Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy.

AIMS: The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients were evaluated. METHODS AND RESULTS: Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71-plex cytokines/chemokines, troponin I and B-type natriuretic peptide analysis. Major adverse cardiovascular events (MACE) were defined as appropriate implantable cardioverter-defibrillator shock, stroke, cardiac arrest, orthotopic heart transplant and death. Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations (adjusted hazard ratio [HR] 6.89, 95% confidence interval [CI] 1.78-26.6; p = 0.005), with the highest risk among those that had DNMT3A, TET2 and ASXL1 mutations (adjusted HR 5.76, 95% CI 1.51-21.94; p = 0.010). Several cytokines (IL-1ra, IL-6, IL-17F, TGFα, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene-positive HCM patients with CH. CONCLUSIONS: These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene-positive patients with HCM have lower rates of MACE.

Peripartum Cardiomyopathy: A Case Report of Mortality From a Rare and Potentially Fatal Condition.

Peripartum cardiomyopathy (PPCM) poses a significant challenge in maternal health, characterized by heart failure with reduced ejection fraction during late pregnancy or early postpartum. Despite advances in understanding PPCM, it remains life-threatening with substantial maternal morbidity and mortality. This article reviews the epidemiology, etiology, diagnostic challenges, management strategies, and outcomes associated with PPCM. A case report of a 29-year-old woman with PPCM is presented, emphasizing the importance of early recognition and tailored management. The patient's presentation was marked by atypical symptoms, including dysuria, lumbar pain, persistent fever, and oral intake intolerance. Despite aggressive medical intervention, the patient experienced a tragic outcome, succumbing to cardiopulmonary arrest within 48 h of admission. This case underscores the challenges in diagnosing and managing PPCM, particularly when presenting with nonspecific symptoms and emphasizes the urgent need for improved diagnostic criteria and therapeutic interventions to mitigate adverse outcomes in affected individuals.

Unraveling cardiomyocyte responses and intercellular communication alterations in primary carnitine deficiency cardiomyopathy via single-nucleus RNA sequencing.

Background: Primary Carnitine Deficiency (PCD) is a potentially life-threatening autosomal recessive monogenic disorder arising from mutations in the organic cation transporter 2 (OCTN2) gene. Dilated cardiomyopathy (DCM) is a prevalent symptom associated with this condition, and episodes of metabolic disturbance may lead to sudden death. However, the pathogenic mechanism remains unclear. Here, we sought to investigate the response of cardiomyocytes and alterations in the intercellular communication in individuals with PCD DCM. Methods: The GSE211650 dataset was downloaded. Subsequently, modular analysis was performed using hdWGCNA. SCENIC was employed for transcription factor analysis. Monocle2 and SCP were applied to conduct trajectory inference and characterize dynamic features. CellChat was used to investigate intercellular interactions. Results: OCTN2-deficient cardiomyocytes displayed transcriptomic alterations indicative of reduced contractility, developmental abnormalities, and fibrosis. The reduced expression of genes encoding troponin, myosin, and calcium ion transporters may underlie the observed decrease in contractility. Suppressed Wnt signaling and downregulated transcription factors associated with myocardial development suggest potential developmental disturbances in cardiomyocytes. Growth arrest-specific 6 (GAS6) secreted by TNNC1 high cardiomyocytes is implicated in myocardial inflammation and fibrosis. Macrophages-derived secreted phosphoprotein 1 (SPP1) promotes the activation of fibroblasts. Furthermore, there was a reduction in neuronal genes in the OCTN2-deficient group. Conclusions: Our research has unveiled, for the first time, the responses of cardiomyocytes and alterations in the intercellular communication in PCD DCM, offering valuable insights for the precision treatment of this condition.

Protective role of the CD73-A2AR axis in cirrhotic cardiomyopathy through negative feedback regulation of the NF-κB pathway.

Background: Myocardial inflammation and apoptosis induced by cirrhosis are among the primary mechanisms of cirrhotic cardiomyopathy. CD73, a common extracellular nucleotidase also known as 5'-nucleotidase, is associated with the progression of inflammation and immunity in multiple organs. However, the mechanism by which CD73 contributes to myocardial inflammation and apoptosis in cirrhosis remains unclear. Methods: In this study, a cirrhotic cardiomyopathy model in mice was established by bile duct ligation. Myocardial-specific overexpression of CD73 was achieved by tail vein injection of AAV9 (adeno-associated virus)-cTNT-NT5E-mCherry, and cardiac function in mice was assessed using echocardiography. Myocardial inflammation infiltration and apoptosis were evaluated through pathological observation and ELISA assays. The expression of CD73, A2AR, apoptotic markers, and proteins related to the NF-κB pathway in myocardial tissue were measured. Results: In the myocardial tissue of the cirrhotic cardiomyopathy mouse model, the expression of CD73 and A2AR increased. Overexpression of CD73 in the myocardium via AAV9 injection and stimulation of A2AR with CGS 21680 inhibited myocardial inflammation and cardiomyocyte apoptosis induced by cirrhosis. Additionally, overexpression of CD73 suppressed the activation of the NF-κB pathway by upregulating the expression of the adenosine receptor A2A. Conclusion: Our study reveals that the CD73/A2AR signaling axis mitigates myocardial inflammation and apoptosis induced by cirrhosis through negative feedback regulation of the NF-κB pathway.

The role of autophagy in the progression of HIV infected cardiomyopathy.

Although highly active antiretroviral therapy (HAART) has changed infection with human immunodeficiency virus (HIV) from a diagnosis with imminent mortality to a chronic illness, HIV positive patients who do not develop acquired immunodeficiency syndrome (AIDs) still suffer from a high rate of cardiac dysfunction and fibrosis. Regardless of viral load and CD count, HIV-associated cardiomyopathy (HIVAC) still causes a high rate of mortality and morbidity amongst HIV patients. While this is a well characterized clinical phenomena, the molecular mechanism of HIVAC is not well understood. In this review, we consolidate, analyze, and discuss current research on the intersection between autophagy and HIVAC. Multiple studies have linked dysregulation in various regulators and functional components of autophagy to HIV infection regardless of mode of viral entry, i.e., coronary, cardiac chamber, or pericardial space. HIV proteins, including negative regulatory factor (Nef), glycoprotein 120 (gp120), and transactivator (Tat), have been shown to interact with type II microtubule-associated protein-1 ß light chain (LC3-II), Rubiquitin, SQSTM1/p62, Rab7, autophagy-specific gene 7 (ATG7), and lysosomal-associated membrane protein 1 (LAMP1), all molecules critical to normal autophagy. HIV infection can also induce dysregulation of mitochondrial bioenergetics by altering production and equilibrium of adenosine triphosphate (ATP), mitochondrial reactive oxygen species (ROS), and calcium. These changes alter mitochondrial mass and morphology, which normally trigger autophagy to clear away dysfunctional organelles. However, with HIV infection also triggering autophagy dysfunction, these abnormal mitochondria accumulate and contribute to myocardial dysfunction. Likewise, use of HAART, azidothymidine and Abacavir, have been shown to induce cardiac dysfunction and fibrosis by inducing abnormal autophagy during antiretroviral therapy. Conversely, studies have shown that increasing autophagy can reduce the accumulation of dysfunctional mitochondria and restore cardiomyocyte function. Interestingly, Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, has also been shown to reduce HIV-induced cytotoxicity by regulating autophagy-related proteins, making it a non-antiviral agent with the potential to treat HIVAC. In this review, we synthesize these findings to provide a better understanding of the role autophagy plays in HIVAC and discuss the potential pharmacologic targets unveiled by this research.

A case report of right-sided heart failure secondary to JAK2-mutation Loeffler endocarditis.

Loeffler's endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome. We present a case of LE in a 45-year-old female, resulting in diffuse endothelial fibrosis and severe right-sided heart failure. The patient was admitted with dyspnoea and oedema, with haematology revealing an absolute eosinophil count of 20.9 × 109. Imaging showed near-complete obliteration of the right ventricular apical and formation of thromboses. Endomyocardial biopsy indicated diffuse fibrous hyperplasia of the endocardium with fibrinous thrombi rich in eosinophils. Molecular and cytogenetic analyses of bone marrow cells showed no signs of FIP1L1-PDGFRA fusion, PDGFRB mutation, abnormal myeloid maturation, or a lymphoproliferative disorder. Flow cytometry indicated no clonality, ruling out chronic eosinophilic leukaemia. Gene mutation screening discovered a p.L583_A586delinesS mutation in the JAK2 gene. Following treatment with ruxolitinib, the patient's eosinophil levels normalized, but unfortunately, the damage to the heart was irreversible. The patient was hospitalized multiple times due to right heart failure and resistance to diuretics. After thorough discussions with the medical team, it was determined that a heart transplantation would be the most effective treatment. Following the surgery, the patient successfully navigated the postoperative critical period with the support of an intra-aortic balloon pump (IABP), continuous renal replacement therapy (CRRT), and ventilator-assisted ventilation but subsequently developed an acquired Intensive care unit-acquired weakness (ICU-AW) and a depressive state. Fortunately, the patient gradually recovered from these complications.

Modern Perspectives on Hypertrophic Cardiomyopathy-No One Size Fits All.

Despite substantial advances in the management of hypertrophic cardiomyopathy, advanced heart failure remains a major cause of morbidity in this patient population. This narrative review presents the case of a patient with hypertrophic obstructive cardiomyopathy who underwent alcohol septal ablation to frame a discussion of modern therapies for hypertrophic cardiomyopathy. The current treatment landscape includes medications, both old and new, and surgical and procedural interventions to relieve mechanical obstruction. Several promising new modalities for relieving obstruction are in the nascent stages of development.

Quality of Life and Exercise Capacity in Early Stage and Subclinical Hypertrophic Cardiomyopathy: A Secondary Analysis of the VANISH Trial.

BACKGROUND: The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being. METHODS: VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort. RESULTS: Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P=0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P=0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P=0.01) but did not significantly impact CPET performance. CONCLUSIONS: Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.

Cardiac Amyloidosis: A Comprehensive Review of Pathophysiology, Diagnostic Approach, Applications of Artificial Intelligence, and Management Strategies.

Cardiac amyloidosis (CA) is a serious and often fatal condition caused by the accumulation of amyloid fibrils in the heart, leading to progressive heart failure. It involves the misfolding of normally soluble proteins into insoluble amyloid fibrils, with transthyretin and light-chain amyloidosis being the most common forms affecting the heart. Advances in diagnostics, especially cardiac magnetic resonance imaging and non-invasive techniques, have improved early detection and disease management. Artificial intelligence has emerged as a diagnostic tool for cardiac amyloidosis, improving accuracy and enabling earlier intervention through advanced imaging analysis and pattern recognition. Management strategies include volume control, specific pharmacotherapies like tafamidis, and addressing arrhythmias and advanced heart failure. However, further research is needed for novel therapeutic approaches, the long-term effectiveness of emerging treatments, and the optimization of artificial intelligence applications in clinical practice for better patient outcomes. The article aims to provide an overview of CA, outlining its pathophysiology, diagnostic advancements, the role of artificial intelligence, management strategies, and the need for further research.

Influencing and prognostic factors of end-stage hypertrophic cardiomyopathy.

AIMS: End-stage hypertrophic cardiomyopathy (ES-HCM) is a disease with severe complications and a poor prognosis. This study aimed to explore the influencing and prognostic factors of ES-HCM. METHODS AND RESULTS: A total of 1282 patients with HCM who were hospitalized for the first time at Fujian Medical University Union Hospital between 1 January 2013 and 30 September 2021 were recorded. The patients with HCM and left ventricular ejection fraction (LVEF) < 50% were defined as having ES-HCM, and a control group (LVEF ≥ 50%) was generated from the collected medical records of HCM. The patients were matched in a ratio of 4:1 based on age and sex. Logistic regression analysis was used to determine the influencing factors of ES-HCM. Kaplan-Meier survival analysis was performed to analyse the clinical outcomes of ES-HCM patients. A total of 250 inpatients with HCM were enrolled in the study; 50 patients had ES-HCM, and 200 had HCM with LVEF ≥ 50%. The mean age of the patients at enrolment was 62.5 ± 10.3 years, and 215 patients (215/250, 86.0%) were male. The median follow-up time of the patients was 2.8 (1.4-5.4) years. The incidence of all-cause death and cardiovascular death in patients with ES-HCM was higher than those in patients with HCM and LVEF ≥ 50% (22/50 [44.0%] vs. 13/200 [6.5%]; 12/50 [24.0%] vs. 4/200 [2.0%], all P < 0.001). Multivariate logistic regression analysis showed that the influencing factors associated with ES-HCM included age at first symptom onset (odds ratio [OR] = 0.95, 95% CI [0.90, 1.00], P = 0.042), New York Heart Association (NYHA) class (OR = 7.73, 95% CI [2.93, 20.41], P < 0.001), heart rate (OR = 1.07, 95% CI [1.02, 1.12], P = 0.003), QRS duration (OR = 1.03, 95% CI [1.00, 1.05], P = 0.020), left ventricular end-diastolic diameter (LVEDD) (OR = 1.15, 95% CI [1.04, 1.28], P = 0.006), left atrial anteroposterior diameter (LAD) (OR = 1.13, 95% CI [1.03, 1.24], P = 0.012), and maximum left ventricular wall thickness (MLVWT) (OR = 0.80, 95% CI [0.68, 0.93], P = 0.005). Among the 50 patients with ES-HCM, NYHA class (P < 0.001) and heart rate (P = 0.017) were each associated with a higher likelihood and earlier occurrence of heart transplantation or all-cause mortality in univariate analyses. CONCLUSIONS: The influencing factors for ES-HCM included the age at first symptom onset, NYHA class, heart rate, QRS duration, LVEDD, LAD, and MLVWT. Both NYHA class and heart rate were related to the prognosis of ES-HCM.

Mechanical and electrical uncoupling: the role of cardiac magnetic resonance imaging in arrhythmogenic cardiomyopathy. Proof of concept.

OBJECTIVES: Arrhythmogenic cardiomyopathy (ACM) is a complex cardiac disorder associated with ventricular arrhythmias. Understanding the relationship between mechanical uncoupling and cardiac structural changes in ACM patients is crucial for improved risk stratification and management. METHODS: In this study, we enrolled 25 ACM patients (median age 34 years, 72% men) based on the 2019 Modified Task Force and Padua criteria. Patients were categorized by the presence or absence of clinically relevant ventricular tachycardia (crVT), necessitating emergency interventions. Right ventricular-arterial coupling (VAC) was assessed using echocardiography. Low-rank regression splines were employed to model left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) in relation to VAC. RESULTS: Positive associations were observed between VAC and LVEF (ρ = 0.472, p = 0.023), RVEF (ρ = 0.522, p = 0.038), and right ventricular (RV) indexed stroke volume (ρ = 0.79, p < 0.001). Patients with crVT exhibited correlations with RV shortening, reduced RVEF (39.6 vs. 32.2%, p = 0.025), increased left ventricular (LV) mass (38.99 vs. 45.55, p = 0.045), and LV end-diastolic volume (LVEDV) (56.99 vs. 68.15 mL/m2, p = 0.045). Positive associations for VAC were noted with LVEDV (p = 0.039) and LV mass (p = 0.039), while negative correlations were observed with RVEF by CMR (p = 0.023) and RV shortening by echocardiography (p = 0.026). CONCLUSIONS: Our findings underscore the significance of right VAC in ACM, demonstrating correlations with RV and LVEF, RV stroke volume, and clinically relevant arrhythmias. Insights into RVEF, LV mass, and end-diastolic volume provide valuable contributions to the understanding of ACM pathophysiology and may inform risk assessment strategies.

OBJETIVOS: La miocardiopatía arritmogénica (MCA) es un trastorno cardíaco complejo asociado con arritmias ventriculares (AV). Comprender la relación entre el desacoplamiento mecánico y los cambios estructurales cardíacos en pacientes con MCA es crucial para una estratificación de riesgos y una gestión mejorada. MÉTODOS: En este estudio, reclutamos a 25 pacientes con MCA (edad media 34 años, 72% hombres) basándonos en los criterios del Task Force 2019 y los criterios de Padua. Los pacientes se clasificaron según la presencia o ausencia de taquicardia ventricular clínicamente relevante (crVT), que requería intervenciones de emergencia. Se evaluó el acoplamiento ventricular derecho-arterial (VAC) mediante ecocardiografía. Se utilizaron low-rank regression splines para modelar la fracción de eyección del ventrículo izquierdo (FEVI) y la fracción de eyección del ventrículo derecho (FEVD) en relación con el VAC. RESULTADOS: Se observaron asociaciones positivas entre el VAC y la FEVI (ρ = 0.472, p = 0.023), la FEVD (ρ = 0.522, p = 0.038) y el volumen de eyección indexado del ventrículo derecho (ρ = 0.79, p < 0.001). Los pacientes con crVT mostraron correlaciones con acortamiento del ventrículo derecho, disminución de la FEVD (39.6 vs. 32.2%, p = 0.025), aumento de la masa ventricular izquierda (38.99 vs. 45.55, p = 0.045) y volumen diastólico final del ventrículo izquierdo (VDVI) (56.99 vs. 68.15 mL/m2, p = 0.045). Se observaron asociaciones positivas para el VAC con el VDVI (p = 0.039) y la masa ventricular izquierda (p = 0.039), mientras que se observaron correlaciones negativas con la FEVD por RMC (p = 0.023) y el acortamiento del ventrículo derecho por ecocardiografía (p = 0.026). CONCLUSIONES: Nuestros hallazgos subrayan la importancia del VAC derecho en la MCA, demostrando correlaciones con la FEVD y FEVI, el volumen de eyección del ventrículo derecho y arritmias clínicamente relevantes. Las percepciones sobre la FEVD, la masa ventricular izquierda y el volumen diastólico final proporcionan contribuciones valiosas para comprender la fisiopatología de la MCA y pueden informar estrategias de evaluación de riesgos.

Blockade of thromboxane A2 signaling attenuates ethanol-induced myocardial inflammatory response in mice.

BACKGROUND: Alcohol-associated cardiomyopathy (ACM) is a cardiac muscle disease characterized by inflammation and oxidative stress. Thromboxane-prostanoid receptor (TP-R) plays an important role in the pathogenesis of cardiovascular disease. Herein, we hypothesize that TP-R mediates alcohol-induced early cardiac injury. METHODS: Eight-week-old male C57BL/6 wild-type mice were fed a chronic ethanol (ET) or control diet (CON) for 10 days followed by a single binge of ethanol or maltose-dextrin through oral gavage. A cohort of ethanol-fed mice received SQ 29,548 (SQ), a TP-R antagonist. RNA sequencing, real-time PCR, and western blot analysis were performed on left ventricle to investigate alterations in genes and/or proteins mediating oxidative stress, inflammation, and cardiac remodeling. Sirius Red staining was performed to measure myocardial fibrosis. RESULTS: RNA-sequencing analysis of myocardium from CON and ET groups identified 142 genes that were significantly altered between the two groups. In particular, the gene expression of thioredoxin-interacting protein (TXNIP), a component of NLR family pyrin domain containing 3 (NLRP3) signaling, which mediates oxidative stress and inflammatory response, was upregulated in response to ethanol exposure. The myocardial protein levels of TP-R and thromboxane A2 synthase were increased upon alcohol exposure. Ethanol increased the levels of 4-hydroxynonenal, a marker of oxidative stress, with a concomitant increase in the protein levels of TXNIP and NLRP3, and administration of SQ attenuated these effects. Additionally, ethanol increased the protein levels of pro-inflammatory mediators, including tumor necrosis factor alpha and the NLRP3 downstream product, secretory interleukin 1 beta, and SQ blunted these effects. Finally, the Sirius red staining of the myocardium revealed an increase in collagen deposition in ethanol-fed mice which was attenuated by TP-R antagonism. CONCLUSION: This study demonstrates that ethanol promotes the NLRP3 signaling pathway within the myocardium, leading to a pro-inflammatory milieu that potentially initiates early myocardial remodeling, and TP-R antagonism attenuates this effect.

Pulmonary artery banding for cardiomyopathy in young children: First trial in China.

AIMS: Heritable dilated cardiomyopathy (DCM) or DCM associated with congenital or acquired left ventricular diseases carries a significant mortality risk. Pulmonary artery banding (PAB) has been proposed as an alternative to heart transplantation. This study aimed to delineate the clinical development, ventricular reverse remodelling, and functional regeneration of the dilated left ventricle, presenting as a pioneering approach in China. METHODS AND RESULTS: This prospective study was initiated in November 2021, involving paediatric patients with a significant dilated left ventricle and preserved right ventricle who underwent surgical PAB. The baseline characteristics and clinical information during follow-up were collected. Seven patients (five boys) with a median age of 240 (148, 1028) days have been included thus far. No procedural or follow-up mortality was observed. The modified Ross functional class improved from treatment to follow-up of 348 (200, 629) days, and the median left ventricular ejection fraction increased from 27.0 (15.0, 34.0) % before surgery to 61.0 (52.0, 68.0) % (P < 0.05); the median left ventricular end-diastolic diameter and corresponding Z-scores decreased from 43.0 (40.0, 55.0) mm [+9.4 (+7.7, +11.7)] to 33.0 (29.0, 39.0) mm [+1.8 (+1.3, +3.8)] (P < 0.05). Functional regeneration of the left ventricle was observed in five patients. Three of them underwent balloon dilation of the PAB to relieve excessively elevated right ventricular pressures. CONCLUSIONS: The application of PAB should adhere to strict criteria. Initial results are promising for infants and even toddlers with a dilated left ventricle and limited probability of spontaneous recovery. PAB can be an alternative when there is a shortage of donor transplants and assist devices, especially for low- and middle-income countries.

Pathological mutations in the phospholamban cytoplasmic region affect its topology and dynamics modulating the extent of SERCA inhibition.

Phospholamban (PLN) is a 52 amino acid regulin that allosterically modulates the activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in the heart muscle. In its unphosphorylated form, PLN binds SERCA within its transmembrane (TM) domains, approximately 20 Å away from the Ca2+ binding site, reducing SERCA's apparent Ca2+ affinity (pKCa) and decreasing cardiac contractility. During the enzymatic cycle, the inhibitory TM domain of PLN remains anchored to SERCA, whereas its cytoplasmic region transiently binds the ATPase's headpiece. Phosphorylation of PLN at Ser16 by protein kinase A increases the affinity of its cytoplasmic domain to SERCA, weakening the TM interactions with the ATPase, reversing its inhibitory function, and augmenting muscle contractility. How the structural changes caused by pathological mutations in the PLN cytoplasmic region are transmitted to its inhibitory TM domain is still unclear. Using solid-state NMR spectroscopy and activity assays, we analyzed the structural and functional effects of a series of mutations and their phosphorylated forms located in the PLN cytoplasmic region and linked to dilated cardiomyopathy. We found that these missense mutations affect the overall topology and dynamics of PLN and ultimately modulate its inhibitory potency. Also, the changes in the TM tilt angle and cytoplasmic dynamics of PLN caused by these mutations correlate well with the extent of SERCA inhibition. Our study unveils new molecular determinants for designing variants of PLN that outcompete endogenous PLN to regulate SERCA in a tunable manner.

Upregulation of utrophin improves the phenotype of Duchenne muscular dystrophy hiPSC-derived CMs.

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease. Although it leads to muscle weakness, affected individuals predominantly die from cardiomyopathy, which remains uncurable. Accumulating evidence suggests that an overexpression of utrophin may counteract some of the pathophysiological outcomes of DMD. The aim of this study was to investigate the role of utrophin in dystrophin-deficient human cardiomyocytes (CMs) and to test whether an overexpression of utrophin, implemented via the CRISPR-deadCas9-VP64 system, can improve their phenotype. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) lacking either dystrophin (DMD) or both dystrophin and utrophin (DMD KO/UTRN(+/-)). We carried out proteome analysis, which revealed considerable differences in the proteins related to muscle contraction, cell-cell adhesion, and extracellular matrix organization. Furthermore, we evaluated the role of utrophin in maintaining the physiological properties of DMD hiPSC-CMs using atomic force microscopy, patch-clamp, and Ca2+ oscillation analysis. Our results showed higher values of afterhyperpolarization and altered patterns of cytosolic Ca2+ oscillations in DMD; the latter was further disturbed in DMD KO/UTRN(+/-) hiPSC-CMs. Utrophin upregulation improved both parameters. Our findings demonstrate for the first time that utrophin maintains the physiological functions of DMD hiPSC-CMs, and that its upregulation can compensate for the loss of dystrophin.

Unlocking the Therapeutic Symphony: A Systematic Review Exploring the Role of Levosimendan in the Management of Heart Failure.

Levosimendan, a novel drug, a calcium-sensitizing inotrope, has emerged as a potential therapeutic modulator for heart failure (HF). This review appraises the efficacy and safety of levosimendan in managing HF, in different clinical settings. The study aims to examine the clinical outcomes reported in the selected trials to determine the effectiveness of levosimendan in improving key parameters related to HF. Seven relevant studies encompassing 1200 participants were identified from three databases. Inclusion criteria included clinical trials that investigated the therapeutic efficacy of levosimendan in the treatment of HF, and studies involving both adult and pediatric participants. Exclusion criteria involved studies with insufficient data, studies other than clinical trials, case reports, letters to the editor, conference papers, grey literature, and studies published in a language other than English. Upon evaluating the included studies, it was found that levosimendan shows improved hemodynamics and clinical efficacy in patients with severe septic cardiomyopathy. Levosimendan enhanced right ventricular (RV) function in patients with RV dysfunction after mitral valve (MV) surgeries and decreased the amount of N-terminal pro-B-type natriuretic peptide (NT-ProBNP) in non-ST elevated myocardial infarction (NSTEMI) patients with elevated NT-proBNP, all without increasing the overall cost or duration of hospitalization. Despite variations in study designs and participant characteristics, evidence suggests levosimendan significantly improves left ventricular ejection fraction (LVEF) and exercise tolerance measured by a six-minute walk distance. Notably, its safety profile appears favorable with minimal arrhythmic events and comparable rates of adverse effects to a placebo. This systematic review highlights levosimendan's promising potential for HF management, warranting further research to solidify its clinical role.