Protective role of cardiac-specific overexpression of caveolin-3 in cirrhotic cardiomyopathy

Cirrhotic cardiomyopathy is a clinical syndrome in patients with liver cirrhosis characterized by blunted cardiac contractile responses to stress and/or heart rate-corrected QT (QTc) interval prolongation. Caveolin-3 (Cav-3) plays a critical role in cardiac protection and is an emerging therapeutic target for heart disease. We investigated the protective role of cardiac-specific overexpression (OE) of Cav-3 in cirrhotic cardiomyopathy. Biliary fibrosis was induced in male Cav-3 OE mice and transgene negative (TGneg) littermates by feeding a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 0.1%) for 3 wk. Liver pathology and blood chemistries were assessed, and stress echocardiography, telemetry, and isolated heart perfusion studies to assess adrenergic responsiveness were performed. Cav-3 OE mice showed a similar degree of hyperdynamic contractility, pulmonary hypertension, and QTc interval prolongation as TGneg mice after 3 wk of DDC diet. Blunted systolic responses were shown in both DDC-fed Cav-3 OE and TGneg hearts after in vivo isoproterenol challenge. However, QTc interval prolongation after in vivo isoproterenol challenge was significantly less in DDC-fed Cav-3 OE hearts compared with DDC-fed TGneg hearts. In ex vivo perfused hearts, where circulatory factors are absent, isoproterenol challenge showed hearts from DDC-fed Cav-3 OE mice had better cardiac contractility and relaxation compared with DDC-fed TGneg hearts. Although Cav-3 OE in the heart did not prevent cardiac alterations in DDC-induced biliary fibrosis, cardiac expression of Cav-3 reduced QTc interval prolongation after adrenergic stimulation in cirrhosis. NEW & NOTEWORTHY Prevalence of cirrhotic cardiomyopathy is up to 50% in cirrhotic patients, and liver transplantation is the only treatment. However, cirrhotic cardiomyopathy is associated with perioperative morbidity and mortality after liver transplantation; therefore, management of cirrhotic cardiomyopathy is crucial for successful liver transplantation. This study shows cardiac myocyte specific overexpression of caveolin-3 (Cav-3) provides better cardiac contractile responses and less corrected QT prolongation during adrenergic stress in a cirrhotic cardiomyopathy model, suggesting beneficial effects of Cav-3 expression in cirrhotic cardiomyopathy.

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Translating the gap in the evaluation of drug-induced QTc-interval prolongation from in vivo to the clinic

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2014.03.055 ◽

2014 ◽

Vol 70 (3) ◽

pp. 324

Author(s):

Vincent F.S. Dubois ◽

Piet van der Graaf ◽

Derek Leishman ◽

David Gallacher ◽

Nick McMahon ◽

...

Keyword(s):

Qtc Interval ◽

Interval Prolongation ◽

Drug Induced ◽

Qtc Interval Prolongation

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QTc interval prolongation and hepatic encephalopathy in patients candidates for liver transplantation: A valid inference?

International Journal of Cardiology ◽

10.1016/j.ijcard.2015.04.026 ◽

2015 ◽

Vol 188 ◽

pp. 43-44 ◽

Cited By ~ 5

Author(s):

Vincenzo Marafioti ◽

Valentina Benetti ◽

Umberto Montin ◽

Vincenzo Carbone ◽

Alfredo Petrosino ◽

...

Keyword(s):

Liver Transplantation ◽

Hepatic Encephalopathy ◽

Qtc Interval ◽

Interval Prolongation ◽

Valid Inference ◽

Qtc Interval Prolongation

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Role of Co-occurring Alcohol and Substances Abuse on QTc Interval Prolongation Among Psychiatric Patients: A Cross-sectional National Survey

European Psychiatry ◽

10.1016/j.eurpsy.2017.01.2151 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S201-S202

Author(s):

M. Corbo ◽

T. Acciavatti ◽

F. Fiori ◽

R. Santacroce ◽

A. Aguglia ◽

...

Keyword(s):

National Survey ◽

Psychotropic Drugs ◽

Polymorphic Ventricular Tachycardia ◽

Qtc Interval ◽

Interval Prolongation ◽

Qtc Prolongation ◽

Cross Sectional ◽

Star Network ◽

Qtc Interval Prolongation

IntroductionQTc interval prolongation is considered a risk factor for fatal polymorphic ventricular tachycardia, which can result in sudden cardiac death. Most psychotropic drugs have a dose-dependent potential to prolong the QTc interval. However, other factors require appropriate consideration, including: age; gender; other medications; electrolyte abnormalities; severe comorbid conditions, such as co-occurring alcohol or substances abuse/dependence.ObjectivesThe objective was to study the potential mediating roles of alcohol/substances abuse on QTc prolongation.AimsThe Italian research group STAR Network, in collaboration with the Young Italian Psychiatrists Association, aimed to evaluate the frequency of QTc interval prolongation in a sample of patients under treatment with psychotropic drugs through a cross-sectional national survey.MethodsA sample of 2411 unselected patients were enrolled after performing an ECG during the recruitment period. Sociodemographic and clinical characteristics were collected from medical records. Collected data underwent statistical analysis.ResultsA total of 11.2% of patients reported alcohol abuse, and only 8.9% psychotropic substances. According to the threshold, less than 20% of patients had a borderline value of QTc, and 1% a pathological value. Patients with co-occurring alcohol misuse and drug abuse were more likely to have longer QTc interval.ConclusionsThe present study describes the frequency of QTc prolongation in real-world clinical practice. Before prescribing a psychotropic drug, the physician should carefully assess its risks and benefits to avoid this type of adverse reaction, particularly when additional risk factors are present. The potential role of alcohol and substances on QTc length could be particularly useful in emergency settings.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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Endocannabinoids acting at CB1receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00538.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. H1689-H1695 ◽

Cited By ~ 82

Author(s):

Sándor Bátkai ◽

Partha Mukhopadhyay ◽

Judith Harvey-White ◽

Raouf Kechrid ◽

Pál Pacher ◽

...

Keyword(s):

Blood Pressure ◽

Liver Cirrhosis ◽

Cardiac Contractility ◽

Receptor Expression ◽

Contractile Dysfunction ◽

Cirrhotic Cardiomyopathy ◽

Cardiac Contractile ◽

Cardiac Contractile Dysfunction

Advanced liver cirrhosis is associated with hyperdynamic circulation consisting of systemic hypotension, decreased peripheral resistance, and cardiac dysfunction, termed cirrhotic cardiomyopathy. Previous studies have revealed the role of endocannabinoids and vascular CB1receptors in the development of generalized hypotension and mesenteric vasodilation in animal models of liver cirrhosis, and CB1receptors have also been implicated in the decreased β-adrenergic responsiveness of isolated heart tissue from cirrhotic rats. Here we document the cardiac contractile dysfunction in vivo in liver cirrhosis and explore the role of the endocannabinoid system in its development. Rats with CCl4-induced cirrhosis developed decreased cardiac contractility, as documented through the use of the Millar pressure-volume microcatheter system, low blood pressure, and tachycardia. Bolus intravenous injection of the CB1antagonist AM251 (3 mg/kg) acutely increased mean blood pressure, as well as both load-dependent and -independent indexes of systolic function, whereas no such changes were elicited by AM251 in control rats. Furthermore, tissue levels of the endocannabinoid anandamide increased 2.7-fold in the heart of cirrhotic compared with control rats, without any change in 2-arachidonoylglycerol levels, whereas, in the cirrhotic liver, both 2-arachidonoylglycerol (6-fold) and anandamide (3.5-fold) were markedly increased. CB1-receptor expression in the heart was unaffected by cirrhosis, as verified by Western blotting. Activation of cardiac CB1receptors by endogenous anandamide contributes to the reduced cardiac contractility in liver cirrhosis, and CB1-receptor antagonists may be used to improve contractile function in cirrhotic cardiomyopathy and, possibly, in other forms of heart failure.

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Ranolazine as you have never seen it before: an antiarrhythmic for atrial fibrillation

European Heart Journal ◽

10.1093/ehjci/ehaa946.0555 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J.P Sousa ◽

L Puga ◽

J Ribeiro ◽

J Lopes ◽

C Saleiro ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cohort Studies ◽

Meta Analysis ◽

Rhythm Control ◽

Current Evidence ◽

Qtc Interval ◽

Interval Prolongation ◽

Qtc Interval Prolongation ◽

Secondary Endpoints

Abstract Background Currently available pharmacological options for rhythm control in atrial fibrillation (AF) are overshadowed by suboptimal efficacy and both frequent and potentially severe adverse events. Recent studies have added evidence to the hypothesis that ranolazine might exert antiarrhythmic effects, particularly in atrial tachyarrhythmias. Purpose To perform a systematic review with meta-analysis in order to ascertain the potential role of ranolazine in the management of AF. Methods We systematically searched MEDLINE, Embase and Scopus for randomized controlled trials (RCTs) and cohort studies addressing the association between ranolazine and AF outcomes, published up until December 1, 2019. The primary endpoint was incidence of AF, which was evaluated under a ranolazine versus placebo design. In this regard, patients in the setting of postcardiac surgery were further investigated separately. Secondary endpoints included AF cardioversion outcomes, which were addressed through comparison between ranolazine plus amiodarone and amiodarone alone for proportional efficacy and temporal requirements (time-to-cardioversion). The latter analysis was also undertaken in a dose-sensitive fashion (≤1000mg vs. 1500mg of ranolazine). Tertiary endpoints covered AF burden and episodes, in paroxysmal AF patients, and safety outcomes, namely death, QTc interval prolongation and hypotension. Study-specific odds ratios (ORs) were pooled using meta-analytic techniques with a random-effects model. Results A total of 10 RCTs comprising 8.109 participants and 3 cohort studies encompassing 37.112 patients were regarded as eligible for evaluation. Ranolazine was found to attenuate patients' odds of developing AF (OR 0.53, 95% CI: 0.41–0.69, p<0.001, i2=58%). This effect held true, with an even larger effect size, in the context of post-cardiac surgery (OR 0.34, 95% CI: 0.16–0.72, p=0.005, i2=64%). Ranolazine increased the chances of successful AF cardioversion when added to amiodarone over amiodarone alone (OR 6.67, 95% CI: 1.49–29.89, p=0.01, i2=76%), while significantly reducing time-to-cardioversion [SMD 9.54h, 95% CI: −13.3–5.75, p<0.001, i2=99%]. Interestingly, cardioversion was faster with ≤1000mg of ranolazine (SMD −13.16h, 95% CI: −15.07–11.25, p<0.001, i2=95%) than with 1500mg (SMD −3.57h, 95% CI: −5.06–2.08, p<0.001, i2=23%). In paroxysmal AF, ranolazine was also proved to significantly reduce both AF burden and episodes. There were no safety signals regarding mortality odds, QTc interval prolongation (mostly clinically insignificant) and hypotension (mostly transitory). Conclusion Current evidence suggests that ranolazine provides an effective and safe option for a chemical rhythm control strategy in AF management, a field in which medical breakthroughs are desperately needed. Funding Acknowledgement Type of funding source: None

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Evaluation of Moxifloxacin in Canine and Non‐Human Primate Telemetry Assays: Comparison of QTc Interval Prolongation by Timepoint and Concentration‐QTc Analysis

Clinical and Translational Science ◽

10.1111/cts.13103 ◽

2021 ◽

Author(s):

Ray W. Chui ◽

Joel Baublits ◽

Fiona A. Chandra ◽

Zack W. Jones ◽

Michael J. Engwall ◽

...

Keyword(s):

Qtc Interval ◽

Interval Prolongation ◽

Qtc Interval Prolongation ◽

Human Primate

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Drugs, QTc Interval Prolongation and Final ICH E14 Guideline

Drug Safety ◽

10.2165/00002018-200528110-00003 ◽

2005 ◽

Vol 28 (11) ◽

pp. 1009-1028 ◽

Cited By ~ 91

Author(s):

Rashmi R Shah

Keyword(s):

Qtc Interval ◽

Interval Prolongation ◽

Qtc Interval Prolongation ◽

Ich E14

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Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes

Scientific Reports ◽

10.1038/s41598-021-84758-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mille K. Lyhne ◽

Andreas Vegge ◽

Gro Klitgaard Povlsen ◽

Rita Slaaby ◽

Jonas Kildegaard ◽

...

Keyword(s):

Plasma Glucose ◽

Fold Increase ◽

Diabetic Group ◽

Large Animal ◽

Qtc Interval ◽

Interval Prolongation ◽

Hyperinsulinaemic Hypoglycaemia ◽

Large Animal Models ◽

Qtc Interval Prolongation ◽

Electrocardiographic Recordings

AbstractThe potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.

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