Cardiomyopathy, familial dilated

Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20–48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant

AFM macro-probes to investigate whole 3D cardiac spheroids

In its many applications, the Atomic Force Microscope (AFM) is a promising tool in cardiac mechanobiology because it can unravel the viscoelastic and mechano-dynamic properties of individual cardiomyocytes. However, the biophysical investigation of more accurate 3D models is hampered by commercial probes, which typically operate at the cell sub-compartmental resolution. We have previously shown how flat macro-probes can overcome these limitations by extending the AFM mechanical measurements to multicellular aggregates. Such macro-probes are fabricated by standard micromachining and carry a flat polymeric wedge to offset the AFM mounting tilt. Therefore, the AFM is upgraded to a micro-parallel plate rheometer with unmatched force range and sensitivity. In this article, we show how these macro-probes can be applied to reveal the global rheology of primary cardiomyocytes spheroids, by performing stress-relaxation tests. More importantly, we demonstrate that these macro-probes can be used as passive sensors capable of monitoring the spheroid beating force and beating pattern, and to perform a “micro-CPR” on the spheroid itself

Trattamento dello scompenso cardiaco con terapia genica: i risultati inattesi del trial CUPID 2

Lo scompenso cardiaco \ue8 ancora oggi un\u2019importante causa di morbilit\ue0 e mortalit\ue0 in tutto il mondo. La terapia genica dei meccanismi implicati nello scompenso cardiaco \ue8 emersa sin dagli anni \u201990 come potenziale target terapeutico incoraggiando studi preclinici su piccoli e poi pi\uf9 grandi modelli animali. Le prime esperienze in letteratura hanno documentato una ridotta espressione del reticolo sarcoplasmatico/endoplasmatico Ca2+-ATPasi2a (SERCA2a) nello scompenso cardiaco. Questi risultati hanno portato allo sviluppo di trial clinici sul trasferimento genico di SERCA2a. I primi risultati positivi in termini di fattibilit\ue0, sicurezza ed endpoint clinici hanno aperto la strada al primo grande trial randomizzato, il CUPID, su pazienti con scompenso cardiaco e frazione di eiezione ridotta in cui sono stati arruolati 250 pazienti a infusione intracoronarica di virus adeno-associati di tipo 1 (AAV1)/SERCA2a o placebo. Le grandi aspettative riposte sono state disattese e non si \ue8 osservato alcun miglioramento in termini di outcome nei pazienti trattati. In questa revisione abbiamo rivisitato i precedenti lavori che hanno portato al disegno di questo trial, analizzato le sue principali caratteristiche e risultati, fornendo infine alcune ipotesi sul motivo di un fallimento parzialmente inatteso in modo da comprendere quali possano essere le future prospettive per la terapia genica nello scompenso cardiaco

Neonatal rat ventricular myocytes interfacing conductive polymers and carbon nanotubes

Carbon nanotubes (CNTs) have become promising advanced materials and a new tool to specifically interact with electroresponsive cells. Likewise, conductive polymers (CP) appear promising electroactive biomaterial for proliferation of cells. Herein, we have investigated CNT blends with two different conductive polymers, polypyrrole/CNT (PPy/CNT) and PEDOT/CNT to evaluate the growth, survival, and beating behavior of neonatal rat ventricular myocytes (NRVM). The combination of CP/CNT not only shows excellent biocompatibility on NRVM, after 2 weeks of culture, but also exerts functional effects on networks of cardiomyocytes. NRVMs cultured on CNT-based substrates exhibited improved cellular function, i.e., homogeneous, non-arrhythmogenic, and more frequent spontaneous beating; particularly PEDOT/CNT substrates, which yielded to higher beating amplitudes, thus suggesting a more mature cardiac phenotype. Furthermore, cells presented enhanced structure: aligned sarcomeres, organized and abundant Connexin 43 (Cx43). Finally, no signs of induced hypertrophy were observed. In conclusion, the combination of CNT with CP produces high viability and promotes cardiac functionality, suggesting great potential to generate scaffolding supports for cardiac tissue engineering

Sex differences in natural history of cardiovascular magnetic resonance- and biopsy-proven lymphocytic myocarditis

Aims: the role of sex in determining the profile and the outcomes of patients with myocarditis is largely unexplored. We evaluated the impact of sex as a modifier factor in the clinical characterization and natural history of patients with definite diagnosis of myocarditis. Methods and results: we retrospectively analysed a single-centre cohort of consecutive patients with definite diagnosis of myocarditis (i.e. endomyocardial biopsy or cardiac magnetic resonance proven). Specific sub-analyses were performed in cohorts of patients with chest pain, ventricular arrhythmias, and heart failure as different main symptoms at presentation. The primary outcome measure was a composite of all-cause mortality or heart transplantation (HTx). We included 312 patients, of which 211, 68% of the whole population, were males. Despite no clinically relevant differences found at baseline presentation, males had a higher indexed left ventricular end-diastolic volume (62 ± 23 mL/m2 vs. 52 ± 20 mL/m2, P = 0.011 in males vs. females, respectively) at follow-up evaluation. At a median follow-up of 72 months, 36 (17%) males vs. 8 (8%) females experienced death or HTx (P = 0.033). Male sex emerged as predictors of all-cause mortality or HTx in every combination of covariates (HR 2.600; 1.163–5.809; P = 0.020). Results were agreeable regardless of the main symptom of presentation. Conclusions: in a large cohort of patients with definite diagnosis of myocarditis, females experienced a more favourable long-term prognosis than males, despite a similar clinical profile at presentation

Natural History of Dilated Cardiomyopathy in Children

The long-term progression of idiopathic dilated cardiomyopathy (DCM) in pediatric patients compared with adult patients has not been previously characterized. In this study, we compared outcome and long-term progression of pediatric and adult DCM populations

Cardiac Hypertrophy, Accessory Pathway, and Conduction System Disease in an Adolescent

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Cellular Biomechanic Impairment in Cardiomyocytes Carrying the Progeria Mutation: An Atomic Force Microscopy Investigation

Given the clinical effect of progeria syndrome, understanding the cell mechanical behavior of this pathology could benefit the patient's treatment. Progeria patients show a point mutation in the lamin A/C gene (LMNA), which could change the cell's biomechanical properties. This paper reports a mechano-dynamic analysis of a progeria mutation (c.1824 C > T, p.Gly608Gly) in neonatal rat ventricular myocytes (NRVMs) using cell indentation by atomic force microscopy to measure alterations in beating force, frequency, and contractile amplitude of selected cells within cell clusters. Furthermore, we examined the beating rate variability using a time-domain method that produces a Poincaré plot because beat-to-beat changes can shed light on the causes of arrhythmias. Our data have been further related to our cell phenotype findings, using immunofluorescence and calcium transient analysis, showing that mutant NRVMs display changes in both beating force and frequency. These changes were associated with a decreased gap junction localization (Connexin 43) in the mutant NRVMs even in the presence of a stable cytoskeletal structure (microtubules and actin filaments) when compared with controls (wild type and non-treated cells). These data emphasize the kindred between nucleoskeleton (LMNA), cytoskeleton, and the sarcolemmal structures in NRVM with the progeria Gly608Gly mutation, prompting future mechanistic and therapeutic investigations