Two-pore channels (TPCs) acts as a hub for excitation-contraction coupling, metabolism and cardiac hypertrophy signalling.

Ca2+ signaling is essential for cardiac contractility and excitability in heart function and remodeling. Intriguingly, little is known about the role of a new family of ion channels, the endo-lysosomal non-selective cation "two-pore channel" (TPCs) in heart function. Here we have used double TPC knock-out mice for the 1 and 2 isoforms of TPCs (Tpcn1/2-/-) and evaluated their cardiac function. Doppler-echocardiography unveils altered left ventricular (LV) systolic function associated with a LV relaxation impairment. In cardiomyocytes isolated from Tpcn1/2-/- mice, we observed a reduction in the contractile function with a decrease in the sarcoplasmic reticulum Ca2+ content and a reduced expression of various key proteins regulating Ca2+ stores, such as calsequestrin. We also found that two main regulators of the energy metabolism, AMP-activated protein kinase and mTOR, were down regulated. We found an increase in the expression of TPC1 and TPC2 in a model of transverse aortic constriction (TAC) mice and in chronically isoproterenol infused WT mice. In this last model, adaptive cardiac hypertrophy was reduced by Tpcn1/2 deletion. Here, we propose a central role for TPCs and lysosomes that could act as a hub integrating information from the excitation-contraction coupling mechanisms, cellular energy metabolism and hypertrophy signaling.

Prognosis of Right Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy.

Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 (P=0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; P=0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank P=0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.

Oligonucleotide Enhancing Compound Increases Tricyclo-DNA Mediated Exon-Skipping Efficacy in the Mdx Mouse Model.

Nucleic acid-based therapeutics hold great promise for the treatment of numerous diseases, including neuromuscular disorders, such as Duchenne muscular dystrophy (DMD). Some antisense oligonucleotide (ASO) drugs have already been approved by the US FDA for DMD, but the potential of this therapy is still limited by several challenges, including the poor distribution of ASOs to target tissues, but also the entrapment of ASO in the endosomal compartment. Endosomal escape is a well recognized limitation that prevents ASO from reaching their target pre-mRNA in the nucleus. Small molecules named oligonucleotide-enhancing compounds (OEC) have been shown to release ASO from endosomal entrapment, thus increasing ASO nuclear concentration and ultimately correcting more pre-mRNA targets. In this study, we evaluated the impact of a therapy combining ASO and OEC on dystrophin restoration in mdx mice. Analysis of exon-skipping levels at different time points after the co-treatment revealed improved efficacy, particularly at early time points, reaching up to 4.4-fold increase at 72 h post treatment in the heart compared to treatment with ASO alone. Significantly higher levels of dystrophin restoration were detected two weeks after the end of the combined therapy, reaching up to 2.7-fold increase in the heart compared to mice treated with ASO alone. Moreover, we demonstrated a normalization of cardiac function in mdx mice after a 12-week-long treatment with the combined ASO + OEC therapy. Altogether, these findings indicate that compounds facilitating endosomal escape can significantly improve the therapeutic potential of exon-skipping approaches offering promising perspectives for the treatment of DMD.

High parasternal intercostal muscle thickening associated with diaphragm dysfunction in myofibrillar myopathy: A case study.

Myofibrillar myopathies (MFM) are a group of heterogenic muscular disorders characterized by histological disorders with accumulation of myofibrillar degradation products and providing disorganization of the myofibril network. Respiratory muscles may be involved in this disease. Ultrasound is used to assess not only the diaphragm but also the parasternal intercostal muscle. Parasternal intercostal muscle thickening may be used as an index of respiratory effort particularly in patients with diaphragm failure. We report the case of high parasternal intercostal muscle thickening associated with diaphragm dysfunction in a patient with MFM.

Effects of C2 hemisection on respiratory and cardiovascular functions in rats.

High cervical spinal cord injuries induce permanent neuromotor and autonomic deficits. These injuries impact both central respiratory and cardiovascular functions through modulation of the sympathetic nervous system. So far, cardiovascular studies have focused on models of complete contusion or transection at the lower cervical and thoracic levels and diaphragm activity evaluations using invasive methods. The present study aimed to evaluate the impact of C2 hemisection on different parameters representing vital functions (i.e., respiratory function, cardiovascular, and renal filtration parameters) at the moment of injury and 7 days post-injury in rats. No ventilatory parameters evaluated by plethysmography were impacted during quiet breathing after 7 days post-injury, whereas permanent diaphragm hemiplegia was observed by ultrasound and confirmed by diaphragmatic electromyography in anesthetized rats. Interestingly, the mean arterial pressure was reduced immediately after C2 hemisection, with complete compensation at 7 days post-injury. Renal filtration was unaffected at 7 days post-injury; however, remnant systolic dysfunction characterized by a reduced left ventricular ejection fraction persisted at 7 days post-injury. Taken together, these results demonstrated that following C2 hemisection, diaphragm activity and systolic function are impacted up to 7 days post-injury, whereas the respiratory and cardiovascular systems display vast adaptation to maintain ventilatory parameters and blood pressure homeostasis, with the latter likely sustained by the remaining descending sympathetic inputs spared by the initial injury. A better broad characterization of the physiopathology of high cervical spinal cord injuries covering a longer time period post-injury could be beneficial for understanding evaluations of putative therapeutics to further increase cardiorespiratory recovery.

Cardiac Outcomes in Adults With Mitochondrial Diseases.

BACKGROUND: Patients with mitochondrial diseases are at risk of heart failure (HF) and arrhythmic major adverse cardiac events (MACE). OBJECTIVES: We developed prediction models to estimate the risk of HF and arrhythmic MACE in this population. METHODS: We determined the incidence and searched for predictors of HF and arrhythmic MACE using Cox regression in 600 adult patients from a multicenter registry with genetically confirmed mitochondrial diseases. RESULTS: Over a median follow-up time of 6.67 years, 29 patients (4.9%) reached the HF endpoint, including 19 hospitalizations for nonterminal HF, 2 cardiac transplantations, and 8 deaths from HF. Thirty others (5.1%) reached the arrhythmic MACE, including 21 with third-degree or type II second-degree atrioventricular blocks, 4 with sinus node dysfunction, and 5 sudden cardiac deaths. Predictors of HF were the m.3243A>G variant (HR: 4.3; 95% CI: 1.8-10.1), conduction defects (HR: 3.0; 95% CI: 1.3-6.9), left ventricular (LV) hypertrophy (HR: 2.6; 95% CI: 1.1-5.8), LV ejection fraction <50% (HR: 10.2; 95% CI: 4.6-22.3), and premature ventricular beats (HR: 4.1; 95% CI: 1.7-9.9). Independent predictors for arrhythmia were single, large-scale mtDNA deletions (HR: 4.3; 95% CI: 1.7-10.4), conduction defects (HR: 6.8; 95% CI: 3.0-15.4), and LV ejection fraction <50% (HR: 2.7; 95% CI: 1.1-7.1). C-indexes of the Cox regression models were 0.91 (95% CI: 0.88-0.95) and 0.80 (95% CI: 0.70-0.90) for the HF and arrhythmic MACE, respectively. CONCLUSIONS: We developed the first prediction models for HF and arrhythmic MACE in patients with mitochondrial diseases using genetic variant type and simple cardiac assessments.

Cyclic Change in Right and Left Ventricular Systolic and Diastolic Function in Patients with Neuromuscular Disorders on Permanent Mechanical Ventilation.

Home mechanical ventilation is classically used to treat neuromuscular patients with chronic respiratory insufficiency. Since the heart and lungs are localized in the thorax, intrathoracic pressure may directly affect heart function. Here, we report the direct cyclic effects of mechanical ventilation on the right and left ventricular systolic and diastolic function in serial cases. These cases highlight the importance of performing Doppler echocardiography in patients with neuromuscular disorders, focusing on the right and left ventricular systolic and diastolic functions in the context of ventilation setting modifications or introduction.

CD38-NADase is a new major contributor to Duchenne muscular dystrophic phenotype.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration. Two important deleterious features are a Ca2+ dysregulation linked to Ca2+ influxes associated with ryanodine receptor hyperactivation, and a muscular nicotinamide adenine dinucleotide (NAD+ ) deficit. Here, we identified that deletion in mdx mice of CD38, a NAD+ glycohydrolase-producing modulators of Ca2+ signaling, led to a fully restored heart function and structure, with skeletal muscle performance improvements, associated with a reduction in inflammation and senescence markers. Muscle NAD+ levels were also fully restored, while the levels of the two main products of CD38, nicotinamide and ADP-ribose, were reduced, in heart, diaphragm, and limb. In cardiomyocytes from mdx/CD38-/- mice, the pathological spontaneous Ca2+ activity was reduced, as well as in myotubes from DMD patients treated with isatuximab (SARCLISA® ) a monoclonal anti-CD38 antibody. Finally, treatment of mdx and utrophin-dystrophin-deficient (mdx/utr-/- ) mice with CD38 inhibitors resulted in improved skeletal muscle performances. Thus, we demonstrate that CD38 actively contributes to DMD physiopathology. We propose that a selective anti-CD38 therapeutic intervention could be highly relevant to develop for DMD patients.

Diaphragm Ultrasound in Cardiac Surgery: State of the Art.

In cardiac surgery, patients are at risk of phrenic nerve injury, which leads to diaphragm dysfunction and acute respiratory failure. Diaphragm dysfunction (DD) is relatively frequent in cardiac surgery and particularly affects patients after coronary artery bypass graft. The onset of DD affects patients' prognosis in term of weaning from mechanical ventilation and hospital length of stay. The authors present a narrative review about diaphragm physiology, techniques used to assess diaphragm function, and the clinical application of diaphragm ultrasound in patients undergoing cardiac surgery.

High parasternal intercostal muscle thickening prior to intubation in COVID-19 infection.

Acute hypoxemic respiratory failure (AHRF) is a major complication of COVID-19 pneumonia and parasternal intercostal muscle thickening may be used as a biomarker to assess inspiratory effort. We report the case of a high utilization of parasternal intercostal muscle prior to the introduction of invasive ventilation in a 66-year old male none vaccinated COVID -19 patient admitted in hospital because of AHRF.

Determinants of diaphragm inspiratory motion, diaphragm thickening, and its performance for predicting respiratory restrictive pattern in Duchenne muscular dystrophy.

INTRODUCTION/AIMS: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD. METHODS: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests. RESULTS: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P = .001), Walton score (P = .012), inspiratory capacity (IC) (P = .004), upright forced vital capacity (FVC) (P < .0001), supine FVC (P = .038), and maximal inspiratory pressure (MIP) (P = .002). Right diaphragm excursion was significantly associated with age (P < .0001), steroid use (P = .008), history of spinal fusion (P < .0001), body mass index (BMI) (P = .002), Walton score (P < .0001), IC (P < .0001), upright FVC (P < .0001), supine FVC (P < .0001), and MIP (P < .0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P = .001) and 0.93 (P < .001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P = .011) and 0.97 (P < .001). DISCUSSION: Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD.

Leadless intracardiac transcatheter pacing system: 20 months follow up in adult Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked muscular dystrophy in relation with dystrophin deficient. Heart and respiratory function are classically involved and affect long-term prognosis. Significant atrio-ventricular block may occur in some patients. Implantation of traditional pacemaker may be challenging in patients with tracheotomy and on permanent home mechanical ventilation. We report the first case of a successful leadless intra-cardiac trans-catheter pacing system implantation in an adult DMD on wheelchair and on permanent home mechanical ventilation.

Cardiopulmonary Pathophysiological Aspects in the Context of COVID-19 and Obesity.

Obesity is a significant public health concern associated with high morbidity. Obese patients are at risk of severe COVID-19 infection, and obesity is a high-risk factor for admission to the intensive care unit. We aimed to write a narrative review of cardiac and pulmonary pathophysiological aspects of obese patients in the context of COVID-19 infection. Obesity affects lung volume, with a decrease in expiratory reserve volume, which is associated with a decrease in lung and chest wall compliance, an increase in airway resistance, and an increase in work of breathing. Obesity affects cardiac structure and hemodynamics. Obesity is a risk factor for hypertension and cardiovascular disorders. Moreover, obesity is associated with a low-grade inflammatory state, endothelial dysfunction, hyperinsulinemia, and metabolic disorders. Obesity is associated with severe COVID-19 and invasive mechanical ventilation. These previous cardiopulmonary pathological aspects may explain the clinical severity in obese patients with COVID-19. Obese patients are at risk of severe COVID-19 infection. Understanding cardiorespiratory pathophysiological aspects may help physicians manage patients in hospitals.

Nutritional status, swallowing disorders, and respiratory prognosis in adult Duchenne muscular dystrophy patients.

Malnutrition and swallowing disorders are common in Duchenne muscular dystrophy (DMD) patients. We assessed, in adult DMD with home mechanical ventilation (HMV) and cough assist device, its prevalence and the relationships with respiratory muscle strength and long-term respiratory prognosis. We reviewed the patients (n = 117, age 18-39 years [median 24]), followed in a reference center, from 2006 to 2015, to obtain clinical baseline, nutritional status, vital capacity (VC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). The median body mass index (BMI) was low (15.6 kg/m²). Included patients had severe restrictive respiratory function with a median VC of 10.5% [7-17] of the predicted value. All patients were on HMV. Prevalence of malnutrition, swallowing disorders, and gastrostomy were respectively 62%, 34%, and 11%. BMI and serum albumin level were significantly associated with MIP, MEP, and VC. The 1-year/5-years cumulative incidences of respiratory events (pulmonary sepsis and acute respiratory distress) were, respectively, 20.7%/44.5%. Using univariate analysis, predictive factors for respiratory events were swallowing disorders (p = .001), transthyretinemia (p = .034), MIP (p = .039), and MEP (p = .03) but not BMI or albuminemia. Using multivariate analysis, only swallowing disorders remained significantly associated with respiratory events (OR = 4.2, IC 95% 1.31-12.2, p = .01). In conclusion, this study highlights the interrelationships between nutritional intake, swallowing function, airway clearance, and respiratory function in adult DMD. A multidisciplinary approach focusing on these previous factors is essential to optimize DMD patient health.

Association between prophylactic angiotensin-converting enzyme inhibitors and overall survival in Duchenne muscular dystrophy-analysis of registry data.

AIMS: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results. CONCLUSION: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.

Impact of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Hypertensive Patients with COVID-19 (COVIDECA Study).

Effect of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) among hypertensive patients with coronavirus disease 2019 (COVID-19) is debated. The aim of the COVIDECA study was to assess the outcome of ACEI and ARB among hypertensive patients presenting with COVID-19. We reviewed from the Assistance Publique-Hôpitaux de Paris healthcare record database all patients presenting with confirmed COVID-19 by RT-PCR. We compared hypertensive patients with ACEI or ARB and hypertensive patients without ACEI and ARB. Among 13,521 patients presenting with confirmed COVID-19 by RT-PCR, 2,981 hypertensive patients (mean age: 78.4 ± 13.6 years, 1,464 men) were included. Outcome of hypertensive patients was similar whatever the use or non-use of ACEI or ARB: admission in ICU (13.4% in patients with ACEI or ARB versus 14.8% in patients without ACEI/ARB, p = 0.35), need of mechanical ventilation (5.5% in patients with ACEI or ARB vs 6.3% in patients without ACEI/ARB, p = 0.45), in-hospital mortality (27.5% in patients with ACEI or ARB vs 26.7% in patients without ACEI/ARB, p = 0.70). In conclusion, the use of ACEI and ARB remains safe and can be maintained in hypertensive patients presenting with COVID-19.

Heart and anorexia nervosa.

Anorexia nervosa, one of the more frequent and severe eating disorders, is a chronic psychiatric disease with potentially serious somatic consequences. This behavioral symptomatology leads to weight loss, undernutrition, and more or less severe-potentially life-threatening-somatic complications including respiratory, hepatic, digestive and cardiac features, electrolyte disturbances, endocrine and bone impairment, immunodepression, and related opportunistic infections. In this review, the authors report an overview of cardiac diseases in this disease.

Analysis of inspiratory and expiratory muscles using ultrasound in rats: A reproducible and non-invasive tool to study respiratory function.

Ultrasound imaging is a non-invasive technique to assess organ function. Its potential application in rodents to evaluate respiratory function remains poorly investigated. We aimed to assess and validate ultrasound technique in rats to analyze inspiratory and expiratory muscles. We measured respiratory parameters to provide normal eupneic values. Histological studies and plethysmography were used to validate the technique and assess the physiological implications. A linear relationship was observed between ultrasound and histological data for diaphragm and rectus abdominis (RA) measurement. The tidal volume was significantly correlated with the right + left RA area (r = 0.76, p < 0.001), and the rapid shallow breathing index was significantly and inversely correlated with the right + left RA area (r=-0.53, p < 0.05). In the supine position, the right and left diaphragm expiratory thickness were not associated with tidal volume obtained in the physiological position. Ultrasound imaging is highly accurate and reproducible to assess and follow up diaphragm and RA structure and function in rats.

Echocardiographic abnormalities in 124 severely malnourished adult anorexia nervosa patients: frequency and relationship with body composition and biological features.

BACKGROUND: Anorexia Nervosa (AN) is a complex psychiatric disorder that can lead to specific somatic complications. Heart abnormalities are frequently reported, while their frequency and associated factors in severely malnourished AN patients remain poorly defined. OBJECTIVES: This study aimed to characterize echocardiographic abnormalities in severely malnourished AN patients and to assess associated clinical, biological and related body composition features. METHODS: Between January 2013 and January 2015, all severely malnourished adult patients with AN (Mental Disorders, 4th Edn.-DSM IVr) were included in a monocentric study performed in in a highly specialized AN inpatient unit. Electrocardiogram (ECG) and echocardiography were used to assess both heart rhythm and function. All inpatients underwent a Doppler echocardiography procedure after undergoing combined blood volume adjustment, micronutrients deficiencies supplementation and electrolyte disorders correction. Right Ventricular (RV) and Left Ventricular (LV) systolic and diastolic functions were collected and compared to 29 healthy normal subjects in a control group. RESULTS: One hundred and 24 patients (119 (96%) women, 5 (4%) men) with a mean age of 30.1 ± 11 years old and an average Body Mass Index (BMI) of 12 kg/m2 were included. Ninety patients (73%) had been diagnosed with AN Restrictive type (AN-R), 34 (27%) an AN Binge eating/Purging type (AN-BP). Eighteen patients (15%) disclosed an abnormal Left Ventricular Ejection Fraction (LVEF) (< 52% for male and < 54% for female). LVEF impairment was associated with AN-BP patients (p < 0.017) and hypertransaminasemia (AST and/or ALT ≥2 N) (p < 0.05). Left Ventricular mass (LV mass) and Left Ventricular End Diastolic Diameter (LVEDD) were significantly reduced in patients (p < 0.001, p < 0.001). Left and right ventricular tissue Doppler Imaging Velocities (TDI) peak were reduced in patients: Septal and Lateral LV Sm velocities peaks respectively 10 ± 2 cm/s (vs 14 ± 2 cm/s in controls, p < 0.001), 12 ± 3 cm/s (vs 16 ± 3 cm/s in controls, p < 0.001), basal RV Sm velocity peaks at 14 ± 3 cm/s (vs 19 ± 3 cm/s in controls, p < 0.001). Additionally, LV and RV diastolic velocity peaks were reduced: LV septal and lateral velocity peaks were respectively 13 ± 3 cm/s (vs 18 ± 2 cm/s p < 0.001), 12 ± 3 cm/s (vs 22 ± 4 cm/s, p < 0.001) and RV diastolic velocity peaks at 14 ± 3 cm/s (vs 21 ± 4 cm/s p < 0.001). LV diastolic velocity TDI peaks were significantly associated with hypertransaminasemia (p < 0.05) and tended to be associated with a low all body Fat-Free Mass Index (FFMI) (using Dual-energy X- ray Absorptiometry (DXA) (HOLOGICQDR 4500) (p = 0.056). Thirty-four patients (27%) had a pericardial effusion and were significantly associated with a decreased all body FFMI (p < 0.036). CONCLUSION: Heart abnormalities are frequent in malnourished patients with AN, particularly in AN-BP type. Both liver enzymes and body composition abnormalities tended to be associated with heart dysfunction (non-significant association). Prospective studies are needed to better characterize and describe the evolution of cardiac abnormalities during the refeeding period and subsequent weight restoration.