Dysfunction In Hypertensive Heart Disease Research Articles

Choline induced cardiac dysfunction by inhibiting the production of endogenous hydrogen sulfide in spontaneously hypertensive rats

To investigate the exact effects of dietary choline on hypertensive heart disease (HHD) and explore the potential mechanisms, male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into five groups as follows: WKY group, WKY + Choline group, SHR group, SHR + Choline group, and SHR + Choline + NaHS group. In choline treatment groups, rats were fed with 1.3% (w/v) choline in the drinking water for 3 months. The rats in the SHR + Choline + NaHS group were intraperitoneally injected with NaHS (100 μmol/kg/day, a hydrogen sulfide (H2S) donor) for 3 months. After 3 months, left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), the indicators of cardiac function measured by echocardiography, were increased significantly in SHR as compared to WKY, although there was no significant difference in collagen volumes and Bax/Bcl-2 ratio between the two groups, indicating the early stage of cardiac hypertrophy. There was a significant decrease in LVEF and LVFS and an increase in collagen volumes and Bax/Bcl-2 ratio in SHR fed with choline, meanwhile, plasma H2S levels were significantly decreased significantly in SHR fed with choline accompanying by the decrease of cystathionine-γ-lyase (CSE) activity. Three months of NaHS significantly increased plasma H2S levels, ameliorated cardiac dysfunction and inhibited cardiac fibrosis and apoptosis in SHR fed with choline. In conclusion, choline aggravated cardiac dysfunction in HHD through inhibiting the production of endogenous H2S, which was reversed by supplementation of exogenous H2S donor.

Correlation between Left Ventricular Hypertrophy with Strain Pattern Electrocardiography and Left Ventricular Diastolic Dysfunction in Hypertensive Heart Disease

Correlation between Left Ventricular Hypertrophy with Strain Pattern Electrocardiography and Left Ventricular Diastolic Dysfunction in Hypertensive Heart Disease

Cardioprotective mechanisms of lifestyle modifications and pharmacotherapies on cardiac remodeling and dysfunction in hypertensive heart disease: an overview.

The incidence of cardiovascular events in hypertensive patients is clearly related to a left ventricular mass during treatment, and a regression of left ventricular hypertrophy is associated with a better prognosis. This is the case even independently of changes in other risk factors, including blood pressure. Evidence indicates that lifestyle modifications such as dietary salt restriction and weight loss are effective means in preventing the development of hypertension and reducing blood pressure and left ventricular mass in hypertensive patients. Salt restriction may also reduce the long-term risk of cardiovascular events. It has been recognized that the primary targets of current antihypertensive drugs are the renin-angiotensin-aldosterone system, calcium homeostasis, the ionic transport mechanisms in the kidneys, and the sympathetic nervous system. Clinical as well as experimental studies have demonstrated the cardioprotective effects of antihypertensive drugs independently of their blood pressure lowering effects. Hypertension is often complicated by other disease states including diabetes, dyslipidemia, and ischemic heart disease. Some of the drugs used for the treatment of such complications are also shown to produce cardioprotective effects in addition to their original effects. We ought to better understand these pleiotropic effects for the most effective treatments of hypertension and its complications.

Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Diabetes mellitus (DM) is a major risk factor for heart failure, independent of coronary artery disease or hypertension (HT). Therefore, our study was designed to examine the mechanisms of DM-induced left ventricular (LV) diastolic dysfunction. In this study, we made five different 10-week treatment groups of Dahl salt-sensitive rats as follows: Control; a low-salt (0.5% NaCl) diet, HT; a high-salt (5% NaCl) diet, DM; a low-salt diet with streptozotocin (STZ) injection (30 mg kg(-1) i.p.), HT+DM; a high-salt diet with STZ injection, and the Olmesartan group; a high-salt diet with STZ treated with an angiotensin receptor blocker, olmesartan (1 mg kg(-1) day(-1)). Cardiac diastolic dysfunction with a preserved systolic function was noted in the HT group, and was most prominently noted in the HT+DM group, characterized by enhanced cardiac fibrosis, whereas the extent of HT and myocardial hypertrophy was comparable between the two groups. Myocardial expressions of collagen III, transforming growth factor-beta2, angiotensin-converting enzyme (ACE), angiotensin II type-1 receptor and myocardial oxidative stress (evaluated by 4-hydroxy-2-nonenal-modified protein) were mostly enhanced in the HT+DM group. Importantly, there was a positive correlation between the extent of diastolic dysfunction and that of myocardial ACE expression. All these cardiac abnormalities induced by DM and HT were ameliorated in the olmesartan group. These results indicate that DM accelerates diastolic dysfunction in hypertensive heart disease through activation of the renin-angiotensin system, with subsequent inflammatory and oxidative stresses and myocardial fibrosis, suggesting that an inhibition of the system is effective for the treatment of diastolic dysfunction in this combined disorder.

Analysis of Left Ventricular Systolic Function Using Midwall Mechanics in Patients >60 Years of Age With Hypertensive Heart Disease and Heart Failure

Normal ejection fraction (EFs) is often equated with normal systolic function. However, midwall mechanics reveal systolic dysfunction in hypertensive heart disease accompanied by hypertrophic remodeling. Midwall mechanics are unstudied in patients with acute diastolic heart failure (HF). This study analyzed left ventricular (LV) midwall stress-shortening relations in 61 patients aged >60 years with hypertensive heart disease, HF, and normal EF. Sixty-one hypertensive patients (mean age 78 +/- 10 years) who presented with HF, each with an EF >50%, underwent echocardiography. Midwall mechanics were compared with those of 79 controls (mean age 75 +/- 8 years) without structural heart disease. Relative wall thickness (0.63 +/- 0.11 vs 0.46 +/- 0.10 mm) and LV mass (237 +/- 67 vs 177 +/- 57 g) were significantly greater in patients with HF compared with controls. Mean EFs were similar in patients with HF and controls (64 +/- 9% vs 67 +/- 9%). Although mean endocardial fractional shortening (35 +/- 7% vs 37 +/- 7%) was not significantly different, midwall shortening in patients with HF was significantly less compared with controls (16 +/- 2% vs 19 +/- 3%, p <0.05). Eighteen of the 61 patients with HF (30%) had midwall shortening that was <95% confidence intervals of the normal midwall stress-shortening relations. By this criterion, these patients had systolic dysfunction despite normal EF; they had smaller LV chambers (in dimension and volume), greater relative wall thickness, and smaller stroke volumes. In conclusion, almost 1/3 of patients hospitalized with diastolic HF had systolic dysfunction, characterized by abnormal midwall stress-shortening relations.

Diastolic Dysfunction in Hypertensive Hearts: Roles of Perivascular Inflammation and Reactive Myocardial Fibrosis

There is increasing evidence that myocardial fibrosis plays a role in the pathogenesis of diastolic dysfunction in hypertensive heart disease. However, it has been difficult to explore the mechanisms of isolated diastolic dysfunction in hypertensive hearts because of the lack of adequate animal models. Recently, we demonstrated that Wistar rats with a suprarenal aortic constriction (AC) can be used as a model of cardiac hypertrophy associated with preserved systolic, but impaired diastolic function without overt congestive heart failure. In this model, acute pressure elevation induces reactive myocardial fibrosis (perivascular fibrosis followed by intermuscular interstitial fibrosis) and myocyte/left ventricular (LV) hypertrophy. Perivascular macrophage infiltration, which is mediated by monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1, exerts a key role in myocardial fibrosis, but not in myocyte/LV hypertrophy. Transforming growth factor (TGF)-beta is crucial for reactive fibrosis in AC rats. MCP-1 function blocking not only inhibits macrophage infiltration and TGF-beta induction but also prevents reactive fibrosis and diastolic dysfunction, without affecting blood pressure, myocyte/LV hypertrophy, or systolic function. Accordingly, a substantial role of inflammation is indicated in myocardial fibrosis and diastolic dysfunction in hypertensive hearts. Currently, the precise mechanisms whereby acute pressure elevation triggers inflammation remain unknown, but it is likely that activation of the tissue angiotensin system is involved in the induction of the inflammatory process.

Myocardial fibrosis and diastolic dysfunction in deoxycorticosterone acetate-salt hypertensive rats is ameliorated by the peroxisome proliferator-activated receptor-alpha activator fenofibrate, partly by suppressing inflammatory responses associated with the nuclear factor-kappa-b pathway

ObjectivesWe sought to clarify that a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activator inhibits myocardial fibrosis and its resultant diastolic dysfunction in hypertensive heart disease, as well as to investigate whether inflammatory mediators through the nuclear factor (NF)-kappa-B pathway are involved in the effects. BackgroundPatients with hypertensive heart disease often have diastolic heart failure without systolic dysfunction. Meanwhile, it has been well established in atherosclerosis that PPAR-alpha activation negatively regulates early inflammation. In hypertensive hearts, however, it is still unclear whether PPAR-alpha activation inhibits inflammation and fibrosis. MethodsTwenty-one rats were randomly separated into the following three groups: deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with a PPAR-alpha activator, fenofibrate (80 mg/kg/day for 5 weeks); DOCA-salt rats treated with vehicle only; and uni-nephrectomized rats as normotensive controls. ResultsFenofibrate significantly inhibited the elevation of left ventricular end-diastolic pressure and the reduction of the magnitude of the negative maximum rate of left ventricular pressure rise and decline, corrected by left ventricular pressure (−dP/dtmax/P), which are indicators of diastolic dysfunction. Next, fenofibrate prevented myocardial fibrosis and reduced the hydroxyproline content and procollagen I and III messenger ribonucleic acid expression. Finally, inflammatory gene expression associated with NF-kappa-B (interleukin-6, cyclooxygenase-2, vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1), which is upregulated in DOCA-salt rats, was significantly suppressed by fenofibrate. Activation of NF-kappa-B and expression of I-kappa-B-alpha in DOCA-salt rats were normalized by fenofibrate. ConclusionsA PPAR-alpha activator reduced myocardial fibrosis and prevented the development of diastolic dysfunction in DOCA-salt rats. The effects of a PPAR-alpha activator may be mediated partly by prevention of inflammatory mediators through the NF-kappa-B pathway. These results suggest that treatment with PPAR-alpha activators will improve diastolic dysfunction in hypertensive heart disease.

Assessment of global and regional left ventricular diastolic function in hypertensive heart disease using automated border detection techniques.

Acoustic quantification (AQ) and color kinesis (CK) are techniques that involve automated detection and tracking of endocardial borders. These methods are useful for the evaluation of global and regional left ventricular (LV) systolic function and more recently have been applied to evaluating LV diastolic performance. Assessment of diastolic dysfunction in hypertensive heart disease is a relevant clinical issue in which these techniques have proven useful. The diastolic portion of left atrium and LV AQ area waveforms are frequently abnormal in patients with left ventricular hypertrophy (LVH). Left ventricular AQ curves consistently demonstrate reduced rapid filling fraction (RFF) and peak rapid filling rate (PRFR), elevated atrial filling fraction (AFF), peak atrial filling rate (PAFR), and reductions in the ratio PRFR/PAFR. Acoustic quantification complements traditional Doppler echocardiographic evaluation of global diastolic function. Many patients with significant LVH and normal Doppler diastolic parameters can be identified as having diastolic dysfunction with AQ. In addition, CK has allowed the evaluation of regional diastolic performance in hypertensive patients. Regional filling curves obtained from CK have demonstrated that endocardial diastolic motion is commonly delayed and heterogeneous in patients with LVH.

Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism.

Hypertension is an important clinical problem and is often accompanied by left ventricular (LV) hypertrophy and dysfunction. Whether the myocardial high-energy phosphate (HEP) metabolism is altered in human hypertensive heart disease and whether this is associated with LV dysfunction is not known. Eleven patients with hypertension and 13 age-matched healthy subjects were studied with magnetic resonance imaging at rest and with phosphorus-31 magnetic resonance spectroscopy at rest and during high-dose atropine-dobutamine stress. Hypertensive patients showed higher LV mass (98+/-28 g/m2) than healthy control subjects (73+/-13 g/m2, P<0.01). LV filling was impaired in patients, reflected by a decreased peak rate of wall thinning (PRWThn), E/A ratio, early peak filling rate, and early deceleration peak (all P<0. 05), whereas systolic function was still normal. The myocardial phosphocreatine (PCr)/ATP ratio determined in patients at rest (1. 20+/-0.18) and during stress (0.95+/-0.25) was lower than corresponding values obtained from healthy control subjects at rest (1.39+/-0.17, P<0.05) and during stress (1.16+/-0.18, P<0.05). The PCr/ATP ratio correlated significantly with PRWThn (r=-0.55, P<0.01), early deceleration peak (r=-0.56, P<0.01), and with the rate-pressure product (r=-0.53, P<0.001). Myocardial HEP metabolism is altered in patients with hypertensive heart disease. In addition, there is an association between impaired LV diastolic function and altered myocardial HEP metabolism in humans. The level of myocardial PCr/ATP is most likely determined by the level of cardiac work load.

Treatment and post-treatment effects of α- versus β-receptor blockers on left ventricular structure and function in essential hypertension

This study was undertaken to compare the effects of α-receptor blockade and β-receptor blockade on left ventricular structure and function in essential hypertension. The increase in left ventricular mass in patients with essential hypertension is at least partly induced by the sympathetic nervous system. We conducted a double-blind, randomized, controlled clinical trial to compare the effects of α-blockers and β-blockers on left ventricular structure and function. Forty-three patients with mild to moderate essential hypertension were randomly allocated to receive antihypertensive therapy with either the α-blocker bunazosin ( n = 23) or the β-blocker metoprolol ( n = 20). Twenty-four—hour blood pressure measurements and echocardiographic measurements of left ventricular structure and function were performed before therapy, after 6 months of therapy, and 4 weeks after discontinuation of therapy. Bunazosin and metoprolol led to similar reductions in systolic/diastolic blood pressure ( −11 ± 11 −9 ± 8 mm Hg vs −11 ± 12 −8 ± 9 mm Hg , respectively) and left ventricular mass (−25 ± 42 gm vs −28 ± 44 gm, respectively) ( p = no significant difference, bunazosin vs metoprolol). Neither metoprolol nor bunazosin significantly affected left ventricular systolic function. Diastolic left ventricular filling, however, was increased with β-blocker medication, as indicated by a decrease in atrial filling fraction (39% ± 5% to 34% ± 5%; p < 0.05), but not with the α-blocker. The effect of metoprolol resulted from its bradycardiac effect. Four weeks after discontinuation of therapy, blood pressure and left ventricular mass increased to pretreatment levels in both groups similarly. Furthermore, the increase in diastolic filling was lost shortly after withdrawal of metoprolol concomitant with the increase in heart rate. We conclude that α-blockers and β-blockers are equally capable of reducing left ventricular mass in hypertensive patients. β-Blockers lead to an increase in diastolic left ventricular filling. This effect may be of therapeutic value because diastolic dysfunction may precede systolic dysfunction in hypertensive heart disease.

Transthoracic Doppler Assessment of Pattern of Left Ventricular Dysfunction in Hypertensive Heart Disease: Combined Analysis of Mitral and Pulmonary Venous Flow Velocity Patterns

Transthoracic Doppler Assessment of Pattern of Left Ventricular Dysfunction in Hypertensive Heart Disease: Combined Analysis of Mitral and Pulmonary Venous Flow Velocity Patterns

Transthoracic Doppler assessment of pattern of left ventricular dysfunction in hypertensive heart disease: combined analysis of mitral and pulmonary venous flow velocity patterns.

Although mitral flow velocity pattern changes with the progression of left ventricular (LV) diastolic dysfunction, it lacks predictive value in individual patients because of pseudonormalization in the presence of congestive heart failure and many physiologic and pathologic contributors to the mitral flow velocity pattern. To determine whether analysis of pulmonary venous flow velocity patterns complements the information obtainable from the mitral flow velocity patterns in the evaluation of patterns of LV dysfunction of hypertensive heart disease in individual patients, the ratio of the peak early diastolic filling velocity/peak filling velocity at atrial contraction (E/A ratio) in the mitral flow velocity pattern and the ratio of the peak systolic forward flow velocity (S)/peak diastolic forward flow velocity (D) (S/D ratio) in the pulmonary venous flow velocity pattern by the transthoracic approach were determined in 107 hypertensive patients with and without congestive heart failure. Age-related normal values of the E/A and S/D ratios were determined in 61 normal subjects and used to judge the normality or abnormality of the patterns. Results of the study indicate that (1) although an increased mitral E/A ratio is strongly indicative of heart failure with normal LV systolic function, the mitral E/A ratio is frequently within the normal range in hypertensive patients with heart failure; (2) association of decreased pulmonary venous S/D ratios with a normal mitral flow velocity pattern indicates the presence of heart failure as a result of LV systolic dysfunction that is usually observed at the most advanced pattern of LV dysfunction; (3) mild LV diastolic dysfunction is likely to exist in patients with normal E/A ratios if the pulmonary venous S/D ratio is higher than normal value; (4) predictive accuracy in the detection of LV systolic and diastolic dysfunction would be improved if both mitral and pulmonary venous flow velocity patterns rather than the mitral flow velocity pattern alone were analyzed. In conclusion, analysis of pulmonary venous flow velocity recordings improves accuracy and reliability of the Doppler assessment of LV systolic and diastolic dysfunction, particularly in individual hypertensive patients with normal mitral flow velocity patterns.

Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation

The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.

Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy.

In genetic and acquired hypertension, a structural remodeling of the nonmyocyte compartment of the myocardium, including the accumulation of fibrillar collagen within the interstitium and adventitia of intramyocardial coronary arteries and a medial thickening of these vessels, represents a determinant of pathological hypertrophy that leads to ventricular dysfunction. To evaluate the benefit of angiotensin converting enzyme inhibition in reversing this interstitial and vascular remodeling in the rat with genetic spontaneous hypertension (SHR) and established left ventricular hypertrophy (LVH), we treated 14-week-old male SHR with oral lisinopril (average dose, 15 mg/kg/day) for 12 weeks. Myocardial stiffness and coronary vascular reserve to adenosine (800 micrograms/min) were examined in the isolated heart; myocardial collagen and intramural coronary artery architecture were analyzed morphometrically. In lisinopril-treated SHR compared with 14-week-old baseline or 26-week-old untreated SHR and age- and sex-matched Wistar-Kyoto (WKY) controls, we found 1) a regression in LVH and normalization of blood pressure, 2) a complete regression of interstitial fibrosis, represented by a decrease of interstitial collagen volume fraction from 7.0 +/- 1.3% to 3.2 +/- 0.3% (p less than 0.025; WKY, 2.8 +/- 0.5%), 3) normalization of myocardial stiffness constant from 19.5 +/- 0.9 to 13.7 +/- 1.3 (p less than 0.025; WKY, 13.8 +/- 2.2), 4) a reversal of intramural coronary artery remodeling, including a decrease in the ratio of perivascular fibrosis to vessel lumen size from 1.4 +/- 0.2 to 0.4 +/- 0.1 (p less than 0.025; WKY, 0.6 +/- 0.1) and medial thickening from 12.3 +/- 0.6 to 7.4 +/- 0.5 microns (p less than 0.005; WKY, 7.4 +/- 0.4 microns), and 4) a restoration of coronary vasodilator response to adenosine from 12.3 +/- 0.9 to 26.0 +/- 1.4 ml/min/g (p less than 0.005; WKY, 21.8 +/- 2.2 ml/min/g). Thus, in SHR with LVH and adverse structural remodeling of the cardiac interstitium, lisinopril reversed fibrous tissue accumulation and medial thickening of intramyocardial coronary arteries and restored myocardial stiffness and coronary vascular reserve to normal. These cardioreparative properties of angiotensin converting enzyme inhibition may be valuable in reversing left ventricular dysfunction in hypertensive heart disease.