Effects of antibodies obtained from patients with dilated cardiomyopathy on the function of isolated rat hearts

BACKGROUND: Cardiac autoantibodies may play a pathophysiological role in cardiac dysfunction of patients suffering from dilated cardiomyopathy (DCM). Immunoadsorption (IA), which removes antibodies from patients' plasma, may consequently improve cardiac function in DCM. The functional effects of DCM antibodies are only partly understood. MATERIALS AND METHODS: DCM patients (n = 10) were treated with IA by application of antibody columns directed against human immunoglobulin (Ig). IA was also performed with plasma taken from 10 healthy donors (controls). The antibodies eliminated and purified by IA were collected and dialysed. Rat hearts were isolated and perfused retrogradely via the aorta in Langendorff mode. During constant-pressure and constant-volume perfusion of the hearts, the influence of diluted antibodies on contractility, relaxation, and on coronary perfusion was analysed. RESULTS: Antibodies obtained from controls had no effect on contractility and relaxation of isolated perfused hearts during constant-pressure and constant-volume perfusion. In contrast, during constant-pressure perfusion, collected DCM antibodies caused immediate and dose-related reduction of contractility (dLVP/dtmax: dilution -1:32 = -7.1 +/- 1.1%; dilution -1:2 = -20.1 +/- 2.1%; P < 0.001) and diastolic relaxation (dLVP/dtmin: dilution -1:32 = -11.1 +/- 1.5%; dilution -1:2 = -23.9 +/- 2.2%; P < 0.001). The heart rate did not change significantly in either group. The effects of DCM antibodies on contractility and relaxation remained detectable during constant-volume perfusion. The observed reduction of contractility and diastolic relaxation was accompanied by impairment of coronary perfusion. CONCLUSION: In the rat heart, antibodies obtained from DCM patients may impair contractility and relaxation, and thereby probably also coronary perfusion.     

基于深度学习的1.5T心脏磁共振Cine序列在肥厚型心肌病和扩张型心肌病患者左心室功能评估中的应用

目的:探讨一种基于深度学习的1.5T心脏磁共振Cine序列自动量化不同心肌病左心室功能的性能。方法:回顾性分析2014年3月至2019年11月393例心脏MRI受检者的相关临床资料。对肥厚型心肌病(HCM)患者(HCM组,n=125)、扩张型心肌病(DCM)患者(DCM组,n=133)和健康个体(对照组,n=135)的左心室功能,分别通过手动和自动测量进行评估。手动分析由2位经验丰富的医师完成;自动分析后,从左心室分割精度和左心室功能参数准确性两方面对卷积神经网络(CNN)的性能进行评价。采用Pearson相关分析、Bland-Altman分析和受试者工作特征曲线(ROC),评价手动与自动方法诊断HCM和DCM的相关性与一致性。结果:CNN评估左心室功能时,在HCM组中与手动分析的一致性最好,对照组次之,在DCM中表现最差。HCM组左心室功能4个参数的自动分析与手动分析结果具有较高的相关性(P0.01);DCM组所有参数自动与手动分析的相关性均弱于HCM,特别是射血分数和每搏输出量。ROC曲线分析表明,自动分割算出的射血分数对DCM、HCM的诊断灵敏度分别为92.31%和78.05%,特异度分别为82.96%和54.07%。结论:在不同心肌疾病中,基于CNN的心功能分析性能可能不同,在HCM中表现优于DCM,但对DCM的诊断价值优于HCM。     

Mutations in genes for sarcomeric proteins

Idiopathic cardiomyopathy(ICM) is by definition of unknown etiology. There are four clinical types of ICM; hypertrophic cardiomyopathy(HCM) characterized by ventricular hypertrophy associated with reduced compliance of the heart and accompanied by myofibrillar disarray, dilated cardiomyopathy(DCM) characterized by dilated ventricles associated with systolic dysfunction, restricted cardiomyopathy (RCM) and arrhythmogenic right ventricular cardiomyopathy(ARVC). Recent molecular genetic analyses have now revealed disease-associated mutations in ICM, especially in familial HCM and familial DCM. Mutations in 9 different disease genes (MYH7, TNNT2, TPM1, MYBPC3, MYL3, MYL2, TNNI3, CACT and TTN) cause HCM, while mutations in 3 different genes(CACT, DES and DMD) cause DCM in adults. In this review, I will summarize our current data on sarcomere mutations found in Japanese ICM, especially in HCM and DCM.     

Molecular aspects of cardiac hypertrophy and their implications in cardiomyopathies

Cardiac hypertrophy or hypertrophy of cardiomyocytes is an adaptive response of the heart against an intrinsic or extrinsic damage in cardiomyocytes. A typical intrinsic defect causing cardiac hypertrophy is the sarcomere mutations found in hypertrophic cardiomyopathy (HCM) and extrinsic defects include cardiac ischemia, pressure- or volume-overload, metabolic diseases and arrhythmias. The hypertrophic response is a compensatory mechanism to augments cardiac output, however, sustained hypertrophy may lead to systolic dysfunction or de-compensation state. It is well known that some patients with HCM develop to dilated-phase or burn-out phase, which resembles dilated cardiomyopathy (DCM). In this review, molecular mechanisms underlying the cardiac hypertrophy in HCM and DCM will be discussed.     

Cardiomyocyte apoptosis and progression of heart failure to transplantation

BACKGROUND: Cardiomyocyte apoptosis has been found in congestive heart failure, but its clinical significance has been difficult to study. We compared the occurrence of cardiomyocyte apoptosis in explanted hearts with the progression of severe heart failure until the need for transplantation. DESIGN: Using the TUNEL assay, apoptotic cardiomyocytes were quantified in explanted failing hearts from patients with either idiopathic dilated cardiomyopathy (n = 21) or ischaemic heart disease (n = 14). The percentage was compared with the clinical severity and progression of endstage heart failure. Samples obtained at autopsy and during open heart surgery served as controls. RESULTS: The number of apoptotic cardiomyocytes was significantly increased in failing hearts regardless of aetiology (medians 0.075% in ischaemic heart disease and 0.119% in dilated cardiomyopathy) compared with control myocardium. In patients with dilated cardiomyopathy, apoptotic cardiomyocytes were more numerous in subjects with a rapidly deteriorating clinical course (0.192%, n = 10) than in patients with intermediate (0.093%, n = 6, P = 0.03) or slow (0.026%, n = 5, P = 0.003) progression. No such association was observed in patients with ischaemic heart disease, in whom we found significantly increased cardiomyocyte apoptosis adjacent to scars of previous infarctions (0.576%) in contrast to the diffuse distribution seen in dilated cardiomyopathy. Expression of Bcl-2, an antiapoptotic protein, was increased in all failing hearts by immunohistochemistry. CONCLUSION: Cardiomyocyte apoptosis is a consistent feature of end-stage heart failure in man and appears to be quantitatively related to the clinical severity of deterioration in dilated cardiomyopathy. Increased expression of Bcl-2 in cardiomyocytes indicates activation of an antiapoptotic response. These observations suggest that cardiomyocyte apoptosis is a clinically relevant and potentially modifiable pathophysiological phenomenon in severe heart failure.     

Prognosis of hypertrophic and dilated cardiomyopathy

Hypertrophic and dilated cardiomyopathies are a heterogeneous disease, both clinically and genetically. Hypertrophic cardiomyopathy(HCM) is important causes of sudden cardiac death and death from congestive heart failure, although HCM has a relatively benign prognosis. The prognosis of dilated cardiomyopathy(DCM) has improved due to advances in earlier diagnosis and therapy, however, sudden cardiac death and death from congestive heart failure still occur in DCM. Accordingly, it is of importance to know possible risk factors on risk stratification for a high-risk group in HCM and DCM. Possible risk factors may contribute to the construction of therapeutic strategies for the prevention of sudden cardiac death or death from congestive heart failure in patients with HCM and DCM.     

“Burnt out” dilated hypertrophic cardiomyopathy causing acute LVAD thrombosis

Case report illustrates obstruction encountered in a patient with end‐stage dilated hypertrophic cardiomyopathy (HCM) who underwent LVAD implantation. The morphology reversed in early postoperative period to HCM. Pump replacement required coring of the ventricular muscle. Dilated end‐stage hypertrophic cardiomyopathy can revert back to the original morphology on decompression.     

HLA and hepatitis C virus positive cardiomyopathy

The relationship between HCV (hepatitis C virus) and the susceptibility of cardiomyopathy has been indicated, but the detailed mechanism for close association is still unknown. It is well known that the human leukocyte antigen (HLA) may regulate the development of chronic hepatitis in HCV positive patients. We have analyzed the distribution of HLA class II alleles in Japanese patients with HCV antibody positive dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), and HLA-DPB1*0901 was significantly increased in HCV Ab positive DCM, and the HLA-DRB1*0901-DQB1*0303 haplotype was in HCV Ab positive HCM. These results suggested that molecular mechanism for the development of cardiomyopathy mediated by HCV is different between DCM and HCM.     

多种病毒感染与心肌疾病发病的关系

目的：检测不同临床表现的心肌疾病心肌组织中多种病毒基因，结合病理诊断进一步探讨多种病毒感染与心肌疾病的关系。方法：50例临床诊断为扩张型心肌病、病毒性心肌炎、肥厚型心肌病、限制型心肌病以及冠心病患者行心内膜心肌活检，分别检测肠道病毒RNA、腺病毒DNA、巨细胞病毒DNA、单纯疱疹病毒DNA及EB病毒DNA，12例脑外伤死亡者心肌组织作正常对照。结果：22例扩张型心肌病患者，病理学支持者17例，其中Evs RNA阳性者为8例（47．1％）、ADV DNA阳性者7例（41．2％）、EBV DNA阳性者1例（5．9％）；17例心肌炎，11例病理学证实，其病毒基因检测阳性率分别为Evs RAN72．7％（8／11）、ADV DNA18．2％（2／11）、EBV DNA9．1％（1／11）；1例肥厚型心肌病EvsRNA阳性。结论：多种病毒参与了心肌疾病的发病。     

Molecular diagnosis of myocardial disease

Myocardial disorders are major causes of morbidity and mortality, including heart failure, sudden death and the need for heart transplantation. The two most common forms of myocardial disorders, dilated cardiomyopathy and hypertrophic cardiomyopathy are paradigms of left ventricular systolic dysfunction and diastolic dysfunction. The genetics of these disorders are increasingly understood with the sarcomere playing a central role in the development of HCM and the link between sarcomere and sarcolemma being key to the development of DCM. In this review, the genetics of the myocardial diseases will be described.     

Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart.

To elucidate the expression of the atrial natriuretic polypeptide (ANP) gene in the ventricle of the human failing heart, we have measured ANP and ANP messenger RNA (ANPmRNA) levels in left ventricular aneurysm obtained at operation, biopsy specimens of left ventricles from dilated cardiomyopathy (DCM) and autopsy samples of old myocardial infarction (OMI) and DCM hearts, and compared the levels with those in the normal ventricle. The ANP level (mean +/- SE) was 17.5 +/- 6.9 ng/g in the normal ventricle, and increased to 660.3 +/- 122.2 ng/g in the left ventricular aneurysm tissues and to 3,138.6 +/- 1,642.1 ng/g in the biopsy specimens of the DCM ventricle. These levels were approximately 40 and 200 times higher than in the normal ventricle. The increase of ANP levels was observed in both infarcted and noninfarcted regions of the OMI heart, and in the entire ventricle of the DCM heart. A significant positive correlation was found between the ANP level in aneurysm tissues and pulmonary capillary wedge pressure (r = 0.85). The ANPmRNA level in the left ventricular aneurysm showed about a 10-fold increase compared with that in the normal heart and reached 23% of that in the atrium of the same heart. A similar increase in the ANPmRNA level was observed in the entire ventricle of DCM. These data clearly indicate that the expression of the ANP gene in the ventricle is augmented in the failing heart in accordance with the severity of heart failure. In the atrium of the failing heart, ANP and ANPmRNA levels were only two times higher than those in the normal atrium. Thus, the augmentation in the expression of the ANP gene was more prominent in the ventricle than in the atrium. Taking tissue weight into account, the total content of ANPmRNA in the ventricle of the failing heart is much the same as that in the normal atrium. The ratio of the ANP level to the ANPmRNA level in the ventricle is much smaller than that in the atrium. These results suggest more rapid secretion of ANP after synthesis in the ventricle. These findings demonstrate that the expression of the ANP gene is augmented in the human ventricle of the failing heart and suggest that the ventricle becomes a substantial source of circulating ANP in congestive heart failure.     

Genetic mutations and mechanisms in dilated cardiomyopathy

Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.     

Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation.

To examine the role of alterations in myofibrillar function in human dilated cardiomyopathies, we determined isometric tension-calcium relations in permeabilized myocytesized myofibrillar preparations (n = 16) obtained from left ventricular biopsies from nine patients with dilated cardiomyopathy (DCM) during cardiac transplantation or left ventricular assist device implantation. Similar preparations (n = 10) were obtained from six normal hearts used for cardiac transplantation. Passive and maximal Ca2+-activated tensions were similar for the two groups. However, the calcium sensitivity of isometric tension was increased in DCM compared to nonfailing preparations ([Ca2+]50=2.46+/-0.49 microM vs 3.24+/-0.51 microM, P < 0.001). In vitro treatment with the catalytic subunit of protein kinase A (PKA) decreased calcium sensitivity of tension to a greater degree in failing than in normal preparations. Further, isometric tension-calcium relations in failing and normal myofibrillar preparations were similar after PKA treatment. These findings suggest that the increased calcium sensitivity of isometric tension in DCM may be due at least in part to a reduction of the beta-adrenergically mediated (PKA-dependent) phosphorylation of myofibrillar regulatory proteins such as troponin I and/or C-protein.     

磁共振T1 mapping成像评价肥厚型和扩张型心肌病弥漫性心肌纤维化

目的 探讨磁共振纵向弛豫时间定量(T1 mapping)成像评价肥厚型心肌病(HCM)和扩张型心肌病(DCM)心肌纤维化的价值,及心肌纤维化与左心室射血分数的关系。方法 收集经临床诊断证实的30例HCM患者(HCM组)、27例DCM患者(DCM)和符合纳入标准的33例患者(对照组)。对所有受检者均行心脏电影成像、对比增强前、后T1 mapping成像、延迟对比增强(LGE)成像。测量不同受检者增强前、后左心室平均T1值及心功能参数并进行统计学分析,分析心肌平均T1值与心功能指标的相关性。结果 HCM组22例(22/30,73.33%)患者存在延迟强化,DCM组15例(15/27,55.56%)患者存在延迟强化,对照组无延迟强化。比增强前,HCM组[(1294.79±85.22)ms]、DCM组[(1312.88±59.57)ms]左心室心肌T1值均较对照组[(1266.56±57.33)ms]显著增加(P均<0.05);对比增强后,HCM组[(491.31±121.59)ms]、DCM组[(466.77±126.34)ms]左心室心肌T1均值较对照组[(534.09±92.73)]显著减低(P均<0.05)。HCM患者左心室心肌增强前T1值与左心室射血分数呈负相关(r=-0.58,P<0.05),增强后T1值与其呈正相关(r=0.59,P<0.05);DCM患者左心室心肌增强前T1值与左心室射血分数呈负相关(r=-0.55,P<0.05),增强后T1值与其呈正相关(r=0.51,P<0.05)。结论 HCM和DCM患者心肌纤维化与心功能相关;T1 mapping成像有助于评价HCM和DCM患者心肌纤维化。     

动态三维重建房室瓣腱索的临床价值

目的：评价房室瓣腱索在房室瓣病变的诊断和治疗中的临床价值。方法：我们应用动态三维重建技术,研究了３３例房室瓣病变患者的腱索,其中男性１８例,女性１５例,年龄１４～５６岁,全部病例经手术及／或心导管证实,图像采集使用ＨＰＳＯＮＯＳ２５００超声心动图仪（配有３．７／５．０ＭＨｚ的多平面经食道探头）,三维重建采用ＴＯＭＴＥＣＥＣＨＯＳＣＡＮ系统,将采集的图像提取并重建,从房室的侧面观察房室瓣腱索及瓣膜情况。结果：本组瓣膜病患者,有两组腱索增粗并钙化者及腱索稀疏与断裂者均行瓣膜置换术,仅单组腱索增粗者行瓣膜球囊扩张术,两组腱索增粗而无钙化者行瓣膜闭式分离术,动态三维重建技术展示了二维显像所不能获得的房室瓣腱索的立体图像。结论：动态三维重建房室瓣腱索能全面评价房室瓣病变,在瓣膜病的诊断与治疗中有重要意义。     

Protective effect of omapatrilat, a vasopeptidase inhibitor, on the metabolism of bradykinin in normal and failing human hearts

Because part of the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitors results from their protective effects on cardiac bradykinin (BK) metabolism, the purpose of this study was to define the metabolism of BK in normal and failing human hearts and to compare the effect of omapatrilat, a vasopeptidase inhibitor (VPI), which simultaneously inhibits both neutral endopeptidase (NEP) and ACE, with that of an ACE inhibitor. Exogenous BK at a nanomolar concentration was incubated alone, in the presence of an ACE inhibitor (ramiprilat, 36 nM), or in the presence of a VPI (omapatrilat, 61 nM) with left ventricular membranes prepared from normal donor hearts (n = 7), and hearts from patients with an ischemic (n = 11) or dilated (n = 12) cardiomyopathy (DCM). The half-lives calculated for BK alone (199 +/- 60, 224 +/- 108, and 283 +/- 122 s; P = NS) exhibited similar values for normal, ischemic, and DCM heart tissues, respectively. Ramiprilat significantly increased the half-life of BK (P <.01), but the effect was similar for the three kinds of tissues (297 +/- 104, 267 +/- 157, and 407 +/- 146 s, respectively; P = NS). The potentiating effect of the VPI omapatrilat on the kinetic parameter of BK (478 +/- 210, 544 +/- 249, and 811 +/- 349 s, respectively) was greater than that of the ACE inhibitor (P <.01). Moreover, omapatrilat had a more important potentiating effect with DCM than normal heart membranes (P <.05). These results show that not only ACE but also and mainly NEP play an important role in the degradation of BK in human heart membranes. Omapatrilat, a VPI, has a greater protective effect on BK metabolism than that of a pure ACE inhibitor. Thus, inhibition of both ACE and NEP with omapatrilat could be more cardioprotective than ACE inhibition alone.     

Analysis of shape and motion of the mitral annulus in subjects with and without cardiomyopathy by echocardiographic 3-dimensional reconstruction.

The shape and dynamics of the mitral annulus of 10 patients without heart disease (controls), 3 patients with dilated cardiomyopathy, and 5 patients with hypertrophic obstructive cardiomyopathy and normal systolic function were analyzed by transesophageal echocardiography and 3-dimensional reconstruction. Mitral annular orifice area, apico-basal motion of the annulus, and nonplanarity were calculated over time. Annular area was largest in end diastole and smallest in end systole. Mean areas were 11.8 +/- 2.5 cm(2) (controls), 15.2 +/- 4.2 cm(2) (dilated cardiomyopathy), and 10.2 +/- 2.4 cm(2) (hypertrophic cardiomyopathy) (P = not significant). After correction for body surface, annuli from patients with normal left ventricular function were smaller than annuli from patients with dilated cardiomyopathy (5.9 +/- 1.2 cm(2)/m(2) vs 7.7 +/- 1.0 cm(2)/m(2); P <.02). The change in area during the cardiac cycle showed significant differences: 23.8% +/- 5.1% (controls), 13.2% +/- 2.3% (dilated cardiomyopathy), and 32.4% +/- 7.6% (hypertrophic cardiomyopathy) (P <.001). Apico-basal motion was highest in controls, followed by those with hypertrophic obstructive and dilated cardiomyopathy (1.0 +/- 0.3 cm, 0.8 +/- 0.2 cm, 0.3 +/- 0.2 cm, respectively; P <.01). Visual inspection and Fourier analysis showed a consistent pattern of anteroseptal and posterolateral elevations of the annulus toward the left atrium. In conclusion, although area changes and apico-basal motion of the mitral annulus strongly depend on left ventricular systolic function, nonplanarity is a structural feature preserved throughout the cardiac cycle in all three groups.     

Genotypic effect of a mutation of the MYBPC3 gene and two phenotypes with different patterns of inheritance

Background

MYBPC3 mutations have been described in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). A mutation, c.3373G>A, has been reported to cause autosomal recessive form of HCM. Here, we report that this mutation can cause autosomal dominant form of DCM.

Methods

Next‐generation sequencing using targeted panel of a total of 23 candidate genes and following Sanger sequencing was applied to detect causal mutations of DCM. Computational analyses were also performed using available software tools. In silico structural and functional analyses including protein modeling and prediction were done for the mutated MYBPC3 protein.

Results and Conclusion

Targeted sequencing showed one variant c.3373G>A (p.Val1125Met) in the studied family following autosomal dominant inheritance. Computational programs predicted a high score of pathogenicity. Secondary structure of the region surrounding p.Val1125 was changed to a shortened beta‐strand based on prediction of I‐TASSER and Phyre2 servers with high confidence value for the mutation. cMyBP‐C protein was modeled to 3dmkA. Our findings suggest that one single mutation of MYBPC3 may have different effects on the cellular mechanisms based of its zygosity. Various factors might be considered for explaining this phenomenon. This gene may have an important role in Iranian DCM and HCM patients.

     

肥厚型与扩张型心肌病的心电图改变

目的观察肥厚型与扩张型心肌病病例的心电图改变。方法对9例肥厚型心肌病与19例扩张型心肌病患者心电图资料进行分析。结果肥厚型心肌病组77．8％心电图出现异常,以ST—T改变发生率最高（6例,67％）,左心室肥大次之（5例,56％）,传导障碍（3例,33％）,有1例V3-V5导联出现巨大倒置T波（11％）。扩张型心肌病组全部患者均有不同程度心电图改变,ST—T改变发生率（12例,63％）与肥厚型大致相等,P波改变（12例,63％）、传导障碍（9例,47％）、心房颤动（4例,21％）、室性心动过速（3例,16％）发生率均较肥厚型高,左心室肥大较肥厚型低（37％）。结论肥厚型与扩张型心肌病均可引起多种类型心电图改变,重视临床及心电图变化,采取进一步的检查措施可以最大限度地减少该病的误诊。     

Alterations in cardiac adrenergic signaling and calcium cycling differentially affect the progression of cardiomyopathy

The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.