phillips RA, Goldman ME, Ardeljan M, Arora R, Eison HB, Yu BY, et al. Determinants of abnormal left ventricular filling in early hypertension. J Am Coll Cardiol 1989; 14: 979–985

  34. Ren JF, Pancholy SB, Iskandrian AS, Lighty GW Jr, Mallavarapu C, Segal BL. Doppler echocardiagraphic evaluation of the spectrum of left ventricular diastolic dysfunction in essential hypertension. Am Heart J 1994; 127: 906–913

  35. Vasan RS, Benjamin EJ, Levy D. Prevalence, clinical features and prognosis of diastolic heart failure: an epidemiologic perspective. J Am Coll Cardiol 1995; 26: 1565–1574

  36. Fagard R, Pardaens K. Left ventricular diastolic function predicts outcome in uncomplicated hypertension. Am J Hypertens 2001; 14: 504–508

  37. Frohlich ED, Tarazi RC, Dustan HP. Clinical–physiological correlations in the development of hypertensive heart disease. Circulation 1971; 44: 446–455

  38. de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH, et al. Assessment of left ventricular function by midwall fractional shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol 1994; 23: 1444–1451

  39. Cuocolo A, Sax FL, Brush JE, Maron BJ, Bacharach SL, Bonow RO. Left ventricular hypertrophy and impaired diastolic filling in essential hypertension. Diastolic mechanisms for systolic dysfunction during exercise. Circulation 1990; 81: 978–986

  40. Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin KM, et al. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med 2001; 344: 17–22

  41. Vasan RS, Benjamin EJ. Diastolic heart failure—no time to relax. NEngl J Med 2001; 344: 56–59

  42. Shah PM, Pai RG. Diastolic heart failure. Curr Probl Cardiol 1992; 17: 781–868

  43. Kramer K, Kirkman P, Kitzman D, Little WC. Flash pulmonary edema: association with hypertension and re-ocurrence despite coronary revascularization. Am Heart J 2000; 140: 451–455

  44. Tavazzi L. Towards a more precise definition of heart failure aetiology. Eur Heart J 2001; 22: 192–195

  45. Iriarte M, Murga N, Sagastagoitia D, Molinero E, Morillas M, Salcedo A, et al. Congestive heart failure from left ventricular diastolic dysfunction in systemic hypertension. Am J Cardiol 1993; 71: 308–312

  46. Di Bello V, Giorgi D, Talini E, Dell’ Omo G, Palagi C, Romano MF, et al. Incremental value of ultrasonic tissue characterization (backscatter) in the evaluation of left ventricular myocardial structure and mechanics in essential arterial hypertension. Circulation 2003; 107: 74–80

  47. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 1999; 33: 1948–1955

  48. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: 1028–1034

  49. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 115 mm Hg. JAMA 1970; 213: 1143–1152

  50. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–3264

  51. Moser M, Hebert PR. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J Am Coll Cardiol 1996; 27: 1214–1218

  52. Neal B, MacMohan S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000; 356: 1955–1964

  53. The ALLHAT officers and coordinators for the ALLHAT collaborative research group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–2997

  54. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003; 348: 583–592

  55. MacNeill BD, Hayase M, Hajjar RJ. Targeting signaling pathways in heart failure by gene transfer. Curr Atheroscler Rep 2003; 5: 178–185

  56. Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 2000; 102: 1388–1393