Browsing by Subject "Cardiomyopathies"
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Item Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry(Oxford University Press, 2023) Crotti, Lia; Spazzolini, Carla; Nyegaard, Mette; Overgaard, Michael T.; Kotta, Maria-Christina; Dagradi, Federica; Sala, Luca; Aiba, Takeshi; Ayers, Mark D.; Baban, Anwar; Barc, Julien; Beach, Cheyenne M.; Behr, Elijah R.; Bos, J. Martijn; Cerrone, Marina; Covi, Peter; Cuneo, Bettina; Denjoy, Isabelle; Donner, Birgit; Elbert, Adrienne; Eliasson, Håkan; Etheridge, Susan P.; Fukuyama, Megumi; Girolami, Francesca; Hamilton, Robert; Horie, Minoru; Iascone, Maria; Jiménez-Jaimez, Juan; Jensen, Henrik Kjærulf; Kannankeril, Prince J.; Kaski, Juan P.; Makita, Naomasa; Muñoz-Esparza, Carmen; Odland, Hans H.; Ohno, Seiko; Papagiannis, John; Porretta, Alessandra Pia; Prandstetter, Christopher; Probst, Vincent; Robyns, Tomas; Rosenthal, Eric; Rosés-Noguer, Ferran; Sekarski, Nicole; Singh, Anoop; Spentzou, Georgia; Stute, Fridrike; Tfelt-Hansen, Jacob; Till, Jan; Tobert, Kathryn E.; Vinocur, Jeffrey M.; Webster, Gregory; Wilde, Arthur A. M.; Wolf, Cordula M.; Ackerman, Michael J.; Schwartz, Peter J.; Pediatrics, School of MedicineAims: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. Methods and results: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. Conclusion: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.Item Divergent actions of Myofibroblast and Myocyte β2-Adrenoceptor in Heart Failure and Fibrotic Remodeling(American Heart Association, 2023) Deng, Bingqing; Zhang, Yu; Zhu, Chaoqun; Wang, Ying; Weatherford, Eric; Xu, Bing; Liu, Xuanhui; Conway, Simon J.; Abel, E. Dale; Xiang, Yang K.; Pediatrics, School of MedicineItem Duchenne Muscular Dystrophy Patients: Troponin Leak in Asymptomatic and Implications for Drug Toxicity Studies(Springer Nature, 2022) Sheybani, Aryaz; Crum, Kim; Raucci, Frank J.; Burnette, William B.; Markham, Larry W.; Soslow, Jonathan H.; Pediatrics, School of MedicineBackground: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), but studies suggest heart failure biomarkers correlate poorly with cardiomyopathy severity. DMD clinical trials have used troponin I (cTnI) as a biomarker of toxicity, but it is unclear if asymptomatic DMD patients have elevated cTnI. We longitudinally evaluated cTnI, brain natriuretic peptide (BNP), and N-terminal pro-BNP (NT-proBNP) in a DMD cohort. Methods: DMD patients were prospectively enrolled and followed for 3 years. Serum was drawn at the time of cardiac magnetic resonance (CMR). Normal biomarker values were derived from healthy subjects. Biomarkers were correlated with CMR markers. Results: All subjects were asymptomatic at the time of enrollment. Several DMD subjects had transiently elevated cTnI. Those with elevated cTnI were more likely to have late gadolinium enhancement on baseline CMR. NT-proBNP correlated with indexed left ventricular end diastolic and maximum left atrial volumes. Otherwise, standard cardiac biomarkers did not correlate with CMR markers of cardiomyopathy. Conclusions: CTnI, BNP, and NT-proBNP do not correlate with CMR assessment of cardiomyopathy progression. A subset of DMD patients have asymptomatic cTnI leak of uncertain clinical significance, though of critical importance if cTnI is used to assess for cardiac toxicity in future drug trials. Impact: Asymptomatic patients with Duchenne muscular dystrophy (DMD) exhibit transient troponin I leak. NT-proBNP correlated with indexed left ventricular end diastolic volume and indexed maximum left atrial volume. Other cardiac biomarkers did not correlate with cardiac magnetic resonance (CMR) markers of cardiomyopathy.Item Fragmented ECG as a risk marker in cardiovascular diseases(Bentham Science, 2014-08) Jain, Rahul; Singh, Robin; Yamini, Sundermurthy; Das, Mithilesh K.; Department of Medicine, IU School of MedicineVarious noninvasive tests for risk stratification of sudden cardiac death (SCD) were studied, mostly in the context of structural heart disease such as coronary artery disease (CAD), cardiomyopathy and heart failure but have low positive predictive value for SCD. Fragmented QRS complexes (fQRS) on a 12-lead ECG is a marker of depolarization abnormality. fQRS include presence of various morphologies of the QRS wave with or without a Q wave and includes the presence of an additional R wave (R') or notching in the nadir of the R' (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory. fQRS represents conduction delay from inhomogeneous activation of the ventricles due to myocardial scar. It has a high predictive value for myocardial scar and mortality in patients CAD. fQRS also predicts arrhythmic events and mortality in patients with implantable cardioverter defibrillator. It also signifies poor prognosis in patients with nonischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome. However, fQRS is a nonspecific finding and its diagnostic prognostic should only be interpreted in the presence of pertinent clinical evidence and type of myocardial involvement (structural vs. structurally normal heart).Item Genetic ablation of Cullin-RING E3 ubiquitin ligase 7 restrains pressure overload-induced myocardial fibrosis(PLOS, 2020-12-22) Anger, Melanie; Scheufele, Florian; Ramanujam, Deepak; Meyer, Kathleen; Nakajima, Hidehiro; Field, Loren J.; Engelhardt, Stefan; Sarikas, Antonio; Medicine, School of MedicineFibrosis is a pathognomonic feature of structural heart disease and counteracted by distinct cardioprotective mechanisms, e.g. activation of the phosphoinositide 3-kinase (PI3K) / AKT pro-survival pathway. The Cullin-RING E3 ubiquitin ligase 7 (CRL7) was identified as negative regulator of PI3K/AKT signalling in skeletal muscle, but its role in the heart remains to be elucidated. Here, we sought to determine whether CRL7 modulates to cardiac fibrosis following pressure overload and dissect its underlying mechanisms. For inactivation of CRL7, the Cullin 7 (Cul7) gene was deleted in cardiac myocytes (CM) by injection of adeno-associated virus subtype 9 (AAV9) vectors encoding codon improved Cre-recombinase (AAV9-CMV-iCre) in Cul7flox/flox mice. In addition, Myosin Heavy Chain 6 (Myh6; alpha-MHC)-MerCreMer transgenic mice with tamoxifen-induced CM-specific expression of iCre were used as alternate model. After transverse aortic constriction (TAC), causing chronic pressure overload and fibrosis, AAV9-CMV-iCre induced Cul7-/- mice displayed a ~50% reduction of interstitial cardiac fibrosis when compared to Cul7+/+ animals (6.7% vs. 3.4%, p<0.01). Similar results were obtained with Cul7flox/flox Myh6-Mer-Cre-MerTg(1/0) mice which displayed a ~30% reduction of cardiac fibrosis after TAC when compared to Cul7+/+ Myh6-Mer-Cre-MerTg(1/0) controls after TAC surgery (12.4% vs. 8.7%, p<0.05). No hemodynamic alterations were observed. AKTSer473 phosphorylation was increased 3-fold (p<0.01) in Cul7-/- vs. control mice, together with a ~78% (p<0.001) reduction of TUNEL-positive apoptotic cells three weeks after TAC. In addition, CM-specific expression of a dominant-negative CUL71152stop mutant resulted in a 16.3-fold decrease (p<0.001) of in situ end-labelling (ISEL) positive apoptotic cells. Collectively, our data demonstrate that CM-specific ablation of Cul7 restrains myocardial fibrosis and apoptosis upon pressure overload, and introduce CRL7 as a potential target for anti-fibrotic therapeutic strategies of the heart.Item Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association(American Heart Association, 2021) Landstrom, Andrew P.; Kim, Jeffrey J.; Gelb, Bruce D.; Helm, Benjamin M.; Kannankeril, Prince J.; Semsarian, Christopher; Sturm, Amy C.; Tristani-Firouzi, Martin; Ware, Stephanie M.; Medical and Molecular Genetics, School of MedicineGenetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.Item Genetic Testing in Pediatric Left Ventricular Noncompaction(American Heart Association, 2017-12) Miller, Erin M.; Hinton, Robert B.; Czosek, Richard; Lorts, Angela; Parrott, Ashley; Shikany, Amy R.; Ittenbach, Richard F.; Ware, Stephanie M.; Pediatrics, School of MedicineBackground: Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield. Methods and results: One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic pathogenesis, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, pathogenesis, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively; P<0.01). Conclusions: Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy.Item Genomics of pediatric cardiomyopathy(Springer Nature, 2025) Lee, Teresa M.; Ware, Stephanie M.; Kamsheh, Alicia M.; Bhatnagar, Surbhi; Absi, Mohammed; Miller, Elyse; Purevjav, Enkhsaikhan; Ryan, Kaitlin A.; Towbin, Jeffrey A.; Lipshultz, Steven E.; Pediatrics, School of MedicineCardiomyopathy in children is a leading cause of heart failure and cardiac transplantation. Disease-associated genetic variants play a significant role in the development of the different subtypes of disease. Genetic testing is increasingly being recognized as the standard of care for diagnosing this heterogeneous group of disorders, guiding management, providing prognostic information, and facilitating family-based risk stratification. The increase in clinical and research genetic testing within the field has led to new insights into this group of disorders. Mutations in genes encoding sarcomere, cytoskeletal, Z-disk, and sarcolemma proteins appear to play a major role in causing the overlapping clinical phenotypes called cardioskeletal myopathies through "final common pathway" links. For myocarditis, the high frequency of infectious exposures and wide spectrum of presentation suggest that genetic factors mediate the development and course of the disease, including genetic risk alleles, an association with cardiomyopathy, and undiagnosed arrhythmogenic cardiomyopathy. Finally, while we have made strides in elucidating the genetic architecture of pediatric cardiomyopathy, understanding the clinical implications of variants of uncertain significance remains a major issue. The need for continued genetic innovation in this field remains great, particularly as a basis to drive forward targeted precision medicine and gene therapy efforts. IMPACT: Cardiomyopathy and skeletal myopathy can occur in the same patient secondary to gene mutations that encode for sarcomeric or cytoskeletal proteins, which are expressed in both muscle groups, highlighting that there are common final pathways of disease. The heterogeneous presentation of myocarditis is likely secondary to a complex interaction of multiple environmental and genetic factors, suggesting a utility to genetic testing in pediatric patients with myocarditis, particularly those in higher risk groups. Given the high prevalence of variants of uncertain significance in genetic testing, better bioinformatic tools and pipelines are needed to resolve their clinical meaning.Item IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias(American Society of Hematology, 2021) Gupta, Akash; Fei, Yu-Dong; Kim, Tae Yun; Xie, An; Batai, Ken; Greener, Ian; Tang, Haiyang; Ciftci-Yilmaz, Sultan; Juneman, Elizabeth; Indik, Julia H.; Shi, Guanbin; Christensen, Jared; Gupta, Geetanjali; Hillery, Cheryl; Kansal, Mayank M.; Parikh, Devang S.; Zhou, Tong; Yuan, Jason X-J; Kanthi, Yogendra; Bronk, Peter; Koren, Gideon; Kittles, Rick; Duarte, Julio D.; Garcia, Joe G. N.; Machado, Roberto F.; Dudley, Samuel C.; Choi, Bum-Rak; Desai, Ankit A.; Medicine, School of MedicinePrevious reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.Item Increased Risk of Valvular Heart Disease in Systemic Sclerosis: An Underrecognized Cardiac Complication(Journal of Rheumatology, 2021) Kurmann, Reto D.; El-Am, Edward A.; Radwan, Yasser A.; Sandhu, Avneek S.; Crowson, Cynthia S.; Matteson, Eric L.; Warrington, Kenneth J.; Mankad, Rekha; Makol, Ashima; Medicine, School of MedicineObjective: Cardiac involvement is a poor prognostic marker in systemic sclerosis (SSc). While diastolic dysfunction, myocardial fibrosis, and arrhythmias are traditionally considered features of primary cardiac involvement in SSc, the incidence of valvular heart disease (VHD) is not well reported. Our objective was to examine the prevalence of VHD at the time of SSc diagnosis and incidence of VHD during follow-up compared to non-SSc subjects. Methods: Medical records of patients with suspicion of SSc were reviewed to identify incident cases. SSc subjects were matched 1:2 by age and sex to non-SSc subjects. Results: The study included 78 incident SSc cases and 156 non-SSc comparators (56 yrs [± 15.7], 91% female). A nearly 4-fold increase in the prevalence of moderate/severe VHD prior to SSc diagnosis compared to non-SSc subjects (6% vs 0%; P = 0.004) was identified. During follow-up, 18 SSc and 12 non-SSc patients developed moderate/severe VHD. The cumulative incidence of VHD at 10 years after SSc incidence/index was 17.9% (95% CI 10.7-29.9) in patients with SSc compared with 2.3% (95% CI 0.7-7.0) in non-SSc subjects (HR 4.23, 95% CI 2.03-8.83). Coronary artery disease was the only significant risk factor for VHD. Conclusion: Patients with SSc have a 4-fold increase in the prevalence of moderate/severe VHD at diagnosis compared to non-SSc patients. They also have a 4-fold increased risk of developing moderate/severe VHD after diagnosis of SSc. Aortic stenosis and mitral regurgitation have a much higher prevalence in patients with SSc, besides secondary tricuspid regurgitation. Underlying mechanisms for this association require further elucidation.