Ischemia and fibrosis: the risk mechanisms of hypertensive heart disease

Mechanisms underlying risk associated with hypertensive heart disease (HHD) and left ventricular hypertrophy (LVH) are discussed in this report and provide a rationale for understanding this very common and important cause of death from hypertension and its complications. Emphasized are impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis from increased collagen deposition intramurally and perivascularly. Each is exacerbated by aging and, perhaps, also by increased dietary salt intake. These functional and structural changes promote further endothelial dysfunction, altered coronary hemodynamics, and diastolic as well as systolic ventricular contractile function in HHD. The clinical endpoints of HHD include angina pectoris (with or without atherosclerosis of the epicardial coronary arteries), myocardial infarction, cardiac failure, lethal dysrhythmias, and sudden death. The major concept to be derived from these alterations is that not all that is clinically recognized as LVH is true myocytic hypertrophy and structural remodeling. Other major co-morbid changes occur that serve to increase cardiovascular risk including impaired coronary hemodynamics, endothelial dysfunction, and ventricular fibrosis.

The relative myocardial blood volume differentiates between hypertensive heart disease and athlete's heart in humans

AIMS: The adaptation of the myocardial microcirculation in humans to pathologic and physiologic stress has not been examined in vivo so far. We sought to test whether the relative blood volume (rBV) measured by myocardial contrast echocardiography (MCE) can differentiate between left ventricular (LV) hypertrophy (LVH) in hypertensive heart disease and athlete's heart. METHODS AND RESULTS: Four groups were investigated: hypertensive patients with LVH (n = 15), semi-professional triathletes with LVH (n = 15), professional football players (n = 15), and sedentary control individuals without cardiovascular disease (n = 15). MCE was performed at rest and during adenosine-induced hyperaemia. The rBV (mL mL(-1)), its exchange frequency (beta, min(-1)), and myocardial blood flow (mL min(-1) g(-1)) were derived from steady state and refill sequences of ultrasound contrast agent. Hypertensive patients had lower rBV (0.093 +/- 0.013 mL mL(-1)) than triathletes (0.141 +/- 0.012 mL mL(-1), P < 0.001), football players (0.129 +/- 0.014 mL mL(-1), P < 0.001), and sedentary individuals (0.126 +/- 0.018 mL mL(-1), P < 0.001). Conversely, the exchange frequency (beta) was significantly higher in hypertensive patients (11.3 +/- 3.8 min(-1)) than in triathletes (7.4 +/- 1.8 min(-1)), football players (7.7 +/- 2.3 min(-1)), and sedentary individuals (9.0+/-2.5 min(-1)). An rBV below 0.114 mL mL(-1) distinguished hypertensive patients and triathletes with a sensitivity of 93% and a specificity of 100%. CONCLUSION: Pathologic and physiologic LVH were differentiated non-invasively and accurately by rBV, a measure of vascularisation assessed by MCE.

Do women have impaired regional systolic function in hypertensive heart disease? A 3-dimensional echocardiography study

AIMS: In pressure overload left ventricular (LV) hypertrophy, gender-related differences in global LV systolic function have been previously reported. The goal of this study was to determine regional systolic function of the left ventricle in male and female patients with hypertensive heart disease. METHODS AND RESULTS: Regional LV function was analyzed from multiplane transesophageal echocardiography with three-dimensional (3D) reconstruction of the left ventricle. In 24 patients (13 males and 11 females), four parallel (2 basal and 2 apical) equidistant short axis cross-sections from base to apex were obtained from the reconstructed LV. In each short axis 24 wall-thickness measurements were carried out at 15 degrees intervals at end-diastole and end-systole. Thus, a total of 192 measurements were obtained in each patient. Wall thickening was calculated as difference of end-diastolic and end-systolic wall thickness, and fractional thickening as thickening divided by end-diastolic thickness. Fractional thickening and wall stress were inversely related to end-diastolic wall thickness in both, males and females. Females showed less LV systolic function when compared to males (p<0.001). However, when corrected for wall stress, which was higher in females, there was no gender difference in systolic function. CONCLUSION: There are regional differences in LV systolic function in females and males which are directly related to differences in wall stress. Thus, gender-related differences in LV regional function are load-dependent and not due to structural differences.

Myocardial contrast echocardiography for the distinction of hypertrophic cardiomyopathy from athlete's heart and hypertensive heart disease

BACKGROUND: Myocardial contrast echocardiography (MCE) is able to measure in vivo relative blood volume (rBV, i.e., capillary density), and its exchange frequency b, the constituents of myo-cardial blood flow (MBF, ml min-1 g-1). This study aimed to assess, by MCE, whether left ventricular hypertrophy (LVH) in hypertrophic cardiomyopathy (HCM) can be differentiated from LVH in triathletes (athlete's heart, AH) or from hypertensive heart disease patients (HHD). METHODS: Sixty individuals, matched for age (33 +/- 10 years) and gender, and subdivided into four groups (n = 15) were examined: HCM, AH, HHD and a group of sedentary individuals without LVH (S). rBV (ml ml-1), b (min-1) and MBF, at rest and during adenosine-induced hyperaemia, were derived by MCE in mid septal, lateral and inferior regions. The ratio of MBF during hyperaemia and MBF at rest yielded myocardial blood flow reserve (MBFR). RESULTS: Septal wall rBV at rest was lower in HCM (0.084 +/- 0.023 ml ml-1) than in AH (0.151 +/- 0.024 ml ml-1, p <0.01) and in S (0.129 +/- 0.026 ml ml-1, p <0.01), but was similar to HHD (0.097 +/- 0.016 ml ml-1). Conversely, MBFR was lowest in HCM (1.67 +/- 0.93), followed by HHD (2.8 +/- 0.93, p <0.01), by S (3.36 +/- 1.03, p <0.001) and by AH (4.74 +/- 1.46, p <0.0001). At rest, rBV <0.11 ml ml-1 accurately distinguished between HCM and AH (sensitivity 99%, specificity 99%), similarly MBFR < or =1.8 helped to distinguish between HCM and HHD (sensitivity 100%, specificity 77%). CONCLUSIONS: rBV at rest, most accurately distinguishes between pathological LVH due to HCM and physiological, endurance-exercise induced LVH.

Relaxation in hypertrophic cardiomyopathy and hypertensive heart disease: relations between hypertrophy and diastolic function

AIM To determine the relation between the extent and distribution of left ventricular hypertrophy and the degree of disturbance of regional relaxation and global left ventricular filling. METHODS Regional wall thickness (rWT) was measured in eight myocardial regions in 17 patients with hypertrophic cardiomyopathy, 12 patients with hypertensive heart disease, and 10 age matched normal subjects, and an asymmetry index calculated. Regional relaxation was assessed in these eight regions using regional isovolumetric relaxation time (rIVRT) and early to late peak filling velocity ratio (rE/A) derived from Doppler tissue imaging. Asynchrony of rIVRT was calculated. Doppler left ventricular filling indices were assessed using the isovolumetric relaxation time, the deceleration time of early diastolic filling (E-DT), and the E/A ratio. RESULTS There was a correlation between rWT and both rIVRT and rE/A in the two types of heart disease (hypertrophic cardiomyopathy: r = 0.47, p < 0.0001 for rIVRT; r = -0.20, p < 0.05 for rE/A; hypertensive heart disease: r = 0.21, p < 0.05 for rIVRT; r = -0.30, p = 0.003 for rE/A). The degree of left ventricular asymmetry was related to prolonged E-DT (r = 0. 50, p = 0.001) and increased asynchrony (r = 0.42, p = 0.002) in all patients combined, but not within individual groups. Asynchrony itself was associated with decreased E/A (r = -0.39, p = 0.01) and protracted E-DT (r = 0.69, p < 0.0001) and isovolumetric relaxation time (r = 0.51, p = 0.001) in all patients. These correlations were still significant for E-DT in hypertrophic cardiomyopathy (r = 0.56, p = 0.02) and hypertensive heart disease (r = 0.59, p < 0.05) and for isovolumetric relaxation time in non-obstructive hypertrophic cardiomyopathy (n = 8, r = 0.87, p = 0.005). CONCLUSIONS Non-invasive ultrasonographic examination of the left ventricle shows that in both hypertrophic cardiomyopathy and hypertensive heart disease, the local extent of left ventricular hypertrophy is associated with regional left ventricular relaxation abnormalities. Asymmetrical distribution of left ventricular hypertrophy is indirectly related to global left ventricular early filling abnormalities through regional asynchrony of left ventricular relaxation.

Serum Amyloid P-Component Prevents Cardiac Remodeling in Hypertensive Heart Disease

The potential for serum amyloid P-component (SAP) to prevent cardiac remodeling and identify worsening diastolic dysfunction (DD) was investigated. The anti-fibrotic potential of SAP was tested in an animal model of hypertensive heart disease (spontaneously hypertensive rats treated with SAP [SHR - SAP] × 12 weeks). Biomarker analysis included a prospective study of 60 patients with asymptomatic progressive DD. Compared with vehicle-treated Wistar-Kyoto rats (WKY-V), the vehicle-treated SHRs (SHR-V) exhibited significant increases in left ventricular mass, perivascular collagen, cardiomyocyte size, and macrophage infiltration. SAP administration was associated with significantly lower left ventricular mass (p < 0.01), perivascular collagen (p < 0.01), and cardiomyocyte size (p < 0.01). Macrophage infiltration was significantly attenuated in the SHR-SAP group. Biomarker analysis showed significant decreases in SAP concentration over time in patients with progressive DD (p < 0.05). Our results indicate that SAP prevents cardiac remodeling by inhibiting recruitment of pro-fibrotic macrophages and that depleted SAP levels identify patients with advancing DD suggesting a role for SAP therapy.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?

AIMS: Hypertension is one of the main drivers of the heart failure (HF) epidemic. The aims of this study were to profile fibro-inflammatory biomarkers across stages of the hypertensive heart disease (HHD) spectrum and to examine whether particular biochemical profiles in asymptomatic patients identify a higher risk of evolution to HF.

METHODS AND RESULTS: This was a cross-sectional observational study involving a population of 275 stable hypertensive patients divided into two different cohorts: Group 1, asymptomatic hypertension (AH) (n= 94); Group 2, HF with preserved ejection fraction (n= 181). Asymptomatic hypertension patients were further subdivided according to left atrial volume index ≥34 mL/m(2) (n= 30) and <34 mL/m(2) (n= 64). Study assays involved inflammatory markers [interleukin 6 (IL6), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP1), and tumour necrosis factor α], collagen 1 and 3 metabolic markers [carboxy-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 3 (PIIINP), and carboxy-terminal telopeptide of collagen 1 (CITP)], extra-cellular matrix turnover markers [matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinase 1 (TIMP1)], and the brain natriuretic peptide. Data were adjusted for age, sex, systolic blood pressure, and creatinine. Heart failure with preserved ejection fraction was associated with an increased inflammatory signal (IL6, IL8, and MCP1), an increased fibrotic signal (PIIINP and CITP), and an increased matrix turnover signal (MMP2 and MMP9). Alterations in MMP and TIMP enzymes were found to be significant indicators of greater degrees of asymptomatic left ventricular diastolic dysfunction.

CONCLUSION: These data define varying fibro-inflammatory profiles throughout different stages of HHD. In particular, the observations on MMP9 and TIMP1 raise the possibility of earlier detection of those at risk of evolution to HF which may help focus effective preventative strategies.

Cardiac Magnetic Resonance Assessment Of Interstitial Myocardial Fibrosis And Cardiomyocyte Hypertrophy In Hypertensive Mice Treated With Spironolactone.

Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR). Mice were randomized to l-nitro-ω-methyl ester (l-NAME, 3 mg/mL in water; n=22), or l-NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l-NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo-treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l-NAME (l-NAME+S) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43 ± 0.09 for l-NAME versus 0.25 ± 0.03 for l-NAME+S, P<0.001; τic: 0.42 ± 0.11 for l-NAME groups versus 0.12 ± 0.05 for l-NAME+S group). Mice treated with a combination of l-NAME and spironolactone were similar to placebo-treated controls at 7 weeks. Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure-overload, furthering our understanding of HF progression.

Unexpected Triggers for Pheochromocytoma-Induced Recurrent Heart Failure

Pheochromocytoma crisis typically presents as paroxysmal episodes of headache, tachycardia, diaphoresis or hypertension. We describe an uncommon case of recurrent non-hypertensive heart failure with systolic dysfunction in a young female due to pheochromocytoma compression. It presented as acute pulmonary oedema while straining during pregnancy and later on as cardiogenic shock after a recreational body massage. Such crisis occurring during pregnancy is rare. Moreover, of the few reported cases of pheochromocytoma-induced cardiogenic shock, recreational body massage has not yet been reported as a trigger for this condition.

Assessment of functional capacity through oxygen consumption in patients with asymptomatic probable heart disease

PURPOSE: To compare peak exercise oxygen consumption (VO2peak) of healthy individuals with asymptomatic individuals with probable heart disease. METHODS: Ninety-eight men were evaluated. They were divided into two groups: 1) 39 healthy individuals (group N) with an age range of 50±4.6 years; and 2) 59 asymptomatic individuals with signs of atherosclerotic and/or hypertensive heart disease (group C) with an age range of 51.9±10.4 years. In regard to age, height, body surface area, percentage of fat, lean body mass, and daily physical activity, both groups were statistically similar. Environmental conditions during the ergometric test were also controlled. RESULTS: Maximal aerobic power (watts), VO2peak, maximal heart rate, and maximal pulmonary ventilation were lower in group C (p<0.01) than in group N; weight, however, was lower in group N (p=0.031) than in group C. Differences in the respiratory gas exchange index, heart rate at rest, and the maximal double product of the two groups were not statistically significant. CONCLUSION: Signs of probable heart disease, even though asymptomatic, may reduce the functional capacity, perhaps due to the lower maximal cardiac output and/or muscle metabolic changes.

Left Ventricular Diastolic Function in Essential Hypertensive Patients: Influence of Age and Left Ventricular Geometry

PURPOSE - To evaluate diastolic dysfunction (DD) in essential hypertension and the influence of age and cardiac geometry on this parameter. METHODS - Four hundred sixty essential hypertensive patients (HT) underwent Doppler echocardiography to obtain E/A wave ratio (E/A), atrial deceleration time (ADT), and isovolumetric relaxation time (IRT). All patients were grouped according to cardiac geometric patterns (NG - normal geometry; CR - concentric remodeling; CH- concentric hypertrophy; EH - eccentric hypertrophy) and to age (<40; 40 - 60; >60 years). One hundred six normotensives (NT) persons were also evaluated. RESULTS - A worsening of diastolic function in the HT compared with the NT, including HT with NG (E/A: NT - 1.38±0.03 vs HT - 1.27±0.02, p<0.01), was observed. A higher prevalence of DD occurred parallel to age and cardiac geometry also in the prehypertrophic groups (CR). Multiple regression analysis identified age as the most important predictor of DD (r²=0.30, p<0.01). CONCLUSION - DD was prevalent in this hypertensive population, being highly affected by age and less by heart structural parameters. DD is observed in incipient stages of hypertensive heart disease, and thus its early detection may help in the risk stratification of hypertensive patients.

Coronary reserve impairment prevents the improvement of left ventricular dysfunction and adversely affects the long-term outcome of patients with hypertensive dilated cardiomyopathy

In hypertension, left ventricular (LV) hypertrophy develops as an adaptive mechanism to compensate for increased afterload and thus preserve systolic function. Associated structural changes such as microvascular disease might potentially interfere with this mechanism, producing pathological hypertrophy. A poorer outcome is expected to occur when LV function is put in jeopardy by impaired coronary reserve. The aim of this study was to evaluate the role of coronary reserve in the long-term outcome of patients with hypertensive dilated cardiomyopathy. Between 1996 and 2000, 45 patients, 30 of them male, with 52 +/- 11 years and LV fractional shortening <30% were enrolled and followed until 2006. Coronary flow velocity reserve was assessed by transesophageal Doppler of the left anterior descending coronary artery. Sixteen patients showed >= 10% improvement in LV fractional shortening after 17 +/- 6 months. Coronary reserve was the only variable independently related to this improvement. Total mortality was 38% in 10 years. The Cox model identified coronary reserve (hazard ratio = 0.814; 95% CI = 0.72-0.92), LV mass, low diastolic blood pressure, and male gender as independent predictors of mortality. In hypertensive dilated cardiomyopathy, coronary reserve impairment adversely affects survival, possibly by interfering with the improvement of LV dysfunction. J Am Soc Hypertens 2010;4(1):14-21. (C) 2010 American Society of Hypertension. All rights reserved.