钙调神经磷酸酶在人类心肌中的表达与分布

目的 了解钙调神经磷酸酶(CaN)在人类健康心肌和衰竭心肌中的表达与分布.方法 以12例行移植手术的终末期衰竭心脏和5例因车祸丧生的"健康供体"心脏为研究对象,分别利用免疫组化和Western blot技术对左、右心室中CaN的表达与分布进行研究.结果 CaN在心脏的心肌细胞、纤维母细胞、心外膜间皮细胞中染色阳性,且Western blot实验在后两种细胞中均检测到单一的58 000带,心肌内血管内皮细胞和平滑肌细胞中CaN染色阴性.与"供体"心肌比较,无论左心室还是右心室,衰竭心肌的CaN蛋白水平差异均无统计学意义(衰竭右心室和供体右心室电泳带强度分别为130.20±8.66和139.87±6.21,P=0.33.衰竭左心室和供体左心室电泳带强度分别为106.45和126.34±12.09),且左右心室肌CaN蛋白水平差异也无统计学意义(衰竭心肌左、右心室电泳带强度分别为96.99±10.67和104.58±13.18,P=0.63.供体心肌左、右心室电泳带强度分别为132.12和120.74).结论 CaN存在于人类心脏多数类型细胞中,包括心肌细胞、纤维母细胞和心外膜间皮细胞.心力衰竭时,CaN蛋白水平没有改变.     

Gating of the late Na+ channel in normal and failing human myocardium

We previously reported an ultraslow inactivating late Na+ current (INaL) in left ventricular cardiomyocytes (VC) isolated from normal (NVC) and failing (FVC) human hearts. This current could play a role in heart failure-induced repolarization abnormalities. To identify properties of NaCh contributing to INaL, we examined early and late openings in cell-attached patches of HEK293 cells expressing human cardiac NaCh alpha-subunit (alpha-HEK) and in VC of one normal and three failing human hearts. Two types of the late NaCh openings underlay INaL in all three preparations: scattered late (SLO) and bursts (BO). Amplitude analysis revealed that slope conductance for both SLO and BO was the same compared to the main level of early openings (EO) in both VC (21 vs 22.7pS, NVC; 22.7 vs 22.6pS, FVC) and alpha-HEK (23.2 vs 23pS), respectively. Analysis of SLO latencies revealed voltage-independent ultraslow inactivation in all preparations with tendency to be slower in FVC compared to NCV. EO and SLO render one open voltage-independent state (tau approximately 0.4ms) for NVC and FVC. One open (voltage-dependent) and two closed states (one voltage-dependent and another voltage-independent) were found in BO of both specimens. Burst duration tend to be longer in FVC ( approximately 50ms) than in NVC ( approximately 30ms). In FVC we found both modes SLO and BO at membrane potential of -10mV that is attribute for take-off voltages (from -18 to -2mV) for early afterdepolarizations (EAD's) in FVC. In conclusions, we found a novel gating mode SLO that manifest slow (hundreds of ms), voltage-independent inactivation in both NVC and FVC. We were unable to reliably demonstrate any differences in the properties of the late NaCh in failing vs a normal human heart. Accordingly, the late current appears to be generated by a single population of channels in normal and failing human ventricular myocardium. Both SLO and BO could be implicated in EADs in HF.     

The role of SR Ca(2+)-content in blunted inotropic responsiveness of failing human myocardium

The effects of inotropic agents are blunted in end-stage failing human myocardium. This has been related to a number of subcellular alterations including desensitization of the beta -adrenergic system. However, it is unknown whether alterations in SR Ca(2+)-handling contribute to blunted inotropic responsiveness of failing myocardium. We tested the hypothesis that the reduced effectiveness of Ca(2+)-dependent inotropic interventions results from the inability of the SR to sufficiently increase its Ca(2+)-content in failing human myocardium. Experiments were performed in ventricular muscle preparations from a total of four non-failing and 18 end-stage failing hearts. Isometric twitch force and SR Ca(2+)-content (using rapid cooling contractures; RCCs) were assessed under basal experimental conditions (1 Hz, 37 degrees C, [Ca(2+)](o) 2.5 mmol/l), and at increasing [Ca(2+)](o) (1.25-15 mmol/l), increasing concentrations of the beta -adrenergic agonist isoproterenol (ISO; 0.01-10 micromol/l), or the glycolytic substrate pyruvate (5-15 mmol/l). In addition, paired RCCs were evoked in a subset of experiments to investigate the relative contribution of SR Ca(2+)-uptake v Na(+)/Ca(2+)-exchange to cytosolic Ca(2+)-elimination. In non-failing human myocardium, Ca(2+), ISO, and pyruvate exerted significant positive inotropic effects (increase in twitch force by maximally 396%, 437%, and 82%, respectively). The inotropic effects were associated with increasing RCCs (by 147%, 193%, and 51%, respectively). In failing myocardium, the inotropic effects of Ca(2+) and ISO were significantly less pronounced (with maximal increases in twitch force by 226% and 138%, respectively), associated with blunted effects on RCCs (increase by 33% and 79%, respectively). In contrast, the inotropic effect of pyruvate was unchanged in failing myocardium (increase by 66%), while the corresponding RCCs increased only by 30%. We conclude that the inotropic effects of Ca(2+), ISO, and pyruvate are associated with a significant increase in SR Ca(2+)-content in non-failing human myocardium. In end-stage failing myocardium, the reduced inotropic response to Ca(2+) and ISO is associated with the inability of the SR to appropriately increase its Ca(2+)-content, possibly related to decreased SR Ca(2+)-ATPase and increased Na(+)/Ca(2+)-exchanger expression. In contrast, the maintained inotropic response to pyruvate despite reduced SR Ca(2+)-loading points to additional subcellular effects such as enhanced myofilament Ca(2+)-responsiveness.     

伊布利特对人体心房与心室的电生理作用及其频率依赖性研究

目的探讨伊布利特对人体心房、心室的电生理作用及其频率依赖性。方法25例射频消融术后患者于静脉推注伊布利特（0．0167mg／kg）前后测定两种起搏周长（PCL，400ms与600ms）时的右心房、左心房及右心室的有效不应期（RA-ERP、LA-ERP及RV-ERP），其中通过起搏冠状静脉窦远端问接起搏左心房。结果（1）明显延长RA-ERP（PCL=400ms时，由215．20ms延长至259．60ms，P〈0．001；PCL=600ms时，由231．20ms延长至281．20ms，P〈0．001）；（2）明显延长LA-ERP（PCL=400ms时，由216．60ms延长至247．60ms，P〈0．001；PCL=600ms时，由226.40ms延长至262．40ms，P〈0．001）；（3）明显延长RV-ERP（PCL=400ms时，由219．60ms延长至249．60ms，P〈0．001；PCL=600ms时，由233．20ms延长至268.20ms，P〈0．001）；（4）PCL=400ms与PCL=600ms比较，对RA-ERP、LA-ERP及RV-ERP延长程度均差异无统计学意义（P〉0．05）；（5）明显延长QT与QTc间期，其中QTc由384．36ms延长至450．66ms（P〈0．001），对窦性心率〈82次／min与≥82次／min患者的QT与QTc延长程度差异无统计学意义（P〉0．05）。结论伊布利特可明显延长RA-ERP、LA-ERP、RV-ERP及QT、QTc，而且这些电生理作用无频率依赖性。     

Neuregulin receptors erbB2 and erbB4 in failing human myocardium

Membrane–bound and secreted neuregulin isoforms induce growth, survival and differentiation by activating erbB tyrosine kinase receptors. In cultured cardiomyocytes, erbB2 and erbB4 receptors regulate apoptosis by controlling bcl–x splicing, and conditional elimination of erbB2 induces dilative cardiomyopathy in vivo. Therefore, we analyzed expression and activation of erbB receptors in left ventricular myocardium from 32 heart failure patients, from 10 organ donors, and from 15 heart failure patients prior to and following unloading by ventricular assist devices. ErbB receptors, expressed in cardiomyocytes and noncardiomyocytes, are downregulated in failing myocardium as mRNA (which is renormalized by hemodynamic unloading) and as protein (erbB2: –25%; erbB4: –70%), their phosphorylation is reduced and bcl–x splicing is shifted towards 6.7–fold augmentation of proapoptotic Bcl–xS, compatible with attenuated erbB signaling. However, secreted and membrane–anchored neuregulin–1 isoforms, preferentially expressed in microvascular endothelium, are induced and not lowered with heart failure, while expression of erbB–inhibitory neuregulin isoforms or of autoinhibitory soluble erbB isoforms could not be demonstrated as potential causes of erbB receptor inhibition. We conclude that erbB receptor inactivation by unknown mechanisms results in altered splicing of bcl–x towards enhanced formation of proapoptotic Bcl–xS, thereby contributing to enhanced apoptotic susceptibility of failing human myocardium.     

The effect of xamoterol in failing human myocardium

As the dual pharmacological action of partial beta 1-adrenoceptor agonists should improve left ventricular function while also protecting the myocardium against excessive sympathetic stimulation they may be useful in the treatment of heart failure. Therefore, we studied the pharmacological effects of xamoterol (Corwin, ICI 118, 587), a compound with mixed agonist and antagonistic properties at cardiac beta-adrenoceptors in electrically driven human papillary muscle strips from failing human hearts. Specimens were obtained from patients with different grades of myocardial failure who underwent mitral valve replacement (NYHA II-III) or heart transplantation (NYHA IV). Xamoterol (0.0001-100 mumol l-1) produced only negative inotropic effects, as measured by changes in isometric force of contraction in diseased human papillary muscle strips. However, isoprenaline (0.0001-10 mumol l-1) and ouabain (0.01-0.3 mumol l-1) enhanced force of contraction in the same hearts. Prestimulation with noradrenaline (3 mumol l-1) augmented the negative inotropic effect of xamoterol. It is concluded that xamoterol exerts primarily beta-adrenoceptor antagonistic activity in the failing human myocardium.     

Evidence for electrogenic Na+ pumping in human atrial myocardium

The resting potential of "sodium-loaded' cardiac cells can transiently hyperpolarize to levels negative to the steady state resting potential [3,5,6]. Hyperpolarization is associated with the coupled efflux of Na+ and influx of K+ driven by an active transport process and may result from an increased K+ equilibrium potential (EK), an outward pump current or both. Using conventional microelectrode techniques, we found that Na+-loaded human atrial myocardium can also transiently hyperpolarize. Na+ loading was induced by cooling to 2 degrees to 3 degrees C. Upon rewarming to 37 degrees C in a 20 mM K+ solution, the resting potential transiently hyperpolarized to levels at least 11 mV negative to the calculated EK and 29 +/- 2 mV (mean +/- S.E.) negative to the steady state level (- 33 +/- 2 mV) recorded some 15-20 minutes later. An increase in K+ conductance induced by acetylcholine exposure [2,7,10] during the transient hyperpolarization caused a depolarization, indicating that the resting potential was indeed negative to EK. These findings cannot be explained by either conductance changes or electroneutral Na+ pumping and concomitant extracellular K+ depletion. We conclude that the Na+-loaded human atrium can generate net pump current.     

Effects of biventricular pacing on interstitial remodelling, tumor necrosis factor-alpha expression, and apoptotic death in failing human myocardium.

AIMS: Recent data from the COMPANION trial have documented that cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing reduces mortality and hospitalization in patients with advanced CHF, but little is known regarding the cellular and molecular mechanisms of CRT. Our aim is to evaluate interstitial remodelling, tumor necrosis factor-alpha (TNF-alpha) expression, and apoptosis in patients with advanced CHF treated with CRT. METHODS AND RESULTS: We performed endomyocardial biopsies in 10 patients, aged 62, with dilated cardiomyopathy before and 6 months after the implantation of a BiV pacing device. Clinical status and left ventricular (LV) architecture and function were assessed as well as myocardial histology, TNF-alpha expression, and apoptotic index. CRT improved clinical status, as shown by a significant reduction of the Minnesota living with heart failure questionnaire (MLHFQ) score (from 53 to 40) and 6-min walked distance (from 290 to 330 m) (all P<0.05 vs. baseline). This was associated with reverse LV remodelling substantiated by significant reductions of LV volumes and end-systolic circumferential wall stress. Examination of myocardial tissue revealed a significant decrease of collagen volume fraction (CVF) (from 25.16 to 18.0%), TNF-alpha expression (from 9.5 to 3.6 pixel x 10(3)), and apoptotic index (from 2030 to 1408 apoptotic nuclei/10(6)), with increased capillary density (from 1801 to 2011 capillary/mm(2)) after 6 months of CRT (all P<0.05 vs. baseline). Moreover, changes in TNF-alpha expression were positively correlated with both CVF and end-systolic circumferential wall stress (r=0.80 and 0.70, respectively). CONCLUSION: We provide the first evidence that CRT reduces interstitial remodelling, TNF-alpha expression, and apoptosis. The data may explain the beneficial effects of CRT on CHF progression and survival.     

Altered hetero- and homeometric autoregulation in the terminally failing human heart

OBJECTIVE AND METHODS: To further investigate length-dependent force generation in human heart, nonfailing (donor hearts, NF) and terminally failing (heart transplants, dilated cardiomyopathy, DCM) left ventricular myocardium was studied under various preload (4-40 mN/mm2) or length conditions. In addition, morphological studies (van Giesson Trichrome staining, electron microscopy) were performed. RESULTS: In NF, a biphasic increase in force of contraction (FOC) was observed after elevating the preload (4-40 mN/mm2): there was an immediate fast increase (FOCf,), followed by a slow increase over several minutes (FOCs), which was paralleled by an increase in the systolic fura-2 transient. In DCM, FOCf, FOCs and the systolic fura-2 transient were blunted and diastolic tension was increased at increasing muscle length. Only in NF, a stretched induced increase in diastolic fura-2 ratio was observed. In DCM, no obvious interstitial fibrosis and no difference in basement membrane structure and attachment were observed. CONCLUSIONS: Since FOCf has been attributed to the Frank-Starling mechanism, whereas FOCs represents a length-dependent increase in the intracellular Ca2+-transient, the impaired length-dependent force generation in failing myocardium results from a dysregulation of both myofibrillar Ca2+-sensitivity as well as the intracellular Ca2+-homeostasis. Interstitial fibrosis may have only minor impact on force generation in human end-stage heart failure.     

Abnormal mitochondrial respiration in failed human myocardium

Chronic heart failure (HF) is associated with morphologic abnormalities of cardiac mitochondria including hyperplasia, reduced organelle size and compromised structural integrity. In this study, we examined whether functional abnormalities of mitochondrial respiration are also present in myocardium of patients with advanced HF. Mitochondrial respiration was examined using a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles obtained from myocardium of failed explanted human hearts due to ischemic (ICM, n=9) or idiopathic dilated (IDC, n=9) cardiomyopathy. Myocardial specimens from five normal donor hearts served as controls (CON). Basal respiratory rate, respiratory rate after addition of the substrates glutamate and malate (V(SUB)), state 3 respiration (after addition of ADP, V(ADP)) and respiration after the addition of atractyloside (V(AT)) were measured in scar-free muscle bundles obtained from the subendocardial (ENDO) and subepicardial (EPI) thirds of the left ventricular (LV) free wall, interventricular septum and right ventricular (RV) free wall. There were no differences in basal and substrate-supported respiration between CON and HF regardless of etiology. V(ADP)was significantly depressed both in ICM and IDC compared to CON in all the regions studied. The respiratory control ratio, V(ADP)/V(AT), was also significantly decreased in HF compared to CON. In both ICM and IDC, V(ADP)was significantly lower in ENDO compared to EPI. The results indicate that mitochondrial respiration is abnormal in the failing human heart. The findings support the concept of low myocardial energy production in HF via oxidative phosphorylation, an abnormality with a potentially impact on global cardiac performance.     

Sarcoplasmic reticulum Ca2+ regulatory protein gene expression in human right atrium under hemodynamic overload

Summary Sarcoplasmic reticulum (SR) Ca²⁺-adenosine triphosphatase (ATPase) mRNA expression is reduced in the failing human myocardium. However, it is not known whether SR Ca²⁺-regulatory protein gene expression is altered in human myocardial tissue subjected to pressure overload or volume overload. We sought to determine whether SR Ca²⁺-regulatory protein gene expression is altered in human atrial tissue subjected to mechanical overload. We obtained right atrial myocardial tissue (about 250mg) at open-heart surgery from three groups of patients: no hemodynamic overload to the right atrium (control group; 12 patients), atrial septal defect (ASD group; 8 patients), and tricuspid regurgitation (TR group; 7 patients). We measured the myocyte size, the area of interstitial fibrosis, SR Ca²⁺-ATPase, and ryanodine receptor mRNA abundance. The isolated cardiocyte area and the percent area of interstitial fibrosis were in the order TR > ASD > control (P < 0.05). The SR Ca²⁺-ATPase mRNA level in TR was significantly decreased (P = 0.004) compared with the control, whereas in the ASD group it did not differ significantly from control. There were no significant differences in ryanodine receptor mRNA levels among the three groups. SR Ca²⁺-ATPase gene expression was downregulated in human atrial tissue with TR but not in ASD, which might have resulted from the differences in the degree and/or the type of hemodynamic overload to the myocardium.Supported in part by grants from the Ministry of Education, Science and Culture (No. 06670726), Study Group of Molecular Cardiology, and Kaibara Morikazu Medical Science Promotion Foundation.     

Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation

The goal of this study was to test the hypothesis that the novel anti-ischemic drug ranolazine, which is known to inhibit late I_Na, could reduce intracellular [Na⁺]_i and diastolic [Ca²⁺]_i overload and improve diastolic function. Contractile dysfunction in human heart failure (HF) is associated with increased [Na⁺]_i and elevated diastolic [Ca²⁺]_i. Increased Na⁺ influx through voltage-gated Na⁺ channels (late I_Na) has been suggested to contribute to elevated [Na⁺]_i in HF. In isometrically contracting ventricular muscle strips from end-stage failing human hearts, ranolazine (10 µmol/L) did not exert negative inotropic effects on twitch force amplitude. However, ranolazine significantly reduced frequency-dependent increase in diastolic tension (i.e., diastolic dysfunction) by ~ 30% without significantly affecting sarcoplasmic reticulum (SR) Ca²⁺ loading. To investigate the mechanism of action of this beneficial effect of ranolazine on diastolic tension, Anemonia sulcata toxin II (ATX-II, 40 nmol/L) was used to increase intracellular Na⁺ loading in ventricular rabbit myocytes. ATX-II caused a significant rise in [Na⁺]_i typically seen in heart failure via increased late I_Na. In parallel, ATX-II significantly increased diastolic [Ca²⁺]_i. In the presence of ranolazine the increases in late I_Na, as well as [Na⁺]_i and diastolic [Ca²⁺]_i were significantly blunted at all stimulation rates without significantly decreasing Ca²⁺ transient amplitudes or SR Ca²⁺ content. In summary, ranolazine reduced the frequency-dependent increase in diastolic tension without having negative inotropic effects on contractility of muscles from end-stage failing human hearts. Moreover, in rabbit myocytes the increases in late I_Na, [Na⁺]_i and [Ca²⁺]_i caused by ATX-II, were significantly blunted by ranolazine. These results suggest that ranolazine may be of therapeutic benefit in conditions of diastolic dysfunction due to elevated [Na⁺]_i and diastolic [Ca²⁺]_i.     

Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts

Background and purposePeriostin, a matricellular protein, plays an important role in cardiac development and remodeling. Its expression profile and the association with myocardial fibrosis have not been investigated in human failing hearts. This work aimed to explore the behavior and pathologic significance of periostin in signifying collagen fibrogenesis in human hearts from patients with end-stage heart failure.Methods and subjectsTissues were collected from heart transplant recipients and the control hearts were from unmatched donors. Periostin mRNA and protein were detected using quantitative real-time polymerase chain reaction and Western blotting. Immunohistochemistry staining was employed to directly detect the protein level and distribution of periostin in heart tissues. The extent of myocardial fibrosis was expressed by the percentage of Masson's trichrome staining. Gelatin zymography was used to detect the activities of matrix metalloproteinase (MMP)2 and MMP9.ResultsA low level of periostin mRNA expression was found in control hearts while not detectable at the protein level. Periostin mRNA was increased significantly in failing myocardium compared to that of controls. Periostin was distributed extensively in left ventricle and interventricular septum of the failing hearts. Correlation analysis showed periostin protein expression was positively associated with myocardial fibrosis as well as left ventricular diastolic dimension. The distribution and extent of periostin was consistent with that of myocardial fibrosis. MMP2 activity has an obvious increase about fourfold in heart tissues from HF patients. But there is no quantitative association with the expression of periostin.ConclusionsPeriostin, the distribution and expression of which were consistent with the extent of myocardial fibrosis, might be a potential biomarker of cardiac remodeling in heart failure patients.     

依那普利对心力衰竭大鼠心肌细胞凋亡及凋亡基因bcl-2、Bax的影响

目的:探讨血管紧张素转化酶抑制剂(ACEI)———依那普利对慢性压力负荷性心力衰竭大鼠心肌重构、心肌细胞凋亡、凋亡基因Bcl 2、Bax在心肌细胞中表达的影响,为心力衰竭的发病机制及治疗提供实验依据。方法:结扎大鼠的腹主动脉,复制慢性压力负荷性心力衰竭模型,32只大鼠随机分为心力衰竭组 12 只、依那普利治疗组(治疗组)12只、对照组8只。手术后6周,充血性心力衰竭模型形成。治疗组给予依那普利10 mg·kg-1·d-1灌胃,心力衰竭组和对照组给予同量0.85%氯化钠溶液灌胃。在 3 个月末测量血流动力学指标后,将大鼠处死,取出心脏。用原位脱氧核糖核酸酶末端标记法(TUNEL)检测细胞凋亡;免疫组化法和免疫印迹法测 bcl 2、Bax表达。结果:心力衰竭组与对照组相比,心功能明显减退(P < 0.01);心肌细胞凋亡明显增加(P <0.01);在心肌细胞中bcl 2 表达减低,Bax表达增加。依那普利治疗后能改善心室重构(P<0.05),减少心肌细胞凋亡(P< 0.01),增加bcl 2、减少Bax在心肌细胞中的表达(P<0.05)。结论:在心力衰竭时血管紧张素Ⅱ生成增多,减低bcl 2的表达,增加Bax的表达,从而降低 bcl 2/Bax比率;依那普利可能通过血管紧张素Ⅱ的介导作用,增加bcl 2、减低Bax在心肌细胞中的表达,减轻心肌细胞凋亡。     

Beta-adrenergic receptor blockade modulates Bcl-X(S) expression and reduces apoptosis in failing myocardium

The mechanisms by which beta-adrenergic receptor (beta-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of beta-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-X(S)) and anti-apoptotic (Bcl-X(L)and Bcl-2) gene expression, and Bcl-X(L) and Bcl-X(S) protein in post-infarction HF in rats. In untreated rats, there was significant (P < 0.001) LV dilatation and systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P < 0.005). Fas, Bax, and Bcl-2 mRNA expression was unchanged. However, Fas ligand mRNA and Bcl-X(S) mRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-X(L) mRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-X(S) staining in failing myocardium, with unchanged Bcl-X(L). Metoprolol treatment resulted in: (1) improved LV remodeling (P < 0.025), (2) reduced myocardial apoptosis (P < 0.005), and (3) selective reduction in myocardial Bcl-X(S) expression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-X(L). Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-X(S) protein, reducing the Bcl-X(L)/X(S) ratio and myocyte survival (P < 0.005). ISO-induced Bcl-X(S) expression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a beta1-AR selective antagonist, but not by ICI118,551, a beta2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-X(S) expression via the beta1-AR. beta-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-X(S) expression may be one mechanism underlying this effect.     

Mitochondrial tolerance to stress impaired in failing heart

Mitochondrial integrity is critical in the maintenance of bioenergetic homeostasis of the myocardium, with oxidative or metabolic challenge to mitochondria precipitating cell injury. In heart failure, where cardiac cells are exposed to elevated stress, mitochondrial vulnerability could contribute to the disease state. However, the mitochondrial response to stress is yet to be established in heart failure. Here, mitochondrial function and structure was evaluated prior and following stress using a transgenic (TG) model of heart failure, generated by cardiac overexpression of the cytokine TNFalpha. Compared to the wild type, mitochondria from TG failing hearts demonstrated impaired oxidative phosphorylation, mitochondrial DNA damage, reduced mitochondrial creatine kinase activity, abnormal calcium handling, and altered ultrastructure. Under anoxia/reoxygenation or calcium stress, mitochondria from failing hearts suffered exacerbated energetic failure with pronounced cytochrome c release. Thus, mitochondria from TNFalpha-TG failing hearts demonstrate structural and functional abnormalities, with reduced tolerance to stress manifested by impaired bioenergetics and increased susceptibility to injury. This abnormal vulnerability to stress underscores the impact of mitochondrial dysfunction in the pathobiology of heart failure.     

An unusual cause of heart failure identified by echocardiography in an octogenarian

Non-compaction of the ventricular myocardium is a rare congenital cardiomyopathy that carries an unfavorable prognosis. It is associated with a high incidence of progressive heart failure, thromboembolism and malignant arrhythmias. Echocardiography currently remains the imaging modality most commonly used for diagnosis. We describe an unusual case of isolated non-compaction of the left ventricle in an octogenarian male to highlight the need for echocardiography in all patients with suspected heart failure, in order to determine aetiology, prognosis and assess treatment.