Hypertrophic cardiomyopathy (HCM) is the most common mendelian heart disease, with a prevalence of 1/500. HCM is a primary cause of sudden death, due to an heightened risk of ventricular ...tachyarrhythmias that often occur in young asymptomatic patients. HCM can slowly progress toward heart failure, either with preserved or reduced ejection fraction, due to worsening of diastolic function. Accumulation of intra-myocardial fibrosis and replacement scars underlies heart failure progression and represents a substrate for sustained arrhythmias in end-stage patients. However, arrhythmias and mechanical abnormalities may occur in hearts with little or no fibrosis, prompting toward functional pathomechanisms. By studying viable cardiomyocytes and trabeculae isolated from inter-ventricular septum samples of non-failing HCM patients with symptomatic obstruction who underwent myectomy operations, we identified that specific abnormalities of intracellular Ca
2+
handling are associated with increased cellular arrhytmogenesis and diastolic dysfunction. In HCM cardiomyocytes, diastolic Ca
2+
concentration is increased both in the cytosol and in the sarcoplasmic reticulum and the rate of Ca
2+
transient decay is slower, while the amplitude of Ca
2+
-release is preserved. Ca
2+
overload is the consequence of an increased Ca
2+
entry via L-type Ca
2+
-current due to prolongation the action potential (AP) plateau, combined with a reduced rate of Ca
2+
-extrusion through the Na
+
/Ca
2+
exchanger due to increased cytosolic (Na
+
) and a lower expression of SERCA. Increased late Na
+
current (I
NaL
) plays a major role, as it causes both AP prolongation and Na
+
overload. Intracellular Ca
2+
overload determines an higher frequency of Ca
2+
waves leading to delayed-afterdepolarizations (DADs) and premature contractions, but is also linked with the increased diastolic tension and slower relaxation of HCM myocardium. Sustained increase of intracellular Ca
2+
goes hand-in-hand with the increased activation of Ca
2+
/calmodulin-dependent protein-kinase-II (CaMKII) and augmented phosphorylation of its targets, including Ca
2+
handling proteins. In transgenic HCM mouse models, we found that Ca
2+
overload, CaMKII and increased I
NaL
drive myocardial remodeling since the earliest stages of disease and underlie the development of hypertrophy, diastolic dysfunction and the arrhythmogenic substrate. In conclusion, diastolic dysfunction and arrhythmogenesis in human HCM myocardium are driven by functional alterations at cellular and molecular level that may be targets of innovative therapies.
Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular ...mechanisms underlying arrhythmogenicity and diastolic dysfunction.
We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca(2+) (Ca(2+)(i)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na(+) (I(NaL)) and Ca(2+) (I(CaL)) currents and decreased repolarizing K(+) currents, increased occurrence of cellular arrhythmias, prolonged Ca(2+)(i) transients, and higher diastolic Ca(2+)(i). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function.
We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca(2+)(i) handling proteins changes identified, an enhanced I(NaL) seems to be a major contributor to the electrophysiological and Ca(2+)(i) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I(NaL) inhibition.
Cardiomyocytes derived from human embryonic stem cells constitute a promising cell source for the regeneration of damaged hearts. The assessment of their in vitro functional properties is mandatory ...to envisage appropriate cardiac cell-based therapies. In this study, we characterized human embryonic stem cell-derived cardiomyocytes over a 3-month period, using patch-clamp or intracellular recordings to assess their functional maturation and reverse transcriptase-polymerase chain reaction to evaluate the expression of ion channel-encoding subunits. I(to1) and I(K1), the transient outward and inward rectifier potassium currents, were present in cardiomyocytes only, whereas the rapid delayed rectifier potassium current (I(Kr)), pacemaker current (I(f)), and L-type calcium current (I(Ca,L)) could be recorded both in undifferentiated human embryonic stem cells and in cardiomyocytes. Most of the currents underwent developmental maturation in cardiomyocytes, as assessed by modifications in current density (I(to1), I(K1), and I(Ca,L)) and properties (I(f)). Ion-channel mRNAs were always present when the current was recorded. Intracellular recordings in spontaneously beating clusters of cardiomyocytes revealed changes in action potential parameters and in response to pharmacological tools according to time of differentiation. In summary, human embryonic stem cell-derived cardiomyocytes mature over time during in vitro differentiation, approaching an adult phenotype. Disclosure of potential conflicts of interest is found at the end of this article.
Abstract Background Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, ...whether such clinical profile is different from more prevalent thick-filament–associated disease is unresolved. Objectives This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick-filament HCM. Methods Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years. Results Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593). Conclusions In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction.
HCN Channels Modulators: The Need for Selectivity Novella Romanelli, Maria; Sartiani, Laura; Masi, Alessio ...
Current topics in medicinal chemistry,
07/2016, Letnik:
16, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in ...several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.
Abstract If overexpression has been functionally demonstrated in ventricular myocytes from failing human hearts. Altered expression of If -channels as a consequence of electrophysiological remodeling ...may represent an arrhythmogenic mechanism in heart failure; however, the molecular basis of If overexpression in human cardiac disease is unknown. HCN1, 2 and 4 subtypes, which encode If -channels, have been identified in the heart. The present study was designed to characterize HCN isoform expression in failing and non-failing hearts. Ventricular and atrial samples were obtained from normal or failing hearts explanted from patients with end-stage ischemic cardiomyopathy. If was recorded in patch-clamped left ventricular myocytes. mRNA and protein expression of HCN subunits were measured in both atria and ventricles of control and diseased hearts. HCN2 and HCN4 were detected in human myocardium. Both mRNA and protein levels of HCN2/4 were significantly augmented in failing ventricles ( p < 0.01 for mRNA, p < 0.05 for protein). These results are consistent with the electrophysiological data showing that, in failing ventricular myocytes, If is of larger amplitude and activates at less negative potential. Changes in mRNA and protein expression of both HCN2/4 isoforms in atrial specimens from patients with heart failure mirrored those observed in ventricles ( p < 0.001 for mRNA, p < 0.05 for protein). No disease-dependent alteration was detected for MiRP1, the putative β-subunit of the If -channel. In conclusion, HCN4 is the predominant channel subtype in normal human heart, and its expression is further amplified by disease. HCN upregulation likely contributes to increased If and may play a role in ventricular and atrial arrhythmogenesis in heart failure.
Objective To review new scientific evidence to update the Italian guidelines for managing fever in children as drafted by the panel of the Italian Pediatric Society. Study design Relevant ...publications in English and Italian were identified through search of MEDLINE and the Cochrane Database of Systematic Reviews from May 2012 to November 2015. Results Previous recommendations are substantially reaffirmed. Antipyretics should be administered with the purpose to control the child's discomfort. Antipyretics should be administered orally; rectal administration is discouraged except in the setting of vomiting. Combined use of paracetamol and ibuprofen is discouraged, considering risk and benefit. Antipyretics are not recommended preemptively to reduce the incidence of fever and local reactions in children undergoing vaccination, or in attempt to prevent febrile convulsions in children. Ibuprofen and paracetamol are not contraindicated in children who are febrile with asthma, with the exception of known cases of paracetamol- or nonsteroidal anti-inflammatory drug-induced asthma. Conclusions Recent medical literature leads to reaffirmation of previous recommendations for use of antipyretics in children who are febrile.
Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na
current ...blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro.
To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic Ca
and Ca
waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na
current and reduced intracellular Na
and diastolic Ca
, ultimately preventing the pathological increase of calmodulin kinase activity in treated mice.
Owing to the sustained reduction of intracellular Ca
and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na
current are promising candidates for an early preventive therapy in young phenotype-negative subjects carrying high-risk HCM-related mutations.
To describe frequency, preventability and seriousness of adverse drug reactions (ADRs) in children as cause of emergency department (ED) admission and to evaluate the association between specific ...factors and the reporting of ADRs.
A retrospective analysis based on reports of suspected ADRs collected between January 1st, 2012 and December 31st, 2016 in the ED of Meyer Children's Hospital (Italy). Demographics, clinical status, suspected drugs, ADR description, and its degree of seriousness were collected. Logistic regression was used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of potential predictors of ADR seriousness.
Within 5 years, we observed 834 ADRs (1100 drug-ADR pairs), of whom 239 were serious; of them, 224 led to hospitalization. Patients were mostly treated with one drug. Among patients treated with more than one drug, 78 ADRs presented a potential interaction. The most frequently reported ADRs involved gastrointestinal system. The most frequently reported medication class was antinfectives. Risk of serious ADR was significantly lower in children and infants compared to adolescents (ROR 0.41 95% CI: 0.27-0.61 and 0.47 0.32-0.71, respectively), and it was significantly increased in subjects exposed to more than one drug (ROR 1.87 1.33-2.62 and 3.01 2.07-4.37 for subjects exposed to 2 and 3 or more drugs, respectively). Gender, interactions and off-label drug use did not influence the risk of serious ADRs.
Active surveillance in pharmacovigilance might represent the best strategy to estimate and characterize the clinical burden of ADRs in children.
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