Browsing by Subject "Sudden death"
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Item Abnormal Cardiac Repolarization After Seizure Episodes in Structural Brain Diseases: Cardiac Manifestation of Electrical Remodeling in the Brain?(American Heart Association, 2021-05-04) Mori, Shusuke; Hori, Atsushi; Turker, Isik; Inaji, Motoki; Bello-Pardo, Erika; Miida, Takashi; Otomo, Yasuhiro; Ai, Tomohiko; Medicine, School of MedicineBackground: Abnormal cardiac repolarization is observed in patients with epilepsy and can be associated with sudden death. We investigated whether structural brain abnormalities are correlated with abnormal cardiac repolarizations in patients with seizure or epilepsy. Methods and Results: We retrospectively analyzed and compared 12-lead ECG parameters following seizures between patients with and without structural brain abnormalities. A total of 96 patients were included: 33 women (17 with and 16 without brain abnormality) and 63 men (44 with and 19 without brain abnormality). Brain abnormalities included past stroke, chronic hematoma, remote bleeding, tumor, trauma, and postsurgical state. ECG parameters were comparable for heart rate, PR interval, and QRS duration between groups. In contrast, corrected QT intervals evaluated by Fridericia, Framingham, and Bazett formulas were prolonged in patients with brain abnormality compared with those without (women: Fridericia [normal versus abnormal], 397.4±32.7 versus 470.9±48.9; P=0.002; Framingham, 351.0±40.1 versus 406.2±46.1; P=0.002; Bazett, 423.8±38.3 versus 507.7±56.6; P<0.0001; men: Fridericia, 403.8±30.4 versus 471.0±47.1; P<0.0001; Framingham, 342.7±36.4 versus 409.4±45.8; P<0.0001; Bazett, 439.3±38.6 versus 506.2±56.8; P<0.0001). QT dispersion and Tpeak-Tend intervals were comparable between groups. We also observed abnormal ST-segment elevation in 5 patients. Importantly, no patients showed fatal arrhythmias during or after seizures. Conclusions: Our study demonstrated that brain abnormalities can be associated with abnormal cardiac repolarization after seizures, which might be a manifestation of electrophysiological remodeling in the brain.Item Arrhythmia Mechanism and Dynamics in a Humanized Mouse Model of Inherited Cardiomyopathy Caused by Phospholamban R14del Mutation(American Heart Association, 2021) Raad, Nour; Bittihn, Philip; Cacheux, Marine; Jeong, Dongtak; Ilkan, Zeki; Ceholski, Delaine; Kohlbrenner, Erik; Zhang, Lu; Cai, Chen-Leng; Kranias, Evangelia G.; Hajjar, Roger J.; Stillitano, Francesca; Akar, Fadi G.; Pediatrics, School of MedicineBackground: Arginine (Arg) 14 deletion (R14del) in the calcium regulatory protein phospholamban (hPLNR14del) has been identified as a disease-causing mutation in patients with an inherited cardiomyopathy. Mechanisms underlying the early arrhythmogenic phenotype that predisposes carriers of this mutation to sudden death with no apparent structural remodeling remain unclear. Methods: To address this, we performed high spatiotemporal resolution optical mapping of intact hearts from adult knock-in mice harboring the human PLNWT (wildtype [WT], n=12) or the heterozygous human PLNR14del mutation (R14del, n=12) before and after ex vivo challenge with isoproterenol and rapid pacing. Results: Adverse electrophysiological remodeling was evident in the absence of significant structural or hemodynamic changes. R14del hearts exhibited increased arrhythmia susceptibility compared with wildtype. Underlying this susceptibility was preferential right ventricular action potential prolongation that was unresponsive to β-adrenergic stimulation. A steep repolarization gradient at the left ventricular/right ventricular interface provided the substrate for interventricular activation delays and ultimately local conduction block during rapid pacing. This was followed by the initiation of macroreentrant circuits supporting the onset of ventricular tachycardia. Once sustained, these circuits evolved into high-frequency rotors, which in their majority were pinned to the right ventricle. These rotors exhibited unique spatiotemporal dynamics that promoted their increased stability in R14del compared with wildtype hearts. Conclusions: Our findings highlight the crucial role of primary electric remodeling caused by the hPLNR14del mutation. These inherently arrhythmogenic features form the substrate for adrenergic-mediated VT at early stages of PLNR14del induced cardiomyopathy.Item Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry(Oxford University Press, 2016-06-06) Crotti, Lia; Spazzolini, Carla; Tester, David J; Ghidoni, Alice; Baruteau, Alban-Elouen; Beckmann, Britt-Maria; Behr, Elijah R; Bennett, Jeffrey S; Bezzina, Connie R; Bhuiyan, Zahurul A; Celiker, Alpay; Cerrone, Marina; Dagradi, Federica; De Ferrari, Gaetano M; Etheridge, Susan P; Fatah, Meena; Garcia-Pavia, Pablo; Al-Ghamdi, Saleh; Hamilton, Robert M; Al-Hassnan, Zuhair N; Horie, Minoru; Jimenez-Jaimez, Juan; Kanter, Ronald J.; Kaski, Juan P.; Kotta, Maria-Christina; Lahrouchi, Najim; Makita, Naomasa; Norrish, Gabrielle; Odland, Hans H.; Ohno, Seiko; Papagiannis, John; Parati, Gianfranco; Sekarski, Nicole; Tveten, Kristian; Vatta, Matteo; Webster, Gregory; Wilde, Arthur A. M.; Wojciak, Julianne; George, Alfred L., Jr; Ackerman, Michael J.; Schwartz, Peter J.; Medical and Molecular Genetics, School of MedicineAims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.Item Cardiovascular complications in chronic kidney disease: a review from the European Renal and Cardiovascular Medicine Working Group of the European Renal Association(Oxford University Press, 2023) Zoccali, Carmine; Mallamaci, Francesca; Adamczak, Marcin; Bueno de Oliveira, Rodrigo; Massy, Ziad A.; Sarafidis, Pantelis; Agarwal, Rajiv; Mark, Patrick B.; Kotanko, Peter; Ferro, Charles J.; Wanner, Christoph; Burnier, Michel; Vanholder, Raymond; Wiecek, Andrzej; Medicine, School of MedicineChronic kidney disease (CKD) is classified into five stages with kidney failure being the most severe stage (stage G5). CKD conveys a high risk for coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. Cardiovascular complications are the most common causes of death in patients with kidney failure (stage G5) who are maintained on regular dialysis treatment. Because of the high death rate attributable to cardiovascular (CV) disease, most patients with progressive CKD die before reaching kidney failure. Classical risk factors implicated in CV disease are involved in the early stages of CKD. In intermediate and late stages, non-traditional risk factors, including iso-osmotic and non-osmotic sodium retention, volume expansion, anaemia, inflammation, malnutrition, sympathetic overactivity, mineral bone disorders, accumulation of a class of endogenous compounds called 'uremic toxins', and a variety of hormonal disorders are the main factors that accelerate the progression of CV disease in these patients. Arterial disease in CKD patients is characterized by an almost unique propensity to calcification and vascular stiffness. Left ventricular hypertrophy, a major risk factor for heart failure, occurs early in CKD and reaches a prevalence of 70-80% in patients with kidney failure. Recent clinical trials have shown the potential benefits of hypoxia-inducible factor prolyl hydroxylase inhibitors, especially as an oral agent in CKD patients. Likewise, the value of proactively administered intravenous iron for safely treating anaemia in dialysis patients has been shown. Sodium/glucose cotransporter-2 inhibitors are now fully emerged as a class of drugs that substantially reduces the risk for CV complications in patients who are already being treated with adequate doses of inhibitors of the renin-angiotensin system. Concerted efforts are being made by major scientific societies to advance basic and clinical research on CV disease in patients with CKD, a research area that remains insufficiently explored.Item The cardiovascular-dialysis nexus: the transition to dialysis is a treacherous time for the heart(Oxford University Press, 2021) Chan, Kevin; Moe, Sharon M.; Saran, Rajiv; Libby, Peter; Medicine, School of MedicineChronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.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 Delineation of Molecular Pathways Involved in Cardiomyopathies Caused by Troponin T Mutations(American Society for Biochemistry and Molecular Biology, 2016-06) Gilda, Jennifer E.; Lai, Xianyin; Witzmann, Frank A.; Gomes, Aldrin V.; Cellular and Integrative Physiology, School of MedicineFamilial hypertrophic cardiomyopathy (FHC) is associated with mild to severe cardiac problems and is the leading cause of sudden death in young people and athletes. Although the genetic basis for FHC is well-established, the molecular mechanisms that ultimately lead to cardiac dysfunction are not well understood. To obtain important insights into the molecular mechanism(s) involved in FHC, hearts from two FHC troponin T models (Ile79Asn [I79N] and Arg278Cys [R278C]) were investigated using label-free proteomics and metabolomics. Mutations in troponin T are the third most common cause of FHC, and the I79N mutation is associated with a high risk of sudden cardiac death. Most FHC-causing mutations, including I79N, increase the Ca(2+) sensitivity of the myofilament; however, the R278C mutation does not alter Ca(2+) sensitivity and is associated with a better prognosis than most FHC mutations. Out of more than 1200 identified proteins, 53 and 76 proteins were differentially expressed in I79N and R278C hearts, respectively, when compared with wild-type hearts. Interestingly, more than 400 proteins were differentially expressed when the I79N and R278C hearts were directly compared. The three major pathways affected in I79N hearts relative to R278C and wild-type hearts were the ubiquitin-proteasome system, antioxidant systems, and energy production pathways. Further investigation of the proteasome system using Western blotting and activity assays showed that proteasome dysfunction occurs in I79N hearts. Metabolomic results corroborate the proteomic data and suggest the glycolytic, citric acid, and electron transport chain pathways are important pathways that are altered in I79N hearts relative to R278C or wild-type hearts. Our findings suggest that impaired energy production and protein degradation dysfunction are important mechanisms in FHCs associated with poor prognosis and that cardiac hypertrophy is not likely needed for a switch from fatty acid to glucose metabolism.Item Subcutaneous nerve activity and mechanisms of sudden death in a rat model of chronic kidney disease(Elsevier, 2016-05) Zhao, Ye; Chen, Neal X.; Shirazi, Jonathan T.; Shen, Changyu; Lin, Shien-Fong; Fishbein, Michael C.; Moe, Sharon M.; Chen, Peng-Sheng; Department of Medicine, IU School of MedicineBACKGROUND: The mechanisms of sudden death in chronic kidney disease (CKD) remain unclear. OBJECTIVE: The purpose of this study was to test the hypotheses that subcutaneous nerve activity (SCNA) can be used to estimate sympathetic tone in ambulatory rats and that abrupt reduction of SCNA precedes the spontaneous arrhythmic death of Cy/+ rats. METHODS: Radiotransmitters were implanted in ambulatory normal (N = 6) and Cy/+ (CKD; N = 6) rats to record electrocardiogram and SCNA. Two additional rats were studied before and after chemical sympathectomy with 6-hydroxydopamine. RESULTS: In normal rats, the baseline heart rate (HR) and SCNA were 351 ± 29 bpm and 5.12 ± 2.97 mV·s, respectively. SCNA abruptly increased HR by 4.31% (95% confidence interval 4.15%-4.47%). In comparison, the CKD rats had reduced baseline HR (336 ± 21 bpm, P < .01) and SCNA (4.27 ± 3.19 mV·s, P < .01). When SCNA was observed, HR increased by only 2.48% (confidence interval 2.29%-2.67%, P < .01). All Cy/+ rats died suddenly, preceded by sinus bradycardia, advanced (second- and third-degree) AV block (N = 6), and/or ventricular tachycardia or fibrillation (N = 3). Sudden death was preceded by a further reduction of SCNA (3.22 ± 2.86 mV·s, P < .01) and sinus bradycardia (243 ± 55 bpm, P < .01). Histologic studies in CKD rats showed myocardial calcification that involved the conduction system. Chemical sympathectomy resulted in progressive reduction of SCNA over 7 days. CONCLUSION: SCNA can be used to estimate sympathetic tone in ambulatory rats. CKD is associated with reduced HR response to SCNA and conduction system diseases. Abrupt reduction of sympathetic tone precedes AV block, ventricular arrhythmia, and sudden death of CKD rats.