From left ventricular hypertrophy to congestive heart failure: management of hypertensive heart disease

Other than age, left ventricular hypertrophy (LVH) is the most potent predictor of adverse cardiovascular outcomes in the hypertensive population, and is an independent risk factor for coronary heart disease, sudden death, heart failure and stroke. Although directly related to systolic blood pressure, other factors including age, sex, race, body mass index and stimulation of the renin-angiotensin-aldosterone and sympathetic nervous systems play an important role in the pathogenesis of LVH. LVH involves changes in myocardial tissue architecture consisting of perivascular and myocardial fibrosis and medial thickening of intramyocardial coronary arteries, in addition to myocyte hypertrophy. The physiologic alterations which occur as a result of these anatomical changes include disturbances of myocardial blood flow, the development of an arrhythmogenic myocardial substrate and diastolic dysfunction. The latter is directly related to the degree of myocardial fibrosis and is the hemodynamic hallmark of hypertensive heart disease. When diastolic dysfunction is present, left ventricular end-diastolic pressure increases out-of-proportion to volume and may be elevated at rest or with exertion leading to clinical heart failure. At least one third of heart failure patients in the United States can be considered to have heart failure related to diastolic dysfunction. Compared to heart failure patients with systolic dysfunction, diastolic heart failure patients are more likely to be older, female, and to be hypertensive at the time of presentation. Although it has been assumed that LVH may lead to systolic dysfunction, evidence is lacking that LVH resulting from hypertension is a major risk factor for systolic heart failure independent of coronary artery disease. Treatment of hypertension greatly attenuates the development of LVH and significantly decreases the incidence of heart failure. In patients with established LVH, regression is both possible and desirable and results in a significant reduction in adverse clinical endpoints.     

Chronic administration of adrenomedullin attenuates transition from left ventricular hypertrophy to heart failure in rats

Acute administration of adrenomedullin (AM) exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure (HF). However, chronic effects of AM administration on HF remain unknown. This study sought to examine the effect of chronic infusion of AM on progression of HF in rat. Human recombinant AM was administered by osmotic minipump for 7 weeks in the HF model of Dahl salt-sensitive rats. The effect was compared with vehicle and diuretic treatment group. Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight (P<0.01 for all). AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels (P<0.01 for all). AM also inhibited the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide (P<0.01 for all). These changes were associated with the improvement of cardiac output and systemic vascular resistance (both P<0.05). Furthermore, AM improved left ventricular end-systolic elastance (P<0.01). These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with diuretic (P<0.05) and vehicle (P<0.01) treatment groups. These results suggest that endogenous AM plays a compensatory role in HF and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.     

Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats

OBJECTIVES: We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling. BACKGROUND: Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated. METHODS: In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities. RESULTS: No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo. CONCLUSIONS: Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.     

Hydrogen gas improves left ventricular hypertrophy in Dahl rat of salt-sensitive hypertension

Purpose: Hypertension is an important risk factor for death resulting from stroke, myocardial infarction, and end-stage renal failure. Hydrogen (H₂) gas protects against many diseases, including ischemia-reperfusion injury and stroke. The effects of H₂ on hypertension and its related left ventricular (LV) function have not been fully elucidated. The purpose of this study was to investigate the effects of H₂ gas on hypertension and LV hypertrophy using echocardiography.

Methods: Dahl salt-sensitive (DS) rats were randomly divided into three groups: those fed an 8% NaCl diet until 12 weeks of age (8% NaCl group), those additionally treated with 2% H₂ gas (8% NaCl + 2% H₂ group), and control rats maintained on a diet containing 0.3% NaCl until 12 weeks of age (0.3% NaCl group). H₂ gas was supplied through a gas flowmeter and delivered by room air (2% hydrogenated room air, flow rate of 10 L/min) into a cage surrounded by an acrylic chamber. We evaluated interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), and LV mass using echocardiography.

Results: IVST, LVPWT, and LV mass were significantly higher in the 8% NaCl group than the 0.3% NaCl group at 12 weeks of age, whereas they were significantly lower in the 8% NaCl + 2% H₂ group than the 8% NaCl group. There was no significant difference in systolic blood pressure between the two groups.

Conclusion: Our findings suggest that chronic H₂ gas inhalation may help prevent LV hypertrophy in hypertensive DS rats.     

Differential induction of protein kinase C isoforms at the cardiac hypertrophy stage and congestive heart failure stage in Dahl salt-sensitive rats.

Several protein kinase C (PKC) isoforms may play important roles in cellular signaling pathways. Recent reports have suggested that PKC plays critical isoform-specific roles in the development of cardiac hypertrophy and heart failure. The purpose of the present study was to examine the expression profiles of PKC isoforms in models of cardiac hypertrophy and heart failure. We examined the cardiac expression of individual PKC isoforms at the cardiac hypertrophy stage and the heart failure stage in Dahl salt-sensitive rats by Western blot analysis. The levels of all PKC isoforms increased at the cardiac hypertrophy stage and the heart failure stage, but the pattern of increase differed among PKC isoforms at the heart failure stage. The expressions of PKCalpha, beta, and delta increased at the cardiac hypertrophy stage and remained elevated at the heart failure stage. On the other hand, the expression of PKCepsilon and atypical PKCs (aPKCs) increased at the cardiac hypertrophy stage, but this increase tended to decline at the congestive heart failure stage. These results suggest that there are two groups of PKC isoforms. Several reports have shown that PKCalpha, beta, and delta are involved in the development of cardiac hypertrophy and heart failure, and that PKCepsilon plays a role in the physiological hypertrophic responses and cardioprotective actions. These facts suggest that all PKC isoforms (PKCalpha, beta, delta, epsilon, and aPKCs) expressed in the heart may have similar functions at the cardiac hypertrophy stage, but that two groups of PKC isoforms (PKCalpha, beta, delta, and PKCepsilon, aPKCs) have different functions at the congestive heart failure stage.     

Contribution of reactive oxygen species to the pathogenesis of left ventricular failure in Dahl salt-sensitive hypertensive rats: effects of angiotensin II blockade

OBJECTIVE: We investigated the contribution of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) generation to the pathogenesis of diastolic heart failure (DHF) in Dahl salt-sensitive (DS) hypertensive rats, with the aim of testing our hypothesis that the cardioprotective effects of angiotensin II (Ang II) blockade are provided by the suppression of this pathway. METHODS: DS rats were maintained on high (H: 8.0% NaCl) or low (L: 0.3% NaCl) salt diets from age 7 to 17 weeks. DS/H rats were also treated with candesartan cilexetil (10 mg/kg per day, orally) or a superoxide dismutase mimetic, tempol (3 mmol/l in drinking water) from age 7 to 17 weeks. RESULTS: DS/H rats represented hypertension, left ventricular (LV) relaxation abnormality and myocardial stiffening with preserved systolic heart function. As compared with DS/L rats, DS/H rats showed higher levels of transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF), p22phox and gp91phox mRNA expression, NADPH oxidase activity and thiobarbituric acid-reactive substance (TBARS) contents in LV tissues. Gene expression of uncoupling protein-2 (UCP-2), an inner mitochondrial membrane proton transporter, was also 2.8 +/- 0.5-fold higher. In DS/H rats, treatment with candesartan did not alter blood pressure, but resulted in a marked improvement of the hemodynamic deterioration; these therapeutic effects were accompanied by decreases in myocardial NADPH oxidase activity, TBARS contents and the expression of TGF-beta, CTGF, p22phox, gp91phox and UCP-2. Similar therapeutic effects were provided by treatment with tempol in DS/H rats. CONCLUSIONS: Our data suggest that NADPH oxidase-mediated ROS production contributes to the pathogenesis of DHF in DS hypertensive rats, and that the cardioprotective effects of AngII blockade are, at least partially, mediated through the suppression of this pathway.     

Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats

OBJECTIVE: There are two phenotypes of heart failure, systolic failure and isolated diastolic heart failure with preserved left ventricular systolic function. Although isolated diastolic heart failure frequently occurs, there are only models for diastolic dysfunction unassociated with heart failure and models with overt diastolic heart failure have not been established. We attempted to develop two different models, i.e. diastolic and systolic failure models, based on hypertension. MATERIALS AND METHODS: Dahl salt-sensitive rats were placed on 8% NaCl diet from 7 weeks old (7-week starting group) or 8 weeks old (8-week starting group). As an age-matched control, Dahl salt-sensitive rats were consistently placed on normal chow. In these rats, echocardiogram was serially recorded, followed by hemodynamic and histological studies. RESULTS: The 7-week starting rats showed a steep elevation in blood pressure and progressive left ventricular hypertrophy, and fell into overt heart failure at approximately 19 weeks. The development of heart failure was not associated with a decrease in left ventricular midwall fractional shortening or an increase in left ventricular end-diastolic dimension as compared with the age-matched control, which mimics the characteristics of clinically observed isolated diastolic heart failure. The 8-week starting rats showed a gradual rise in blood pressure and less progressive left ventricular hypertrophy, and fell into heart failure at approximately 26 weeks with a decrease in mid-wall fractional shortening and an increase in left ventricular end-diastolic dimension. Hemodynamic and histological studies at failing stage revealed comparable elevation of left ventricular end-diastolic pressure and comparable left ventricular fibrosis in both groups. CONCLUSION: These two different models of overt heart failure may be useful as models of isolated diastolic heart failure and systolic heart failure based on the same hypertensive heart disease, respectively, and may contribute to discrimination of the mechanisms of the development of the two different phenotypes of heart failure.     

Reduction of development of left ventricular hypertrophy in salt-loaded Dahl salt-sensitive rats by angiotensin II receptor inhibition

To determine the effect of the angiotensin II AT₁ receptor antagonist losartan (DuP753) on echocardiographic left ventricular (LV) anatomy in Dahl rats on high sodium diet, 27 Dahl salt-sensitive (Dahl-S, 13 on drug and 14 receiving tap water) and 27 Dahl salt-resistant rats (Dahl-R, 13 on drug and 14 receiving tap water) were studied by M-mode echocardiography during 8 weeks of 8% NaCl diet. At the endpoint (after 8 weeks or the last echocardiogram for animals who died earlier), Dahl-S receiving losartan had lower LV mass (1.6 ± 0.4 g/kg^0.59) than Dahl-S receiving tap water (2.2 ± 0.7 g/kg^0.59; P < .005), although blood pressure was only partially reduced (167 ± 29 v 195 ± 52; P = .05). This difference was mainly due to lower LV wall thickness (P < .02), with a less consistent decrease in LV chamber size in Dahl-S receiving losartan. Blood pressure was normal in Dahl-R (tap water group = 116 ± 11 mm Hg; losartan group = 115 ± 13 mm Hg) and losartan had no effect on LV mass (1.6 ± 0.4 g/kg^0.59 in both groups). In the majority of rats, echocardiographic measurements were compared between the end of second or third week and the last available study: LV mass increased in salt-loaded Dahl-S receiving tap water (1.6 ± 0.6 to 2.1 ± 0.7 g/kg^0.59, P < .04) and was stable in Dahl-S receiving losartan (1.5 ± 0.1 to 1.5 ± 0.3 g/kg^0.59), paralleling changes in LV chamber dimension. Thus, a high salt diet leads to hypertension and eccentric LV hypertrophy in Dahl-S but not in Dahl-R. Inhibition of angiotensin II AT₁ receptors reduces the development of LV hypertrophy in Dahl-S rats despite lack of efficient control of blood pressure.     

Usefulness of plasma cardiotrophin-1 in assessment of left ventricular hypertrophy regression in hypertensive patients

OBJECTIVE: We investigated whether regression of left ventricular hypertrophy (LVH) in response to antihypertensive treatment is associated with plasma cardiotrophin-1 (CT-1) in hypertensive patients. METHODS: The study was performed in 47 patients with mild to moderate essential hypertension, and LVH was assessed echocardiographically. The family doctor gave antihypertensive treatment and followed all patients. LVH regression was diagnosed if the baseline left ventricular mass index (LVMI) decreased to normal values after 1 year of treatment. Plasma CT-1 was determined by an enzyme-linked immunosorbent assay. RESULTS: The LVMI was normalized in 23 patients (49%) and persisted at an abnormally increased level in 24 patients (51%) after 1 year of treatment, whereas the reduction in clinic and home blood pressure was similar in the two groups: CT-1 decreased (-48%, P < 0.005) and increased (+35%, P < 0.05) in patients in whom LVH regressed and LVH persisted, respectively. Final values of CT-1 were inversely correlated (r = 0.534, P < 0.001) with the decrease in LVMI after treatment in all patients. A significant association (chi2 = 16.87, P < 0.001) was found between normalization of CT-1 and regression of LVH with treatment. A cut-off value of 41 fmol/ml for CT-1 provided a relative risk of 43.13 (95% confidence interval, 4.88-380.48) for detecting LVH regression. CONCLUSION: These results show an association between treatment-induced decrease of plasma CT-1 and LVH regression in essential hypertension. Although preliminary, these findings suggest that the determination of plasma CT-1 may be useful for the follow-up of hypertensive heart disease in routine clinical practice.     

Comprehensive analyses of arrhythmogenic substrates and vulnerability to ventricular tachycardia in left ventricular hypertrophy in salt-sensitive hypertensive rats.

BACKGROUND: The contribution of conduction disturbances to susceptibility to ventricular tachycardia (VT) has not been directly examined in the process of left ventricular hypertrophy (LVH). METHODS AND RESULTS: Dahl salt-sensitive (S) and -resistant rats were raised on a high-salt diet. After echocardiography, a fractionation study was conducted using wavelet transform analysis, which reflects conduction disturbances, recording of monophasic action potential (MAP), measurement of conduction velocity, and programmed extrastimuli for the induction of VT, as well as patch-clamp analysis at 10, 13 and 16 weeks (W) (n=7, each). Systolic blood pressure, wall thickness and MAP duration significantly increased at 10W in S rats, whereas conduction velocity decreased and MAP duration and the power of wavelet transform increased at 13W and 16W. Paired extrastimuli induced polymorphic VT only at 13W and 16W in S rats. VT frequency correlated inversely with conduction velocity and positively with MAP duration. Power of wavelet transform correlated negatively with conduction velocity and positively with VT vulnerability. The patch-clamp study revealed that the action potential duration significantly increased in S rats with aging, and correlated with MAP duration. CONCLUSIONS: Latently progressing slow and inhomogeneous conduction, as well as a repolarization abnormality, may contribute to VT vulnerability in hypertensive LVH.     

Transition from asymptomatic left ventricular dysfunction to congestive heart failure

One of the main goals of modern management and care of heart failure is to prevent the disease to progress toward congestion and death. The achievement of such an objective may, in fact, guarantee a sufficient quality of life and reduce the exposure of patients to the most common life-threatening complications associated with the congestive stage of the disease. Early identification of left ventricular dysfunction as well as a better knowledge of the mechanisms that favor the progression to more advanced stages of heart failure are fundamental requirements for the proper treatment of asymptomatic heart failure and for preventing the transition to symptomatic and more severe heart failure. The authors reviewed the literature on this topic, with emphasis on a series of studies they performed, to characterize the pathophysiologic profile of mild heart failure and the mechanisms that are possibly involved in the progression to congestive heart failure.     

Noninvasive assessment of left ventricular wall stress in chronic congestive heart failure patients

Therapy with prazosin can improve the condition of patients with congestive heart failure due to its vasodilating action. Therefore nine patients with volume overloaded left ventricles due to aortic insufficiency and mitral insufficiency received 1 mg. of prazosin four times a day for two weeks. Peak and end-systolic wall stress were estimated using a noninvasive echocardiographic technique. The peak systolic wall stress in this group was 155 x 10(3) dynes/cm2 which is similar to the reported normal value. However, the end systolic wall stress was 101 x 10(3) dynes/cm2 which is much higher than the reported normal values. Following the administration of oral prazosin, the end systolic stress was normalized while the peak systolic stress was reduced below normal. As a result of therapy with prazosin, the ejection fraction, the percentage of change in the minor axis, and the velocity of circumferential fiber shortening significantly increased. Thus, the oral administration of prazosin can improve left ventricular function in patients with mitral insufficiency and aortic insufficiency.     

Temporal regulation of extracellular matrix components in transition from compensatory hypertrophy to decompensatory heart failure

OBJECTIVE: Extracellular matrix, particularly type I fibrillar collagen, provides tensile strength that allows cardiac muscle to perform systolic and diastolic functions. Collagen is induced during the transition from compensatory hypertrophy to heart failure. We hypothesized that cardiac stiffness during decompensatory hypertrophy is partly due to a decreased elastin:collagen ratio. MATERIALS AND METHODS: We prepared left ventricular tissue homogenates from spontaneously hypertensive rats (SHR) aged 30-36 weeks, which had compensatory hypertrophy with no heart failure, and from SHR aged 70-92 weeks, which had decompensatory hypertrophy with heart failure. Age- and sex-matched Wistar-Kyoto (WKY) rats were used as normotensive controls. In both SHR groups, increased levels of collagen were detected by immuno-blot analysis using type I collagen antibody. Elastin and collagen were quantitated by measuring desmosine/isodesmosine and hydroxyproline spectrophometrically, respectively. To determine whether the decrease in elastin content was due to increased elastinolytic activity of matrix metalloproteinase-2, we performed gelatin and elastin zymography on left ventricular tissue homogenates from control rats, SHR with compensatory hypertrophy and SHR with heart failure. RESULTS: The elastin:collagen ratio was 0.242 +/- 0.008 in hearts from WKY rats. In SHR without heart failure, the ratio was decreased to 0.073 +/- 0.003 and in decompensatory hypertrophy with heart failure, the ratio decreased to 0.012 +/- 0.005. Matrix metalloproteinase-2 activity was increased significantly in SHR with heart failure compared with controls (P < 0.001). The level of tissue inhibitor of metalloproteinase-4 was increased in compensatory hypertrophy and markedly reduced in heart failure. Decorin was strongly reduced in decompensatory heart failure compared with control hearts. CONCLUSIONS: Since collagen was induced in SHR with heart failure, decorin and elastin were decreased and the ratios of gelatinase A and elastase to tissue inhibitor of metalloproteinase-4 were increased, we conclude that heart failure is associated with adverse extracellular matrix remodeling.     

Enhanced myocardial vitamin C accumulation in left ventricular hypertrophy in rats is not attenuated with transition to heart failure

Indirect observations are compatible with cardiac vitamin C deficiency as one contributory factor to oxidative stress in heart failure, but data on ventricular vitamin C content are lacking. Here, we used the well established model of aortic-banded rats at the stage of compensated hypertrophy (6 weeks after banding) and at the transition to cardiac failure (22 weeks after banding) to analyze vitamin C, vitamin E, protein carbonyls and malondialdehyde tissue content together with the respective plasma concentrations. Furthermore, we investigated the expression of the vitamin C transporters SVCT1 and SVCT2 in the left ventricle (LV). Aortic-banded rats, independently from their age, had higher malondialdehyde and protein carbonyl levels in plasma and LV tissue compared to sham-operated animals indicating increased oxidative stress. Plasma vitamin C remained unaffected from cardiac overload, while LV vitamin C was elevated in both stages of hypertrophy together with an increased expression of the vitamin C transporter SVCT2 suggesting increased vitamin C uptake. The levels of antioxidants and lipid peroxides were similar 6 and 22 weeks after aortic banding. Therefore, the accumulation of vitamin C in compensated hypertrophy and in decompensated failure excludes cardiac vitamin C deficiency as a primary factor to oxidative stress in this model.