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.     

Programmed stimulation in the evaluation of life-threatening or potentially life-threatening ventricular arrhythmias

Conclusion In conclusion, programmed stimulation is an excellent and appropriate method to guide thrapy for life-threatening and potentially life-threatening arrhythmias that occur infrequently and with unpredictable timing.The sensitivity and specificity of programmed stimulation is excellent in patients whose clinical presentation is by sustained uniform ventricular tachycardia and cardiac arrest. In contrast, such parameters are substantially less in patients with nonsustained ventricular tachycardia and in those who present wit syncope. The predictive accuracy of therapy guided by programmed electrical stimulation in cohorts with cardiac artest and sustained uniform ventricular tachycardia cohorts is reasonably well established and appears to be very good. Although no large randomized controlled comparative study of noninvasive versus PES-guided therapy has yet been completed, preliminary evidence suggests that there is a decreased incidence of arrhythmia recurrence and sudden cardiac death when therapy is guided by PES. In the minority of patients with syncope in whom sustained uniform ventricular tachycardia is induced during PES, therapy may be effectively guided by this modality. PES appears to be of benefit in managing patients with coronary artery disease who present with nonsustained ventricular tachycardia and depressed ejection fraction thereby defining a high risk subset for a subsequent arrhythmic event. However, we have not found electrophysiologic testing postmyocardial infarction to be prognostically useful.Dr. Josephson is the Robinette Foundation Professor of Medicine (Cardiovascular Diseases)Supported in part by grants from the American Heart Association, Southeastern Pennsylvania Chapter, Philadelphia, PA; and National Heart, Lung, and Blood Institute, Bethesda, MD (HL28093, HL07346, HL24278).     

Aldosterone, mineralocorticoid receptor, and heart failure

Several large clinical studies have demonstrated the important benefit of mineralocorticoid receptor (MR) antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. Aldosterone adjusts the hydro-mineral balance in the body, and thus participates decisively to the control of blood pressure. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical and experimental studies indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels. These deleterious effects include cardiac and renal fibrosis, inflammation and vascular remodeling. It is important to underscore that these effects are due to elevated MR activation that is inadequate for the body salt requirements.Aldosterone is generally considered as the main ligand of MR. However, this is a matter of debate especially in heart. Complexity arises from the glucocorticoids with circulating concentrations much higher than those of aldosterone, and the fact that the MR has a high affinity for 11β-hydroxyglucocorticoids. Nevertheless, the beneficial effects of MR inhibition in patients with heart failure emphasize the importance of this receptor in cardiovascular tissue. Diverse experimental models and strains of transgenic mice have allowed to dissect the effects of aldosterone and the MR in the heart. Taken together experimental and clinical data clearly highlight the deleterious cardiovascular effects of MR stimulation.     

Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain

In the rat brain, the binding of corticosterone is mediated through two receptor types, the type I receptor and the type II receptor, which are presumed to be encoded by genes designated as MR and GR, respectively. We have studied the regulation of these receptors by glucocorticoids, utilizing a cytosol receptor binding assay. In addition, we have employed molecular probes for the GR and the MR to measure receptor mRNAs. The level of type II receptor binding is uniform across several brain regions, as is the expression of GR (type II) mRNA. In contrast, type I receptor binding is concentrated in the hippocampus, and the MR (type I) mRNA similarly shows a higher level of expression in hippocampus than in the other brain regions studied. Removal of endogenous glucocorticoids by adrenalectomy (ADX) induces an increase, and corticosterone administration results in a decrease, in the level of type I and type II binding in the hippocampus; however, no significant changes in the MR (type I) or GR (type II) mRNA levels are seen with these treatments. The diurnal variation of serum corticosterone in intact rats is correlated with a circadian regulation of type I receptor binding in the hippocampus, while MR (type I) mRNA expression is unaffected. Thus, the changes in type I and type II receptor binding capacity elicited by differing steroid conditions cannot be attributed to modulation of the steady state levels of MR (type I) or GR (type II) mRNA.     

Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy

The ErbB2 (Her2) proto-oncogene encodes a receptor tyrosine kinase, which is frequently amplified and overexpressed in human tumors. ErbB2 provides the target for a novel and effective antibody-based therapy (Trastuzumab/Herceptin) used for the treatment of mammary carcinomas. However, cardiomyopathies develop in a proportion of patients treated with Trastuzumab, and the incidence of such complications is increased by combination with standard chemotherapy. Gene ablation studies have previously demonstrated that the ErbB2 receptor, together with its coreceptor ErbB4 and the ligand Neuregulin-1, are essential for normal development of the heart ventricle. We use here Cre-loxP technology to mutate ErbB2 specifically in ventricular cardiomyocytes. Conditional mutant mice develop a severe dilated cardiomyopathy, with signs of cardiac dysfunction generally appearing by the second postnatal month. We infer that signaling from the ErbB2 receptor, which is enriched in T-tubules in cardiomyocytes, is crucial for adult heart function. Conditional ErbB2 mutant mice provide a model of dilated cardiomyopathy. In particular, they will allow a rigorous assessment of the role of ErbB2 in the heart and provide insight into the molecular mechanisms that underlie the adverse effects of anti-ErbB2 antibodies.     

Interdomain interactions in the mineralocorticoid receptor

The potential for interaction between the N-terminal domain and the C-terminal region (hinge and ligand-binding domain) of the mineralocorticoid receptor (MR) was examined using the mammalian-2-hybrid assay. The MR C-terminal region was fused to the GAL4 DNA-binding domain (GAL4-MRC). To examine if the AF-2 is involved in the interaction, as has been reported for other steroid hormone receptors, it was inactivated by point mutation (E962A). The N-terminal domain was fused to the VP16 transactivation domain (VP16-MRNT). In the mammalian-2-hybrid assay both GAL4-MRC and GAL4-MRC(E962A) interact with VP16-MRNT in an aldosterone-dependent manner. The GAL4-MRC(E962A) construct was used in subsequent experiments to examine the AF-2-independent N/C-interaction. The MR antagonist spironolactone inhibits the aldosterone-mediated association of the two domains. GAL4-MRC(E962A) interacts weakly with the GR or AR N-terminal domains in the presence of aldosterone. No dimerization between GAL4-MRC(E962A) and VP16-MRC is observed. Interestingly, cortisol produces a much weaker N/C-interaction than aldosterone, and it is possible that the N/C-interaction may contribute to observed functional differences in the MR bound to the two ligands.     

ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure

The two major outcome trials on the combination of angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor (MR) antagonists in heart failure are RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). There have also been studies in essential hypertension, and in diabetic hypertensive patients, on the cardiac and renal effects of ACE inhibitors and MR antagonists, individually and in combination. In the clinical studies on heart failure, in outcome trials and the smaller studies using surrogate end points, a combination of ACE inhibition and MR blockade is superior to ACE inhibition alone, and in the hypertension studies to either agent alone. Some insight into their distinct sites of protective action may be gained from studies on experimental animal preparations. The principal caveat in the use of combination therapy is the possibility of hyperkalemia, which should be minimal in patients with creatine clearance greater than 30 mL/min and with the low doses of MR antagonist shown to be effective in outcome trials.     

醛固酮合成酶和盐皮质激素受体基因在充血性心力衰竭心肌的表达

目的　研究醛固酮合成酶 (Aldosterone synthase,CYP11B2 )及盐皮质激素受体 (Mineralocorticoid receptor,MR)基因在心功能不全心肌中的表达。方法　选取 2 5例行瓣膜置换术的慢性心力衰竭 (CHF)患者左心室乳头肌组织 10 0 mg,同时取 6例健康心肌组织作为对照 ,提取组织总 RNA,并逆转录为 c DNA,以特定的寡核苷酸为引物进行聚合酶链反应 ,β- actin作为内参照 ,分别观察 CYP11B2及 MR在不同心功能状态心肌中的表达。结果　在 6例正常心肌组织中 CYP11B2基因的表达为阴性 ,2 5例 CHF患者中有 10例表达阳性 ,分别为心功能 级～ 级 2例 , 级～ 级 8例 ;轻度心力衰竭患者 (心功能 ～ 级 )与重度心力衰竭患者 (心功能 ～ 级 )表达阳性率分别为 15 .4 %和 6 6 .7% ,差异有显著性 (P=0 .0 15 )。正常心肌、心功能 ～ 级和心功能 ～ 级心肌 MR/ β- actin分别为 1.2 8± 0 .13,0 .92± 0 .12 ,0 .80± 0 .2 1,与正常对照组相比 ,CHF时 MR基因表达明显下降 (P<0 .0 0 1) ,而心功能 ～ 级与心功能 ～ 级之间 ,无显著性差异 (P=0 .0 83)。慢性心力衰竭患者中 ,CYP11B2基因表达阳性与阴性组之间 MR/ β- actin表达分别为 0 .78± 0 .2 0和 0 .94± 0 .13,二者间具有显著性差异 (P=0 .0 18)。CYP11B2     

Rapid corticosteroid-dependent regulation of mineralocorticoid receptor protein expression in rat brain

Corticosteroid hormones regulate many aspects of neural function via mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Although GR expression is negatively regulated by endogenous corticosteroids, the autologous regulation of MR expression has been less well studied, partly due to limitations of receptor binding assays that cannot measure the ligand-activated form of MR. Using MR-reactive antibodies and Western blot, we examined relative MR protein expression in rat brain and its potential autoregulation by corticosteroids. We found that MR protein expression is autoregulated in a negative fashion by adrenal steroids. Compared with GR, we see a more rapid regulation of MR, such that there is a substantial increase in MR protein within 12 h after adrenalectomy, whereas GR levels show very little increase until more than 24 h after adrenalectomy. Also, in contrast to GR, which has been found to be regulated by both MR and GR, adrenalectomy-induced increase in MR was prevented by treatment with the MR selective agonist, aldosterone, but not the GR selective agonist, RU28362. Interestingly, acute treatment of adrenalectomized rats with corticosterone produced a significant decrease in whole-cell MR protein within 45 min, suggesting ligand-induced rapid degradation of MR. Chronic high levels of corticosterone also produced a significant decrease in MR protein levels below adrenal-intact rat levels. These results have important implications for previous studies that estimated the proportion of MR that are occupied in vivo by various circulating levels of corticosterone. Those studies compared available MR binding levels in adrenal-intact rats with 24-h adrenalectomized rats, with the assumption that there were no differences between the various conditions in total receptor expression. Those studies concluded that MR is nearly fully occupied by even the lowest circulating corticosterone levels. Given the 2- to 3-fold increase in MR protein that we have observed within 24 h after adrenalectomy, it is likely that those studies significantly overestimated the proportion of MR that were occupied by low basal corticosterone levels. These results support the prospect that MR as well as GR can participate in the transduction of phasic corticosteroid signals.     

Structural determinants of ligand binding to the mineralocorticoid receptor

The first and critical step in the mechanism of aldosterone action is its binding to the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Over the last 40 years, numerous studies have attempted to determine the structural determinants of ligand-binding to MR. An initial set of data showed that hsp90 is bound to the receptor via specific regions and maintains it in a ligand-binding competent state. Site-directed mutagenesis and functional studies guided by a 3D model of the MR ligand-binding domain (LBD) made it possible to identify the residues responsible for the high affinity and selectivity for aldosterone, and to characterize the mechanisms of MR activation and inactivation. The recent determination of the X-ray crystal structures of the LBD of the wild-type MR and MR_S810L, which is responsible for a familial form of hypertension, has made it possible to elucidate the peculiar mechanism of activation of MR_S810L and established a clear structure/activity relationship for steroidal and non-steroidal MR antagonists.     

Effect of thrombolysis on heart rate variability and life-threatening ventricular arrhythmias in survivors of acute myocardial infarction

Objectives. The aim of the present study was to determine the influence of early thrombolysis on ventricular tachyarrhythmias (clinical and inducible) and heart rate variability in survivors of myocardial infarction at high risk for life-threatening ventricular arrhythmias.Background, A greater electrical heart stability may be important in improving survival in patients treated with thrombolysis. Few data are available about the influence of fibrinolysis on postinfarction arrhythmic events and other prognostic variables, such as inducible ventricular tachycardia and heart rate variability.Methods. The study group comprised 51 consecutive patients who underwent electrophysiologic study within 30 days of infarction, owing to the presence of two or more of the following criteria: left ventricular ejection fraction <40%, late potentials and repetitive ventricular ectopic beats. Thirty patients underwent thrombolysis within 6 h of the onset of symptoms (Group A), and 21 received conventional treatment (Group B). Inducibility of sustained monomorphic ventricular tachycardia was tested in both groups, and the standard deviation of all normal RR intervals during 24-h Holter monitoring was calculated. All patients were prospectively evaluated for occurrence of arrhythmic events.Results. The two groups were similar with regard to left ventricular ejection fraction (mean ± 1 SD 38 ± 6% [Group A] vs. 36 ± 8% [Group B]). Ventricular tachycardia was induced in 6 (20%) of 30 Group A patients versus 14 (67%) of 21 Group B patients (p = 0.002). The standard deviation of normal RR intervals was higher in Group A than in Group B (113 ± 36 vs. 90 ± 39 ms, p = 0.05). In patients with anterior infarction, the standard deviation of normal RR intervals was higher in 19 patients with thrombolysis than in 16 patients with conventional treatment (118 ± 41 vs. 74 ± 24 ms, p = 0.0002). During a mean follow-up period of 23 ± 11 months, 4 (13%) of 30 Group A patients had an arrhythmic event versus 9 (43%) of 21 Group B patients (p = 0.04).Conclusions. After myocardial infarction, in high risk patients, thrombolysis significantly reduced the occurrence of arrhythmic events independently of left ventricular function. This effect may be related to both an improvement in electrical heart stability, as elucidated by electrophysiologic study, and a favorable action on the cardiac sympathovagal balance.     

Ryanodine receptor phosphorylation, calcium/calmodulin-dependent protein kinase II, and life-threatening ventricular arrhythmias

Ryanodine receptor (RyR2) dysfunction, which may result from a variety of mechanisms, has been implicated in the pathogenesis of cardiac arrhythmias and heart failure. In this review, we discuss the important role of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) in the regulation of RyR2-mediated Ca(2+) release. In particular, we examine how pathological activation of CaMKII can lead to an increased risk of sudden arrhythmic death. Finally, we discuss how reduction of CaMKII-mediated RyR2 hyperactivity might reduce the risk of arrhythmias and may serve as a rationale for future pharmacotherapeutic approaches.