Left ventricular hypertrophy in aortic valve stenosis: preventive or promotive of systolic dysfunction and heart failure?

AIMS: In aortic stenosis (AS), left ventricular (LV) hypertrophy is considered a compensatory response helping maintain systolic function. Recent research in experimental AS suggests, however, that LV hypertrophy is not necessary to sustain LV contractions but may in fact be maladaptive. The present work aimed to clarify the role of LV hypertrophy in AS-related heart failure (HF) in man. METHODS AND RESULTS: We studied 137 adult patients with isolated AS undergoing pre-operative echocardiography and cardiac catheterization. HF was diagnosed by the European criteria and LV hypertrophy by sex-specific limits of echocardiographic LV mass. The higher the LV mass was, the poorer was the LV ejection fraction (beta=-0.26, P< 0.001, linear regression) and the greater the likelihood of HF independent of the severity of AS (P< 0.001, logistic regression). In the subgroup of critical AS (valve area <0.4 cm(2)/m(2), n=85), patients with absent LV hypertrophy (n=19) had better preserved ejection fraction (mean+/-SE, 64+/-3 vs. 57+/-2%, P=0.045) and less HF (16 vs. 48%, P=0.025) than patients with LV hypertrophy (n=66). CONCLUSION: In isolated AS, increased LV mass predicts the presence of systolic dysfunction and HF independent of the severity of valvular obstruction. LV hypertrophy may be maladaptive rather than beneficial in AS in man.     

Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

The role of caspase-independent apoptotic events in heart failure is largely unknown. The present study examined the response of apoptotic factors, which can function independently of caspase machinery including AIF, EndoG, and HtrA2/Omi to high salt diet-induced pathologic heart failure and exercise-induced physiologic cardiac hypertrophy. Following approximately 4 months of a daily diet containing 6% salt, animals developed clinical evidence of heart failure accompanied by changes in AIF, EndoG, and HtrA2/Omi. Assessment of the mitochondria-free cytosolic fraction revealed cytosolic accumulations of AIF and processed HtrA2/Omi in the failed ventricle muscles. The subcellular translocation of AIF from mitochondria to cytosol and nuclei was supported by immunofluorescent analysis using confocal microscopy. However, according to our RT-PCR analyses, AIF and EndoG mRNA were decreased, rather than elevated, in the failed heart relative to control heart. No difference in any of the measured parameters of AIF, EndoG, and HtrA2/Omi was found in the ventricle muscle of either exercise-trained or 6 weeks high salt diet fed animals compared to controls. These findings are consistent with the hypothesis that caspase-independent events are involved in cardiac apoptosis during the late remodeling stage of pathologic heart failure.     

Statins in heart failure

This article reviews the results from several recent reports describing the safety and efficacy of statin therapy in the setting of heart failure. It additionally discusses the ongoing controversy regarding the lipid paradox and possible mechanisms responsible for potential benefit of statin therapy in heart failure.     

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

Myosin is a molecular motor, which interacts with actin to convert the energy from ATP hydrolysis into mechanical work. In cardiac myocytes, two myosin isoforms are expressed and their relative distribution changes in different developmental and pathophysiologic conditions of the heart. It has been realized for a long time that a shift in myosin isoforms plays a major role in regulating myocardial contractile activity. With the recent evidence implicating that alteration in myosin isoform ratio may be eventually beneficial for the treatment of a stressed heart, a new interest has developed to find out ways of controlling the myosin isoform shift. This article reviews the published data describing the role of myosin isoforms in the heart and highlighting the importance of various factors shown to influence myosin isofrom shift during physiology and disease states of the heart.     

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats

OBJECTIVES: The aim of the present study was to determine whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have preventive effects on the development of cardiac hypertrophy and heart failure. BACKGROUND: Statins have been reported to have various pleiotropic effects, such as inhibition of inflammation and cell proliferation. METHODS: Dahl rats were divided into three groups: LS, the rats fed the low-salt diet (0.3% NaCl); HS, the rats fed the high-salt diet (8% NaCl) from the age of 6 weeks; and CERI, the rats fed the high-salt diet with cerivastatin 1 mg/kg/d by gavage from the age of 6 weeks. RESULTS: In HS rats, cardiac function was markedly impaired and all rats showed the signs of heart failure within 17 weeks of age. In CERI rats, cardiac function was better than that of HS and no rats were dead up to 17 weeks of age. The development of cardiac hypertrophy and fibrosis was attenuated, and the number of apoptotic cells and expression of proinflammatory cytokine interleukin (IL)-1beta gene were less as compared with HS rats. Pretreatment of cerivastatin suppressed the adriamycin-induced apoptosis of cultured cardiomyocytes of neonatal rats. CONCLUSIONS: These results suggest that statins have a protective effect on cardiac myocytes and may be useful to prevent the development of hypertensive heart failure.     

Chronic inhibition of Rho kinase blunts the process of left ventricular hypertrophy leading to cardiac contractile dysfunction in hypertension-induced heart failure

The Gq-RhoA-Rho kinase pathway, activated by neurohormonal factors such as angiotensin II (Ang II), has been proposed to be one of the important signaling pathways involved in the progression of left ventricular (LV) hypertrophy to heart failure. We tested the hypothesis that chronic inhibition of Rho kinase prevents this process. Heart failure was induced in Dahl salt-sensitive (DS) rats fed an 8% NaCl diet from 8 until 17 weeks of age. Y-27632 (5 mg/kg per day), a selective Rho kinase inhibitor, was applied orally to DS rats starting at 10 weeks of age for 7 weeks (DS/Y+). DS rats without Y-27632 (DS/Y-) and Dahl salt-resistant (DR) rats fed the 8% NaCl diet were regarded as non-therapeutic and normotensive controls, respectively. At 17 weeks of age, there was no significant difference in the blood pressure of DS/Y- and DS/Y+ rats. DS/Y- rats exhibited: (1) increases in LV mass, cross-sectional area (CSA) of cardiomyocytes, and interstitial fibrosis; (2) contractile dysfunction, i.e. decreases in LV ejection fraction and % fractional shortening, and prolongation of time to peak tension as well as to 50% relaxation in the twitch contraction of isolated papillary muscle; and (3) increases in the protein expression of Galphaq and Rho kinase in the myocardial membrane fraction. In DS/Y+ rats, the degree of myocardial hypertrophy was significantly inhibited in association with improved contractile function, without a decrease in the degree of interstitial fibrosis. Our results suggest the possibility that the Gq-Rho kinase pathway plays an important role in the process of hypertension-induced LV hypertrophy leading to contractile dysfunction.     

充血性心力衰竭患者血清甲状腺激素和心功能的变化

测定56例充血性心力衰竭患者甲状腺激素水平的变化，发现三碘甲状腺原氨酸明显低于正常，反三碘甲状腺原氨酸显著升高。心力衰竭（心衰）程度越重，变化越明显。提示甲状腺激素变化对心衰患者心功能损害程度、治疗和预后具有一定意义。     

Reduction in oxidative stress and modulation of heart failure subsequent to myocardial infarction in rats

BACKGROUND:

Patients surviving myocardial infarction (MI) are at a heightened risk for the development of congestive heart failure. This clinical syndrome has been associated with an antioxidant deficit and elevated oxidative stress in the myocardium. Effects of dietary vitamin E, a lipid-soluble antioxidant, on myocardial anti-oxidant enzyme activities, oxidative stress and hemodynamic function, were examined separately in the viable left ventricle (LV) and right ventricle (RV) of rats at 16 weeks post-MI.

METHODS AND RESULTS:

Animals were fed either a basal diet or a diet enriched with 1500 U of vitamin E/kg beginning two weeks before MI-inducing surgery and continued 16 weeks post-MI. In the MI animals on the basal diet, LV systolic pressure (LVSP) and RVSP were significantly depressed and LV end-diastolic pressure (LVEDP) and RVEDP were significantly elevated. These hemodynamic alterations were accompanied by clinical signs of heart failure including dyspnea, lethargy and cyanotic limbs. Supplementation of MI animals with dietary vitamin E resulted in complete normalization of RVSP and RVEDP. An increase in LVSP and a decrease in LVEDP was observed in the vitamin E-supplemented MI animals, although mild residual LV dysfunction remained. The myocardial enzymatic antioxidants catalase and glutathione peroxidase declined substantially in each of the ventricles of unsupplemented MI animals. Myocardial levels of vitamin E were reduced by 33% in the LV and no change was observed in the RV of the MI animals. Vitamin E-supplemented control animals and MI animals showed a significant increase in vitamin E levels in both ventricles. Myocardial oxidative stress, as assessed by lipid peroxidation and the ratio of reduced to oxidized glutathione, was significantly increased in each of the respective ventricles of untreated MI animals. Supplementation with dietary vitamin E resulted in a substantial increase in the myocardial activities of catalase and glutathione peroxidase in both the LV and RV. Furthermore, an increase in the ratio of reduced to oxidized glutathione concomitant with significantly less lipid peroxidation was also observed in each of the respective ventricles of MI animals supplemented with vitamin E. No overt clinical signs of heart failure were evident in these vitamin E-supplemented animals.

CONCLUSIONS:

An improved myocardial redox state and endogenous antioxidant reserve with vitamin E therapy, coupled with the modulation of the development of heart failure, lend strong support in favour of a pathophysiological role for increased oxidative stress in the pathogenesis of heart failure, at least in experimental animals. Association between an increase in oxidative stress and cardiac events in patients requires further examination.     

他汀类药物多效性及在心力衰竭中的应用

他汀类药物除降脂作用外,还有多效的非调脂作用。近年来很多基础和临床研究都表明他汀类药物多效性对心力衰竭的防治有益。本文就他汀类药物多效性在心力衰竭中的临床应用作一综述。     

Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy,ischemia/reperfusion dysfunction,and heart failure

Recent studies have shown that the JAK-STAT signaling pathway plays a central role in cardiac pathophysiology. JAK-STAT signaling has been implicated in pressure overload-induced cardiac hypertrophy and remodeling, ischemic preconditioning, and ischemia/reperfusion-induced cardiac dysfunction. The different STAT family members expressed in cardiac myocytes appear to be linked to different, and at times, opposite responses, such as cell growth/survival and apoptosis. Thus, differential activation and/or selective inhibition of the STAT proteins by agonists for G-protein coupled receptors, such as angiotensin II, may contribute to cardiac dysfunction during ischemia and heart failure. In addition, JAK-STAT signaling may represent one limb of an autocrine loop for angiotensin II generation, that serves to amplify the actions of angiotensin II on cardiac muscle. The purpose of this article is to provide an overview of recent findings that have been made for JAK-STAT signaling in cardiac myocytes and to highlight some unresolved issues for future investigation. The central focus of this review is on recent studies suggesting that modulation or activation of JAK-STAT signaling by ANG II has pathological consequences for heart function.     

心肌细胞凋亡在老年性心衰发生中的作用

目的探讨心肌细胞凋亡在老年心衰发生中的作用。方法制备大鼠心肌缺血／再灌注（MI／R）模型。雄性SD大鼠被分为4个实验组：青年假手术组（2个月,16只）、老年假手术组（24个月,16只）、青年手术组（2个月,16只）和老年手术组（24个月,16只）。心肌缺血／再灌注组大鼠的左冠状动脉近中段被阻断30rain后恢复血流再灌注3h和24h。通过MillarMikro—Tip导管压力换能器对大鼠左心室（LV）功能指标进行检测,从而对sD大鼠心脏功能进行评价。采用原位末端标记检测（TUNEL）法和Caspase-3活性检测评价心肌细胞凋亡水平,同时测定大鼠血浆中凋亡标志物sFas、TNF—α和IL-6水平。对大鼠心肌组织使用伊文氏蓝-TTC染色并测定血浆cTnI水平以确定心肌坏死程度。结果与青年大鼠相比,老年大鼠在心肌缺血／再灌注后心功能明显降低,同’时心肌细胞凋亡水平及心肌细胞坏死程度显著增加。血浆凋亡标志物的检测结果也表现出相同的趋势。结论年龄导致了缺血／再灌注后心功能的显著降低,心肌细胞凋亡水平的增加可能是引发上述现象的主要原因。     

N末端B型利钠肽原对单纯主动脉瓣狭窄心力衰竭患者的诊断价值

目的 评价N末端B型利钠肽原(NT-proBNP)对单纯主动脉瓣狭窄(AS)心力衰竭(心衰)患者的诊断价值.方法 使用酶联免疫的方法对40例AS心衰患者(AS心衰组)和76例正常对照者(正常组)行NT-pmBNP测定,评价其对AS心衰的诊断价值.结果 与正常组相比,AS心衰组NT-proBNP水平显著增高(P<0.01)且在纽约心功能分级(NYHA分级)Ⅱ、Ⅲ和Ⅳ级者呈逐级显著升高(均为P<0.01);其中,临床代偿心衰差异无统计学意义(P>0.05),而临床失代偿心衰升高8倍(P<0.01);在左室舒张期末内径(LVEDD)>50 mm组显著高于LVEDD≤50mm组(P<0.05),左室射血分数(LVEF)≤60%组显著高于LVEF>60%组(P<0.01);在合并心房颤动组显著高于窦性心律组(P<0.05).NT-pmBNP阈值在1360 ng/L时,是诊断心衰(ROC曲线下面积=0.762,P<0.01)及失代偿心衰(ROC曲线下面积=0.997,P<0.01)的最佳阈值;心衰与失代偿心衰诊断的敏感性分别为67.50%和100.00%,特异性均为96.05%,准确性分别为86.21%和95.83%.单因素和多元逐步回归分析一致显示,Log(NT-proBNP)与NYHA分级和LVEF呈显著正、负相关(P<0.05),且呈独立相关.结论 NT-pwBNP对单纯As心衰患者也有重要诊断价值.建议临床采用1360 ng/L作为阈值,诊断单纯AS伴心衰者准确性高达86.21%,尤其对失代偿者准确性高达95.83%.     

Diagnosis and management of aortic valve stenosis in patients with heart failure

Aortic stenosis (AS) is the most frequent degenerative valvular heart disease in Western countries and its prevalence increases in parallel with the ageing process of the population. Heart failure (HF), defined by the presence of reduced left ventricular ejection fraction, may be present in up to a quarter of patients with severe AS, posing diagnostic and management challenges. The present article reviews the prevalence of HF in severe AS patients, discusses the diagnostic challenges and the advances in multimodality imaging to identify the patients that may benefit from surgical or transcatheter aortic valve replacement, and summarizes the current evidence on management for this group of patients.     

Cardiac resynchronization therapy to prevent life-threatening arrhythmias in patients with congestive heart failure

Various clinical data demonstrate that cardiac resynchronization therapy (CRT) provides a favorable structural as well as electrical remodeling. The CArdiac Resynchronization–Heart Failure study, which tested the pure effect of CRT (using CRT devices without the capability of defibrillation) clearly showed a significant reduction in the total mortality by partly preventing sudden cardiac death. The antiarrhythmic effects of CRT are explained, at least in part, by ionic and genetic modulation of ventricular myocytes. It has been revealed in animal experiments to mimic disorganized ventricular contraction that CRT reverses down-regulation of certain K⁺ channels and abnormal Ca²⁺ homeostasis in the failing heart. However, CRT can be proarrhythmic in some particular cases especially in the early phase of this therapy. According to our study, proarrhythmic effects after CRT can be observed in approximately 10% of patients. The relatively high incidence of the proarrhythmic effects of CRT may promote a trend toward selecting CRT-D rather than CRT-P.     

Matricellular proteins: new molecular targets to prevent heart failure

Matricellular proteins are highly expressed in reparative responses to pressure and volume overload, ischemia, oxidative stress after myocardial injury, and modulate the inflammatory and fibrotic process in ventricular remodeling, which leads to cardiac dysfunction and eventually overt heart failure. Generally, matricellular proteins loosen strong adhesion of cardiomyocytes to extracellular matrix, which would help cells to move for rearrangement and allow inflammatory cells and capillary vessels to spread during tissue remodeling. Among matricellular proteins, osteopontin (OPN) and tenascin-C (TN-C) are de-adhesion proteins and upregulate the expression and activity of matrix metalloproteinases. These matricellular proteins could be key molecules to diagnose cardiac remodeling and also might be targets for the prevention of adverse ventricular remodeling. This review provides an overview of the role of matricellular proteins such as OPN and TN-C in cardiac function and remodeling, as determined by both in basic and in clinical studies.     

Altered myocardial acetylcholine and norepinephrine concentrations in right ventricular hypertrophy and failure

Summary The progression of cardiac hypertrophy and failure is associated with marked changes in cardiac autonomic innervation, and there are sympathetic-parasympathetic interactions in the regulation of cardiac function. Although the indexes of sympathetic innervation have been found to be depressed with the development of heart failure, those of parasympathetic innervation have not yet been fully investigated. In order to better understand changes in markers of autonomic innervation associated with cardiac hypertrophy and failure, we measured the myocardial acetylcholine (ACh) store as a parasympathetic marker and the norepinephrine (NE) store as a sympathetic marker in pressure-overloaded right ventricular hypertrophy in rats. Two weeks after the injection of monocrotaline, significant right ventricular hypertrophy occurred. Three weeks after, severe right ventricular hypertrophy with no sign of heart failure occurred, and 4 weeks after, overt heart failure developed. In the right heart of monocrotaline rats, NE concentrations tended to increase at 1 week, returned to baseline at 2 weeks, decreased to one-half of the control values at 3 weeks, and then fell to 14% of the controls at 4 weeks. ACh concentrations in the right heart tended to increase at 1 week and exhibited a significant increase (136% and 129% of the controls in the right atrium and ventricle, respectively) at 2 weeks. As with NE, ACh concentrations in the right atrium and ventricle decreased to 76% and 54% of the controls at 3 weeks, and continued to decrease to 22% and 24% of the controls at 4 weeks after monocrotaline. Assessing the net changes, ACh contents (i.e., total mass contained in the whole atrium or ventricle) increased at 2 weeks, although NE contents remained unchanged at the early stages. The NE and ACh contents were maintained until 3 weeks after monocrotaline, whereas both contents were depleted at 4 weeks.Our results suggest that parasympathetic innervation shows a transient increase during progressive hypertrophy due to pressure overload, and that both NE and ACh are depleted with the progression of overt heart failure, although NE and ACh contents in the whole atrium or ventricle are maintained during the compensated state of heart failure.     

Failure of left ventricular hypertrophy to regress after surgery for aortic valve stenosis

BACKGROUND: Regression of left ventricular (LV) hypertrophy usually follows surgery for aortic stenosis (AS); however, a significant number of ventricles remain hypertrophied. The extent of this phenomenon, the reasons for failure to regress, and its significance are unclear. METHODS: We investigated 43 patients before and after aortic valve surgery and divided them into two groups: 30 patients with regression of LV hypertrophy (Group A) and 13 patients without regression (Group B). Preoperative echocardiographic measurements, clinical status, and operative factors were compared between the two groups. The patients were followed up for 42 +/- 22 months for the occurrence of hospitalization for congestive heart failure (CHF) or death. RESULTS: Preoperatively, the two groups were similar except for an excess of patients in New York Heart Association (NYHA) functional Class IV and a greater incidence of old myocardial infarcts in Group B. Postoperatively, Group B patients had larger LVs with decreased systolic function. This was associated with a poor prognosis (23% mortality and 38% CHF vs 0% and 4% for Group A patients, P = 0.0002). Cox regression analysis showed previous myocardial infarction (P < 0.001) and percent mass reduction (P = 0.019) to be independent predictors of CHF or death. CONCLUSIONS: Successful regression of LV mass is difficult to predict before surgery; however, its absence is related strongly to a poor long-term prognosis.