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AIMS: The concept of atrial cardiomyopathy (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS: The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION: Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

BACKGROUND: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. OBJECTIVES: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). METHODS: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). RESULTS: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM. RESULTS: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics. CONCLUSIONS: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN.

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.

BACKGROUND: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke. METHODS AND RESULTS: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected > 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility.

INTRODUCTION: Transthyretin amyloidosis (ATTR amyloidosis) is primarily associated with a cardiac or neurologic phenotype, but a mixed phenotype is increasingly described. METHODS: This study describes the mixed phenotype cohort in the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, longitudinal, observational survey of patients with ATTR amyloidosis, including both hereditary (ATTRv) and wild-type disease, and asymptomatic carriers of pathogenic transthyretin variants. Baseline characteristics of patients with a mixed phenotype (at enrollment or reclassified during follow-up) are described (data cutoff: January 4, 2022). RESULTS: Approximately one-third of symptomatic patients (n = 1185/3542; 33.5%) were classified at enrollment or follow-up as mixed phenotype (median age, 66.5 years). Of those, 344 (29.0%) were reclassified to mixed phenotype within a median 1-2 years of follow-up. Most patients with mixed phenotype had ATTRv amyloidosis (75.7%). The most frequent genotypes were V30M (38.9%) and wild type (24.3%). CONCLUSIONS: These THAOS data represent the largest analysis of a real-world mixed phenotype ATTR amyloidosis population to date and suggest that a mixed phenotype may be more prevalent than previously thought. Patients may also migrate from a primarily neurologic or cardiologic presentation to a mixed phenotype over time. These data reinforce the need for multidisciplinary evaluation at initial assessment and follow-up of all patients with ATTR amyloidosis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00628745.

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.

Hypertrophic cardiomyopathy (HCM) remains the most common cardiomyopathy in humans and cats with few preclinical pharmacologic interventional studies. Small-molecule sarcomere inhibitors are promising novel therapeutics for the management of obstructive HCM (oHCM) patients and have shown efficacy in left ventricular outflow tract obstruction (LVOTO) relief. The objective of this study was to explore the 6-, 24-, and 48-hour (h) pharmacodynamic effects of the cardiac myosin inhibitor, CK-586, in six purpose-bred cats with naturally occurring oHCM. A blinded, randomized, five-treatment group, crossover preclinical trial was conducted to assess the pharmacodynamic effects of CK-586 in this oHCM model. Dose assessments and select echocardiographic variables were assessed five times over a 48-h period. Treatment with oral CK-586 safely ameliorated LVOTO in oHCM cats. CK-586 treatment dose-dependently eliminated obstruction (reduced LVOTOmaxPG), increased measures of systolic chamber size (LVIDs Sx), and decreased select measures of heart function (LV FS% and LV EF%) in the absence of impact on heart rate. At all tested doses, a single oral CK-586 dose resulted in improved or resolved LVOTO with well-tolerated, dose-dependent, reductions in LV systolic function. The results from this study pave the way for the potential use of CK-586 in both the veterinary and human clinical setting.

Skeletal muscle actin (ACTA1) mutations are a prevalent cause of skeletal myopathies consistent with ACTA1's high expression in skeletal muscle. Rare de novo mutations in ACTA1 associated with combined cardiac and skeletal myopathies have been reported, but ACTA1 represents only ~20% of the total actin pool in cardiomyocytes, making its role in cardiomyopathy controversial. Here we demonstrate how a mutation in an actin isoform expressed at low levels in cardiomyocytes can cause cardiomyopathy by focusing on a unique ACTA1 variant, R256H. We previously identified this variant in a family with dilated cardiomyopathy, who had reduced systolic function without clinical skeletal myopathy. Using a battery of multiscale biophysical tools, we show that R256H has potent effects on ACTA1 function at the molecular scale and in human cardiomyocytes. Importantly, we demonstrate that R256H acts in a dominant manner, where the incorporation of small amounts of mutant protein into thin filaments is sufficient to disrupt molecular contractility, and that this effect is dependent on the presence of troponin and tropomyosin. To understand the structural basis of this change in regulation, we resolved a structure of R256H filaments using cryoelectron microscopy, and we see alterations in actin's structure that have the potential to disrupt interactions with tropomyosin. Finally, we show that ACTA1R256H/+ human-induced pluripotent stem cell cardiomyocytes demonstrate reduced contractility and sarcomeric organization. Taken together, we demonstrate that R256H has multiple effects on ACTA1 function that are sufficient to cause reduced contractility and establish a likely causative relationship between ACTA1 R256H and clinical cardiomyopathy. [ABSTRACT FROM AUTHOR]

Phospholamban (PLN) plays a crucial role in regulating sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Mutations within the PLN gene have been detected in patients with cardiomyopathy, with the heterozygous variant c.40_42delAGA (p.R14del) of PLN being the most prevalent. Investigations into the mechanisms underlying the pathology of PLN-R14del have revealed that cardiac cells from affected patients exhibit pathological aggregates containing PLN. Herein, we performed comprehensive molecular and cellular analyses to delineate the molecular aberrations associated with the formation of these aggregates. We determined that PLN aggregates contain autophagic proteins, indicating inefficient degradation via the autophagy pathway. Our findings demonstrate that the expression of PLN-R14del results in diminished autophagic flux due to impaired fusion between autophagosomes and lysosomes. Mechanistically, this defect is linked to aberrant recruitment of key membrane fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+ homeostasis. Collectively, these results highlight a novel function of PLN-R14del in regulating autophagy, that may contribute to the formation of pathogenic aggregates in patients with cardiomyopathy. Prospective strategies tailored to ameliorate impaired autophagy may hold promise against PLN-R14del disease. [ABSTRACT FROM AUTHOR]

Background: Although the exact role of mitophagy in the pathogenesis of diabetic cardiomyopathy (DCM) caused by type 2 diabetes mellitus (T2DM) remains controversial, recent studies revealed inhibition of mitophagy exacerbates cardiac injury in DCM. The zinc transporter ZIP7 has been reported to be upregulated by high glucose in cardiomyocytes and ZIP7 upregulation leads to inhibition of mitophagy in mouse hearts in the setting of ischemia/reperfusion. Nevertheless, little is known about the role of ZIP7 and its relationship with mitophagy in DCM caused by T2DM. Methods: T2DM was induced with high-fat diet (HFD) and streptozotocin. The cardiac-specific ZIP7 conditional knockout (ZIP7 cKO) mice were generated by adopting CRISPR/Cas9 system. Cardiac function was evaluated with echocardiography. Mitophagy was assessed by detecting mito-LC3II, mitoKeima, and mitoQC. Reactive oxygen species (ROS) were detected with DHE and mitoB. Results: ZIP7 was upregulated by T2DM in mouse hearts and ZIP7 cKO reduced mitochondrial ROS generation in mouse hearts with T2DM. Mitophagy was suppressed by T2DM in mouse hearts, which was prevented by ZIP7 cKO. T2DM inhibited PINK1 and Parkin accumulation in cardiac mitochondria, an effect that was prevented by ZIP7 cKO, pointing to that ZIP7 upregulation mediates T2DM-induced suppression of mitophagy by inhibiting the PINK1/Parkin pathway. T2DM induced mitochondrial hyperpolarization and decrease of mitochondrial Zn2+ and this was blocked by ZIP7 cKO, indicating that upregulation of ZIP7 leads to mitochondrial hyperpolarization by reducing Zn2+ within mitochondria. Finally, ZIP7 cKO prevented cardiac dysfunction and fibrosis caused by T2DM. Conclusions: ZIP7 upregulation mediates the inhibition of mitophagy by T2DM in mouse hearts by suppressing the PINK1/Parkin pathway. Reduction of mitochondrial Zn2+ due to upregulation of ZIP7 accounts for the inhibition of the PINK1/Parkin pathway. Prevention of ZIP7 upregulation is essential for the treatment of T2DM-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening condition. Due to the scarcity of epidemiological data in North Africa, we conducted this study to assess the outcomes of PPCM in our region. Materials and methods: This monocentric retrospective cohort study involving all patients diagnosed with PPCM was conducted between January 2010 and December 2022. Results: Twenty-seven PPCM patients, with a median age of 33 years (Interquartile range (IQR) = 9), were included. 52% of patients were diagnosed during the postpartum period. Dyspnea New York Heart Association III/IV(NYHA III/IV) was the most common functional symptom (85%). The median left ventricle ejection fraction (LVEF) was 30% (IQR = 11%). Atrial fibrillation occurred in 11.1% of patients, thromboembolic complications occurred in 18.5%, Pulmonary edema occurred in 85% of patients and cardiogenic shock occurred in 14.8% of patients, with two patients requiring Extracorporeal Membrane Oxygenation (ECMO) support. The predominant mode of delivery was a cesarean Sect. (82% of patients), and the indication for a cesarean delivery was obstetrical in 59% of patients. Prematurity occurred in 36% of newborns, and intrauterine fetal death occurred in one pregnancy. The median follow-up was 24 months [6–144 months]. LVEF recovery was noted in 67% of patients. Bromocriptine was administered to six patients (22%), and none of these patients died and out of them, five patients recovered their LVEF (83%). The overall mortality rate during the follow-up period was 15%, comprising three in-hospital cardiac deaths and one occurring two years later due to refractory advanced heart failure. No significant differences were observed between LVEF recovery and LVEF non-recovery groups. Factors significantly associated with mortality were multiparity, poor antenatal care (ANC) attendance, thromboembolic events, cardiogenic shock, and Pulmonary edema. Five patients with LV recovery subsequently became pregnant, none experienced a relapse of PPCM. However, one of the descendants of a patient was diagnosed with dilated cardiomyopathy. Conclusion: This study revealed that the diagnosis of PPCM in our hospital is often delayed until symptoms become more advanced, resulting in high morbi-mortality. [ABSTRACT FROM AUTHOR]

Juvenile hemochromatosis (JH) is a subtype of hereditary hemochromatosis, a genetic disorder characterized by excessive iron absorption and deposition in various organs, leading to cardiomyopathy, cirrhosis, and diabetes. Endocrine dysfunction is a common manifestation and may appear years before end-organ damage. This report describes a rare case of JH, emphasizing the consequences of delayed diagnosis. A 28-year-old woman with a history of hypogonadotropic hypogonadism presented with cardiac arrest complicated by acute renal failure and cerebral vascular accidents. She initially exhibited signs of severe cardiomyopathy and multiorgan failure, which led to workup for an underlying cause. Laboratory values showed significantly elevated ferritin and transferrin saturation. Subsequent genetic screening revealed HJV gene pathogenic variants consistent with juvenile hemochromatosis. Treatment involved aggressive iron chelation therapy and outpatient referral for cardiac transplant. This case calls for heightened awareness and early screening of JH, particularly among patients with unexplained endocrine dysfunction. Early diagnosis and treatment are paramount in preventing irreversible organ damage and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Heart failure, a growing concern in the United States, significantly impacts both morbidity and mortality. Classified by ejection fraction, heart failure with preserved ejection fraction (HFpEF) now accounts for half of all cases and is steadily rising. Unlike its counterpart, heart failure with reduced ejection fraction (HFrEF), HFpEF lacks clear management guidelines. Recognizing this critical gap, we aim to review existing recommendations and formulate effective management strategies for HFpEF. • Heart failure with preserved ejection fraction (HFpEF) now constitutes half of all heart failure cases. • The pharmacological management of HFpEF presents a dilemma, as clear guidelines with evidence-based recommendations are lacking. • The goals of management is to improve symptoms of heart failure, reduce hospitalization and increase functional status. • Outpatient treatment strategies involve initiating SGLT2i, followed by ARNI or MRA depending on individual patients. • Inpatient treatment strategies involve optimizing volume status, followed by SGLT2i, ARNI or ARB. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is highly prevalent. Mechanisms underlying HF remain incompletely understood. Splicing factors (SF), which control pre‐mRNA alternative splicing, regulate cardiac structure and function. This study investigated regulation of the splicing factor heterogeneous nuclear ribonucleoprotein‐L (hnRNPL) in the failing heart. hnRNPL protein increased in left ventricular tissue from mice with transaortic constriction‐induced HF and from HF patients. In left ventricular tissue, hnRNPL was detected predominantly in nuclei. Knockdown of the hnRNPL homolog Smooth in Drosophila induced cardiomyopathy. Computational analysis of predicted mouse and human hnRNPL binding sites suggested hnRNPL‐mediated alternative splicing of tropomyosin, which was confirmed in C2C12 myoblasts. These findings identify hnRNPL as a sensor of cardiac dysfunction and suggest that disturbances of hnRNPL affect alternative splicing in HF. [ABSTRACT FROM AUTHOR]

HIV-associated cardiovascular diseases remain a leading cause of death in people living with HIV/AIDS (PLWHA). Although antiretroviral drugs suppress the viral load, they fail to remove the virus entirely. HIV-1 Nef protein is known to play a role in viral virulence and HIV latency. Expression of Nef protein can be detected in different organs, including cardiac tissue. Despite the established role of Nef protein in HIV-1 replication, its impact on organ function inside the human body is not clear. To understand the effect of Nef at the organ level, we created a new Nef-transgenic (Nef-TG) mouse that expresses Nef protein in the heart. Our study found that Nef expression caused inhibition of cardiac function and pathological changes in the heart with increased fibrosis, leading to heart failure and early mortality. Further, we found that cellular autophagy is significantly inhibited in the cardiac tissue of Nef-TG mice. Mechanistically, we found that Nef protein causes the accumulation of Bcl2 and Beclin-1 proteins in the tissue, which may affect the cellular autophagy system. Additionally, we found Nef expression causes upregulation of the cellular senescence marker p21 and senescence-associated β-galactosidase expression. Our findings suggest that the Nef-mediated inhibition of autophagy and induction of senescence markers may promote aging in PLWHA. Our mouse model could help us to understand the effect of Nef protein on organ function during latent HIV infection. [ABSTRACT FROM AUTHOR]

Several studies have demonstrated that diabetes mellitus can increase the risk of cardiovascular disease and remains the principal cause of death in these patients. Costameres connect the sarcolemma with the cytoskeleton and extracellular matrix, facilitating the transmission of mechanical forces and cell signaling. They are related to cardiac physiology because individual cardiac cells are connected by intercalated discs that synchronize muscle contraction. Diabetes impacts the nanomechanical properties of cardiomyocytes, resulting in increased cellular and left ventricular stiffness, as evidenced in clinical studies of these patients. The question of whether costameric proteins are affected by diabetes in the heart has not been studied. This work analyzes whether type 1 diabetes mellitus (T1DM) modifies the costameric proteins and coincidentally changes the cellular mechanics in the same cardiomyocytes. The samples were analyzed by immunotechniques using laser confocal microscopy. Significant statistical differences were found in the spatial arrangement of the costameric proteins. However, these differences are not due to their expression. Atomic force microscopy was used to compare intrinsic cellular stiffness between diabetic and normal cardiomyocytes and obtain the first elasticity map sections of diabetic living cardiomyocytes. Data obtained demonstrated that diabetic cardiomyocytes had higher stiffness than control. The present work shows experimental evidence that intracellular changes related to cell-cell and cell-extracellular matrix communication occur, which could be related to cardiac pathogenic mechanisms. These changes could contribute to alterations in the mechanical and electrical properties of cardiomyocytes and, consequently, to diabetic cardiomyopathy. NEW & NOTEWORTHY: The structural organization of cardiomyocyte proteins is critical for their efficient functioning as a contractile unit in the heart. This work shows that diabetes mellitus induces significant changes in the spatial organization of costamere proteins, t tubules, and intercalated discs. We obtained the first elasticity map sections of living diabetic cardiomyocytes. The results show statistical differences in the map sections of diabetic and control cardiomyocytes, with diabetic cardiomyocytes being stiffer than normal ones. [ABSTRACT FROM AUTHOR]

Sudden cardiac arrest (SCA) represents a major cause of premature mortality globally, with enormous impact and financial cost to victims, families, and communities. SCA prevention should be considered a health priority in Australia. National Cardiac Arrest Summits were held in June 2022 and March 2023, with inclusion from multi-faceted endeavours related to SCA prevention. It was agreed to establish a multidisciplinary Australian Sudden Cardiac Arrest Alliance (AuSCAA) working group charged with developing a national unified strategy, with clear and measurable quality indicators and standardised outcome measures, to amplify the goal of SCA prevention throughout Australia. A multi-faceted prevention strategy will include i) endeavours to progress community awareness, ii) improved fundamental mechanistic understanding, iii) implementation of best-practice resuscitation strategies for all demographics and locations, iv) secondary risk assessment directed to family members, and v) development of (near) real-time registry of cardiac arrest cases to inform areas of need and effectiveness of interventions. Together, we can and should reduce the impact of SCA in Australia. [ABSTRACT FROM AUTHOR]

Introduction: In children with myocarditis or dilated cardiomyopathy (DCM) on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock, it is often necessary to decompress the left heart to minimize distension and promote myocardial recovery. We compare outcomes in those who underwent balloon atrial septostomy (BAS) versus direct left atrial (LA) drainage for left heart decompression in this population. Methods: Retrospective study of the Extracorporeal Life Support Organization (ELSO) multicenter registry of patients ≤ 18 years with myocarditis or DCM on ECMO who underwent LA decompression. Descriptive and univariate statistics assessed association of patient factors with decompression type. Multivariable logistic regression sought independent associations with outcomes. Results: 369 pediatric ECMO runs were identified. 52% myocarditis, 48% DCM, overall survival 74%. 65% underwent BAS and 35% LA drainage. Patient demographics including age, weight, gender, race/ethnicity, diagnosis, pre-ECMO pH, mean airway pressure, and arrest status were similar. 89% in the BAS group were peripherally cannulated onto ECMO, versus 3% in the LA drainage group (p <.001). On multivariable analysis, LA drainage (OR 3.96; 95% CI, 1.47-10.711; p =.007), renal complication (OR 2.37; 95% CI, 1.41-4.01; p =.001), cardiac complication (OR 3.14; 95% CI, 1.70-5.82; p <.001), and non-white race/ethnicity (OR 1.75; 95% CI, 1.04-2.94; p =.035) were associated with greater odds of mortality. There was a trend toward more episodes of pulmonary hemorrhage in BAS (n = 17) versus LA drainage group (n = 3), p =.08. Comparing only those with central cannulation, LA drainage group was more likely to be discontinued from ECMO due to recovery (72%) versus the BAS group (48%), p =.032. Conclusions: In children with myocarditis or DCM, there was a three times greater likelihood for mortality with LA drainage versus BAS for LA decompression. When adjusted for central cannulation groups only, there was better recovery in the LA drainage group and no difference in mortality. Further prospective evaluation is warranted. [ABSTRACT FROM AUTHOR]

Liver cirrhosis is a significant global health concern, and cirrhotic cardiomyopathy (CCM) is a notable complication affecting both adults and children. While CCM is well-studied in adults, understanding its manifestation and diagnostic criteria in pediatric patients remains a challenge. This review explores the evidence for structural and functional cardiac alterations in children with liver cirrhosis. Structural abnormalities, including increased left ventricular mass index (LVMI) and altered left ventricular wall thickness ratios, are prevalent in pediatric CCM. These abnormalities persist even after liver transplantation, highlighting the systemic impact of liver disease. Evidence suggests that altered systolic and diastolic function, as well as electrocardiographic abnormalities such as prolonged QT intervals, are common in pediatric CCM. Blood biomarkers, including brain natriuretic peptide (BNP) and troponin levels, offer insights into cardiac function in pediatric cirrhotic patients. Elevated BNP levels correlate with adverse outcomes, indicating its potential as a prognostic marker. However, further research is needed to elucidate the diagnostic utility of these biomarkers in pediatric CCM. Conclusion: This review provides estimates of the standardized mean difference among selected cardiac parameters in children with and without cirrhosis. Tailored diagnostic criteria and comprehensive assessment methods will be essential for accurate diagnosis and effective management of pediatric CCM. What is Known: • CCM adds to the burden of care of patients with cirrhosis. • Diagnostic criteria for adults are evolving, but there are no specific criteria for pediatric CCM. What is New: • Cardiac function in children with cirrhosis indicates some parameters not considered in adults are altered. • Effect size estimations for certain parameters provide a guideline for future research into pediatric CCM. [ABSTRACT FROM AUTHOR]

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Cardiomyopathy is a group of disease characterized by structural and functional damage to the myocardium. The etiologies of cardiomyopathies are diverse, spanning from genetic mutations impacting fundamental myocardial functions to systemic disorders that result in widespread cardiac damage. Many specific gene mutations cause primary cardiomyopathy. Environmental factors and metabolic disorders may also lead to the occurrence of cardiomyopathy. This review provides an in‐depth analysis of the current understanding of the pathogenesis of various cardiomyopathies, highlighting the molecular and cellular mechanisms that contribute to their development and progression. The current therapeutic interventions for cardiomyopathies range from pharmacological interventions to mechanical support and heart transplantation. Gene therapy and cell therapy, propelled by ongoing advancements in overarching strategies and methodologies, has also emerged as a pivotal clinical intervention for a variety of diseases. The increasing number of causal gene of cardiomyopathies have been identified in recent studies. Therefore, gene therapy targeting causal genes holds promise in offering therapeutic advantages to individuals diagnosed with cardiomyopathies. Acting as a more precise approach to gene therapy, they are gradually emerging as a substitute for traditional gene therapy. This article reviews pathogenesis and therapeutic interventions for different cardiomyopathies. [ABSTRACT FROM AUTHOR]

Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5‐year result (2017–2021) of molecular autopsy services provided for victims of SCDY (age 1–40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016–2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)‐causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD‐causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at‐risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted. [ABSTRACT FROM AUTHOR]

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy‐three of these have been previously associated with SIDS/SUID/SUDP. Forty‐three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy‐two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID. [ABSTRACT FROM AUTHOR]

In this study, by pooling the clinical data of patients who died with a history of long-term clozapine use and by examining their hearts, it was found that long-term clozapine use can lead to cardiomyopathy and that its presentation resembles arrhythmogenic cardiomyopathy (ACM), i.e., it exhibits a predominantly right ventricular fatty infiltration with mild left ventricular damage. The transcriptomic data of rat cardiomyocytes after clozapine intervention were analyzed by transcriptomic approach to explore the causes of clozapine cardiomyopathy. The cause of clozapine cardiomyopathy was then explored by a transcriptomic approach, which revealed that its clozapine action on cardiomyocytes enriched cardiomyocyte-related differential genes in biological processes such as muscle development and response to hypoxia, as well as pathways such as fatty acid metabolism and cellular autophagy. Transcriptomic analysis showed that Egr1, Egr2, ler2, Jun, Mapk9, Nr1d2, Atf3, Bhlhe40, Crem, Cry1, Cry2, Dbp were hub genes for clozapine injury to the myocardium, and that these genes may play an important role in the myocardial ACM-like changes caused by clozapine. Combined with the results of pathological examination and transcriptomic analysis, it can be concluded that the long-term action of clozapine on cardiomyocytes leads to cellular autophagy and subsequent structural remodeling of the heart, and in the remodeling affects fatty acid metabolism, which eventually leads to ACM-like changes. [ABSTRACT FROM AUTHOR]

Background: Cardiomyopathies are clinically important conditions, with a strong genetic component. National genomic initiatives such as 100,000 Genome Project (100KGP) provide opportunity to study these rare conditions at scale beyond conventional research studies. Methods: We present the clinical and molecular characteristics of the 100KGP cohort, comparing paediatric and adult probands with diverse cardiomyopathies. We assessed the diagnostic yield and spectrum of genetic aetiologies across clinical presentations. We re-analysed existing genomic data using an updated analytical strategy (revised gene panels; unbiased analyses of de novo variants; and improved variant prioritisation strategies) to identify new causative variants in genetically unsolved children. Results: We identified 1918 individuals (1563 probands, 355 relatives) with cardiomyopathy (CM) in 100KGP. Probands, comprising 273 children and 1290 adults, were enrolled under > 55 different recruitment categories. Paediatric probands had higher rates of co-existing congenital heart disease (12%) compared to adults (0.9%). Diagnostic yield following 100KGP's initial analysis was significantly higher for children (19%) than for adults (11%) with 11% of diagnoses overall made in genes not on the existing UK paediatric or syndromic CM panel. Our re-analysis of paediatric probands yields a potential diagnosis in 40%, identifying new probable or possible diagnoses in 49 previously unsolved paediatric cases. Structural and intronic variants accounted for 11% of all potential diagnoses in children while de novo variants were identified in 17%. Conclusions: 100KGP demonstrates the benefit of genome sequencing over a standalone panel in CM. Re-analysis of paediatric CM probands allowed a significant uplift in diagnostic yield, emphasising the importance of iterative re-evaluation in genomic studies. Despite these efforts, many children with CM remain without a genetic diagnosis, highlighting the need for better gene-disease relationship curation and ongoing data sharing. The 100KGP CM cohort is likely to be useful for further gene discovery, but heterogeneous ascertainment and key technical limitations must be understood and addressed. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsThe investigational monoclonal antibody PRX004 is designed to specifically target and deplete TTR amyloid. Here, we report on the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary clinical activity of PRX004 in patients with ATTRv amyloidosis.This global, multicentre, phase 1 trial comprised a 3 + 3 dose-escalation phase and a long-term extension (LTE) phase (NCT03336580). In the dose-escalation phase, patients received PRX004 (0.1, 0.3, 1, 3, 10 or 30 mg/kg), administered intravenously every 28 days for 3 months. In the LTE, eligible patients could receive up to 15 additional doses. Patients who received doses of ≥3 mg/kg for ≥9 months were assessed for Global Longitudinal Strain (GLS) and Neuropathy Impairment Score (NIS). The primary objective was to determine the maximum tolerated dose (MTD) of PRX004.Overall, 21 patients with ATTRv amyloidosis completed the dose-escalation phase; 17 subsequently enrolled in the LTE. The MTD was not reached. PRX004 was well tolerated at all doses, with dose-proportional exposure. GLS and NIS were improved or maintained over 9 months (n = 7).PRX004 was well tolerated in patients with ATTRv amyloidosis and demonstrated potential clinical activity. A phase 2 randomised controlled trial in ATTR cardiomyopathy is ongoing (NCT05442047). [ABSTRACT FROM AUTHOR]

Background: We aimed to clarify the existence and pathological features of obesity cardiomyopathy (OCM) in Japan using our series of autopsy cases. Methods: In this retrospective autopsy study, OCM was defined as cardiac hypertrophy (≥ 400 g in men, ≥ 320 g in women) of unknown aetiology in individuals with obesity (body mass index [BMI] ≥ 25 kg/m2 according to the Japanese definition of obesity). We compared cases of OCM with those with obesity without cardiac hypertrophy (OB) and normal weight without cardiac hypertrophy (normal control). Macroscopically, heart weight and cardiac parameters, including epicardial adipose tissue, were measured. Fibrosis, cardiomyocyte diameter, and adipose tissue infiltration were analysed microscopically. Results: Of the 294 cases, we identified 19 cases of OCM (6.5%) and compared them with the OB and normal control groups. Patients with OCM were slightly younger than non-OCM patients (p = 0.081). The median heart weight was significantly heavier in OCM cases than in OB cases (435 g, interquartile range [IQR] 408–515 g vs. 360 g, IQR 341–385 g). Macroscopically, OCM hearts had a "globoid" appearance with a thickened right ventricular outflow tract. Some OCM cases showed focal interstitial fibrosis in the left ventricle. Approximately half the OCM cases were diagnosed with sudden cardiac death (SCD), with significant differences. Conclusions: The prevalence of OCM may be higher than expected in Japan, and this may be a specific pathological finding. Given that approximately half the cases of OCM were due to SCD, OCM may cause SCD, emphasizing the need to recognise and diagnose OCM. [ABSTRACT FROM AUTHOR]

Background : Altered metabolism plays a role in the pathophysiology of cardiac diseases, such as atrial fibrillation (AF) and heart failure (HF). We aimed to identify novel plasma metabolites and proteins associating with cardiac disease. Methods: Mendelian randomisation (MR) was used to assess the association of 174 metabolites measured in up to 86,507 participants with AF, HF, dilated cardiomyopathy (DCM), and non-ischemic cardiomyopathy (NICM). Subsequently, we sourced data on 1567 plasma proteins and performed cis MR to identify proteins affecting the identified metabolites as well as the cardiac diseases. Proteins were prioritised on cardiac expression and druggability, and mapped to biological pathways. Results: We identified 35 metabolites associating with cardiac disease. AF was affected by seventeen metabolites, HF by nineteen, DCM by four, and NCIM by taurine. HF was particularly enriched for phosphatidylcholines (p = 0.029) and DCM for acylcarnitines (p = 0.001). Metabolite involvement with AF was more uniform, spanning for example phosphatidylcholines, amino acids, and acylcarnitines. We identified 38 druggable proteins expressed in cardiac tissue, with a directionally concordant effect on metabolites and cardiac disease. We recapitulated known associations, for example between the drug target of digoxin (AT1B2), taurine and NICM risk. Additionally, we identified numerous novel findings, such as higher RET values associating with phosphatidylcholines and decreasing AF and HF. RET is targeted by drugs such as regorafenib which has known cardiotoxic side-effects. Pathway analysis implicated involvement of GDF15 signalling through RET, and ghrelin regulation of energy homeostasis in cardiac pathogenesis. Conclusions: This study identified 35 plasma metabolites involved with cardiac diseases and linked these to 38 druggable proteins, providing actionable leads for drug development. [ABSTRACT FROM AUTHOR]

Background: Metoprolol is commonly administered to critically ill patients; however, its effect on mortality in patients with sepsis-induced cardiomyopathy (SICM) remains uncertain. This study aimed to investigate the relationship between metoprolol use and mortality in patients with SICM. Methods: Adults with SICM were identified from the MIMIC-IV database. The exposure of interest was metoprolol treatment. The outcomes assessed were 30-day mortality, 1-year mortality, and in-hospital mortality. Kaplan–Meier survival analysis evaluated the effect of metoprolol on these outcomes. Multivariable Cox proportional hazards and logistic regression analyses were performed to determine the correlation between metoprolol treatment and mortality in patients with SICM. Results: 1163 patients with SICM were identified, with 882 receiving metoprolol treatment (MET group) and 281 not receiving metoprolol treatment (NOMET group). Overall, the 30-day, 1-year, and in-hospital mortality rates were 10.2%, 18.2%, and 8.9%, respectively. Significant differences in mortality existed between the groups. Multivariable Cox analysis revealed that patients in the NOMET group had a higher risk of 1-year mortality (adjusted hazard ratio [HR] 2.493; 95% confidence interval [CI] 1.800–3.451; P < 0.001) and 30-day mortality (adjusted HR 4.280; 95%CI 2.760–6.637; P < 0.001). Metoprolol treatment was associated with lower in-hospital mortality (odds ratio [OR] 5.076; 95% CI 2.848–9.047; P < 0.001). Subgroup analysis supported these findings. Conclusion: Metoprolol treatment is associated with reduced all-cause mortality in patients with SICM. Prospective studies are required to validate these findings. [ABSTRACT FROM AUTHOR]

Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3–protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model. The experimental assay was conducted using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with BioID technology. Proteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction. This study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3. [ABSTRACT FROM AUTHOR]

This paper discusses the cases of siblings that were born healthy, then diagnosed in their neonatal periods with cardiomyopathy and/or severe metabolic acidosis, which ran progressive courses and contributed to death in infancy. Molecular testing of the children confirmed the presence of an m.3303C>T point mutation in the mitochondrial DNA in the MT-TL1 gene, which was also present in their oligosymptomatic mother and their mother’s sister, an asymptomatic carrier. [ABSTRACT FROM AUTHOR]

Background: Chlamydia pneumoniae and human herpesvirus 6 (HHV-6) are uncommon aetiological agents in respiratory tract infections and are rarely associated with cardiogenic shock. This case report presents a rare instance of severe cardiomyopathy linked to these infections in a 19-year-old Asian female. The case highlights the importance of considering a broad differential diagnosis in acute heart failure, especially in young adults. Case report: The patient was admitted with chest pain and diagnosed with ST-elevation myocardial infarction (STEMI) based on electrocardiography. She subsequently developed heart failure, with a marked reduction in myocardial contractility and a left ventricular ejection fraction (LVEF) of 20%. Treatment included broad-spectrum antibiotics and inotropic support guided by hemodynamic monitoring, leading to clinical improvement. The patient was discharged in a significantly improved condition following a stay in the intensive care unit (ICU). Conclusions: This case emphasizes the importance of considering Takotsubo syndrome in differential diagnoses, especially in ICU patients presenting with cardiogenic shock, to improve outcomes and reduce mortality through timely and appropriate management. Inotropic support, often used in the ICU to treat hypoperfusion, may worsen outcomes in patients with Takotsubo syndrome by exacerbating basal hypercontractility and prolonging the acute phase through catecholamine receptor activation. [ABSTRACT FROM AUTHOR]

Danon disease, an X-linked dominant vacuolar cardiomyopathy and skeletal myopathy, is caused by a primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). This disease is one of the autophagy-related muscle diseases. Male patients present with the triad of cardiomyopathy, myopathy, and intellectual disability, while female patients present with cardiomyopathy. The disease's leading cause of death is heart failure, and its prognostic factor is cardiomyopathy. Pathologically, the disease is characterized by the appearance of unique autophagic vacuoles with sarcolemmal features (AVSFs). Twenty-six families have been found to have this disease in Japan. It has been over 40 years since the first report of this disease by Danon et al. and over 20 years since the identification of the causative gene, LAMP2, by Nishino et al. Although the pathogenetic mechanism of Danon disease remains unestablished, the first clinical trials using AAV vectors have finally begun in recent years. The development of novel therapies is expected in the future. [ABSTRACT FROM AUTHOR]

Objective: Inflammatory cardiomyopathy is a disease associated with cardiac dysfunction and ventricular remodeling. Among the most recent diagnostic methods available, histologic characterization through cardiac magnetic resonance imaging (MRI) is used to identify inflammatory changes. Multiple studies have evaluated autoimmune mechanisms in myocardium damage following COVID-19, begging how feasible it is to differentiate and characterize lesions found in post-COVID-19 inflammatory cardiomyopathy. Method: Retrospective study comparing 29 MRI studies (12 diagnosed with post-COVID-19 inflammatory cardiomyopathy and 17 previously diagnosed with autoimmune cardiomyopathy, rheumatoid arthritis, scleroderma, or systemic lupus erythematosus), comparing the histologic characterization of T1, T2 mapping and extracellular volume (ECV) through cardiac MRI. Results: Post-COVID-19 inflammatory cardiomyopathy histologic characterization did not show significant differences compared to autoimmune myocardial lesions. T1 mapping 1109 ± 76 ms, T2 mapping 58 ± 6 ms, ECV 41 ± 9%. Myocardial lesions occurring from an autoimmune etiology showed: T1 mapping 1132 ± 122 ms, T2 mapping 61 ± 4 ms, and ECV 38 ± 8% (p > 0.05). Conclusion: T1-T2 mapping and ECV are similar among patients with post-COVID-19 inflammatory cardiomyopathy and myocardial damage secondary to autoimmune diseases, as there seem to exist similar pathologic mechanisms presenting in both groups, consistent with current literature regarding myocardial damage in SARS-CoV-2 infections. [ABSTRACT FROM AUTHOR]

Objective: Idiopathic dilated cardiomyopathy (DCM) is a serious disease causing mitral regurgitation and contraction defects of the myocardium. Through mitral valve (MV) repair surgery, the clinical status of patients can be improved. Methods: Pediatric patients with DCM and mitral insufficiency who underwent mitral repair procedures between 2019 and 2023 were retrospectively investigated. The patients' demographic characteristics, preoperative and postoperative clinical conditions, and echocardiographic findings were compared. The techniques used in patient operations were examined. Similarly, data regarding the postoperative intensive care unit processes and mortality data of the patients were recorded. Results: Mitral repair was performed in 3 patients during the study period. The mean age of the patients was 4.66 months (±3.05) and body weight was 5.25 kg (±0.25). In the preoperative period, left ventricular ejection fraction decreased slightly in all patients [mean: 43.3% standard deviation (SD): ±2.8]. Although the preoperative and postoperative values of left ventricular end-diastolic diameter (LVEDd) and LVEDd Z-scores were above normal, respectively, they showed a decreasing trend after the operation. Although the mitral annulus diameters decreased slightly after the operation in all three patients, they remained high (mean: 17.6 mm SD: ±1.5). A significant decrease in MV insufficiency was observed in postoperative follow-ups after discharge (1st-2nd degree). Wooler annuloplasty and posterior valve pericardial patch augmentation were applied as the primary approach in all patients. The patients did not develop additional morbidities, and no mortality was observed during hospitalization. Conclusion: Successful surgical interventions to prevent mitral regurgitation in pediatric patients with DCM and mitral regurgitation, may improve the clinical status of these patients. [ABSTRACT FROM AUTHOR]

Background: The diagnosis and follow-up of cardiac involvement in Fabry disease constitutes an important challenge for clinicians caring for affected patients. Combining cardiac imaging with laboratory biomarkers appears most appropriate for longitudinal monitoring. Therefore, we examined the use of NT-proBNP and its association with imaging findings in patients with Fabry disease. Methods: We analysed cardiac MRI and echocardiography data, as well as laboratory results, from a single-centre prospective registry. Results: Repetitive follow-ups of 38 patients with Fabry disease, of whom 18 presented with left ventricular hypertrophy (LVH), revealed a correlation of NT-proBNP with left ventricular (LV) interventricular septal thickness, LV maximum wall thickness, LV and right ventricular (RV) mass index and trabecular mass in patients with LVH. Patients without LVH did not exhibit any tangible association between NT-proBNP and the mentioned parameters. Conversely, we could not detect an association of NT-proBNP with impairment of LV or RV ejection fraction or diastolic volume. Conclusions: NT-proBNP plays a pivotal role as a biomarker for cardiac involvement in patients with Fabry disease. Interestingly, in this specific population with mostly preserved ejection fraction, it seems to reflect ventricular hypertrophy rather than ventricular dysfunction or dilatation. While strong associations were found in hypertrophic patients, NT-proBNP's prognostic value appears limited in non- or pre-hypertrophic stages. [ABSTRACT FROM AUTHOR]

Amyloidosis with cardiac involvement is a fatal disease leading to progressive heart failure. The most common forms of amyloidosis with cardiac involvement are light chain (AL) and transthyretin (ATTR) amyloidosis. To allow effective specific treatment for both forms, precise and early diagnosis is important. This review focuses on diagnostic approaches for AL and ATTR amyloidosis with cardiac involvement, including different strategies, the role of imaging and biomarkers and possible pitfalls. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a major cause of death worldwide. Advanced in vitro models can be the key stone for a better understanding of the mechanisms at the basis of the different pathologies, supporting the development of novel therapeutic protocols. In particular, the implementation of induced pluripotent stem cell (iPSC) technology allows for the generation of a patient-specific pluripotent cell line that is able to differentiate in several organ-specific cell subsets while retaining the patient genetic background, thus putting the basis for personalized in vitro modeling toward personalized medicine. The design of iPSC-based models able to recapitulate the complexity of the cardiac environment is a critical goal. Here, we review some of the published efforts to exploit three dimensional (3D) iPSC-based methods to recapitulate the relevant cardiomyopathies, including genetically and non-genetically determined cardiomyopathies and cardiotoxicity studies. Finally, we discuss the actual method limitations and the future perspectives in the field. [ABSTRACT FROM AUTHOR]

Hutchinson‐Gilford progeria syndrome (HGPS) is a rare premature aging disorder resulting from de novo mutations in the lamin A gene. Children with HGPS typically pass away in their teenage years due to cardiovascular diseases such as atherosclerosis, myocardial infarction, heart failure, and stroke. In this study, we characterized the G608G HGPS mouse model and explored cardiac and skeletal muscle function, along with senescence‐associated phenotypes in fibroblasts. Homozygous G608G HGPS mice exhibited cardiac dysfunction, including decreased cardiac output and stroke volume, and impaired left ventricle relaxation. Additionally, skeletal muscle exhibited decreased isometric tetanic torque, muscle atrophy, and increased fibrosis. HGPS fibroblasts showed nuclear abnormalities, decreased proliferation, and increased expression of senescence markers. These findings provide insights into the pathophysiology of the G608G HGPS mouse model and inform potential therapeutic strategies for HGPS. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD)-related cardiomyopathy is associated with hemodynamic and conduction abnormalities and begins at an early age with subtle symptoms. Methods: The study population included 55 patients with DMD and 54 healthy controls. We compared electrocardiogram (ECG), conventional echocardiography, and tissue Doppler imaging (TDI) assessments between patients with DMD and healthy controls. Also, we investigated atrial electromechanical delay, which has not been previously studied in DMD patients. Mitral, septal, and tricuspid segments were analyzed by TDI. Results: The mean age was 13.6 ± 2.5 years (range, 9.3-17.9 years) in the patient group and 12.8 ± 2.6 years (range, 8-17.5 years) in the control group (P = .1). Patients had higher heart rates, longer QTc intervals, and P-wave dispersion (PWD) than controls (P < .001, P = .004, P < .001, respectively). The patient group had larger left ventricular end-systolic dimension (P < .001), lower left ventricular ejection fraction (EF) (P < .001), MAPSE (P < .001), TAPSE (P < .001), and mitral-E/A (P = .029) values than control subjects. Myocardial performance index (P < .001) was higher, and the E'/A' ratio (P < .001) was lower at all 3 segments in the patient group. Also, atrial electromechanical delay was longer in the patient group at these segments (P < .001). Patients had significantly longer inter-atrial (P = .033) electromechanical conduction delays. EF was negatively correlated with atrial conduction time variables. Conclusion: We have shown deterioration in systolic and diastolic function in both ventricles, PWD, and atrial conduction in children with DMD. Patients with DMD may be at risk of atrial arrhythmias due to disturbed atrial conduction. [ABSTRACT FROM AUTHOR]

This article explores the challenges of managing hypertension in patients with hypertrophic obstructive cardiomyopathy (HCM). It presents a case study of a 52-year-old man with a history of hypertension and other medical conditions. The article emphasizes the importance of understanding the underlying causes of HCM and the different types of antihypertensive medications for effective treatment. It also highlights the need to differentiate between obstructive and nonobstructive forms of HCM and to closely monitor symptoms and avoid certain medications in patients with obstructive physiology. The article concludes by discussing the potential impact of hypertension on HCM and the recommended target blood pressure for patients with this condition. It suggests that a combination of beta-blockers or nondihydropyridine calcium channel blockers may be used as first-line therapy for symptomatic obstructive HCM, but the evidence for this approach is limited. Diuretics should generally be avoided unless there is heart failure. The management of hypertension in HCM should be personalized, considering symptoms, the degree of obstruction, and the risk of exacerbating left ventricular outflow tract obstruction. Collaboration among cardiologists, hypertension specialists, and pharmacists is crucial for optimizing therapy. The article also mentions the potential integration of innovative pharmacotherapies, such as mavacamten, with existing treatments in the future. [Extracted from the article]

Introduction: Myocarditis is an inflammatory disease of the myocardial layer of the heart that can be prone to dilation of chambers with presentation as heart failure secondary to dilated cardiomyopathy. Myocarditis can lead to remodeling and fibrosis that can affect the heart's relaxation-lusitropy and chronotropic function. The current techniques for identifying myocarditis, such as endomyocardial biopsy and imaging, are costly, and intrusive. The current literature aims to identify reliable, accurate, and prognostically educative biomarkers of myocarditis. Areas covered: This review covers the definition, clinical features, diagnostic markers, cardiac imaging, prognosis, and complications of myocarditis. PubMed, Embase, and the Cochrane data bank were searched from inception to 1 January 2024 for relevant articles. Expert opinion: By adopting these diagnostic and prognostic biomarkers, clinicians can have a better comprehension of the progression of the disease and provide early diagnosis and treatment for myocarditis. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to describe baseline characteristics and adherence among patients with transthyretin amyloid cardiomyopathy (ATTR‐CM) treated with tafamidis (VYNDAQEL®) in Japan using the Japanese Medical Data Vision (MDV) database. Methods and results: This study was a non‐interventional, retrospective cohort study of adult (≥18 years old) patients in the Japanese MDV claims database diagnosed with ATTR‐CM and with at least two tafamidis prescriptions of dose strength 4 × 20 mg/day between 1 March 2019 and 31 August 2021. The date of the first prescription was defined as the index date, with follow‐up time defined as the time between the first and last prescription plus the days' supply from the last refill. Baseline characteristics were assessed during a 12 month pre‐index period. Adherence was measured using two metrics: (i) the modified medication possession ratio (mMPR), calculated by taking the sum of days supplied for all fills within the follow‐up period, divided by the number of days of follow‐up, and reported as a percentage, with patients classified as adherent with an mMPR of ≥80%, and (ii) the proportion of days covered (PDC), calculated by taking the total number of days' supply dispensed during the follow‐up period divided by the number of days of follow‐up, adjusting for any days' supply overlap. A total of 210 patients were identified; the mean (standard deviation) age of the cohort was 77 (5.9) years, and the majority (89%) were male. The most common baseline cardiovascular comorbidities were heart failure (85%), ischaemic heart disease (66%), hypertensive diseases (49%), and diabetes (35%); 75% of patients received heart failure medications in the 12 months prior to index, with the most common being beta‐blockers (49%), diuretics (48%), angiotensin receptor blockers (30%), angiotensin‐converting enzyme inhibitors (22%), and sodium–glucose cotransporter‐2 inhibitors (8.1%). Over an average 14 month follow‐up, mean mMPR was 96% with a median of 100% [inter‐quartile range (IQR): 97–101%]; 93% of patients were adherent (defined as an mMPR ≥ 80%). In the same follow‐up period, mean PDC was 93.6% with a median of 99% (IQR: 93–100%). Persistence was high with 78% of patients having a 0 day gap between prescription refills. Conclusions: This study found high adherence rates to tafamidis in this real‐world Japanese patient population. Adherence rates in this study were similar to those reported by the tafamidis clinical trial and a previously published US commercial claims adherence analysis. Further studies should be conducted to assess the impact of real‐world adherence on real‐world outcomes. [ABSTRACT FROM AUTHOR]

Pimobendan is not currently approved for use in cats, although its usefulness in feline hypertrophic cardiomyopathy has been suggested. Reports indicate an increase in arrhythmic events following oral administration to healthy cats. Given the greater potency of intravenous administration compared to oral intake, it is conceivable that the incidence of arrhythmias may be increased following pimobendan injection. Therefore, this study aimed to investigate the proarrhythmic effects of pimobendan injection in cats. Five clinically healthy cats underwent physical examination, echocardiography, blood pressure measurements, and 24-hour Holter electrocardiography immediately before and after receiving pimobendan as an intravenous bolus dose of 0.15 mg/kg twice daily for 3 days. Additionally, a 24-hour Holter electrocardiography recording was conducted on the third day of pimobendan or placebo IV administration to assess heart rate, arrhythmias, and heart rate variability. Following pimobendan administration, there was a significant increase in total 24-hour heart rate. Echocardiography revealed a significant increase in mitral valve annulus systolic velocity (S') on the ventricular septal wall side, indicative of enhanced contractility. Only one cat exhibited paroxysmal ventricular tachycardia and an increase in the frequency of arrhythmic events. Conversely, in the remaining cats, a decreasing trend in the number of arrhythmias was observed. These findings indicate that intravenous administration of pimobendan may not be implicated in the onset of arrhythmias. Nevertheless, further research is warranted to explore the effects of intravenous pimobendan administration in cats with myocardial disease. [ABSTRACT FROM AUTHOR]

Purpose of Review: The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression. Recent Findings: Recent insights into myocardial metabolism shed light on the heart's response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure. Summary: Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a major cause of mortality and morbidity worldwide. Understanding the genetic basis of HF allows for the development of disease-modifying therapies, more appropriate risk stratification, and personalised management of patients. The advent of next-generation sequencing has enabled genome-wide association studies; moving beyond rare variants identified in a Mendelian fashion and detecting common DNA variants associated with disease. We summarise the latest GWAS and rare variant data on mixed and refined HF aetiologies, and cardiomyopathies. We describe the recent understanding of the functional impact of titin variants and highlight FHOD3 as a novel cardiomyopathy-associated gene. We describe future directions of research in this field and how genetic data can be leveraged to improve the care of patients with HF. [ABSTRACT FROM AUTHOR]