Chronic Istaroxime Improves Cardiac Function and Heart Rate Variability in Cardiomyopathic Hamsters

Giudice, Pietro; Mattera, Giovan Giuseppe; Gagnol, J. P.; Borsini, Franco

doi:10.1007/s10557-011-6283-y

Cited by 9 publications

(10 citation statements)

References 28 publications

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“…Our observations of reductions in the total spectral power, the LF component, and the HF component, are in agreement with those they reported. A subsequent study in cardiomyopathic TO-2 hamsters, also reporting similar values for heart rate and HRV as we report here, demonstrated that the lusitropic agent istaroxime improved cardiac function via preservation of autonomic tone (Lo Giudice et al, 2011). Changes in autonomic modulation of the heart in TO-2 cardiomyopathic hamsters was thought to be a reactive compensation to impaired cardiac function (Giudice et al, 2000).…”

Section: Discussionsupporting

confidence: 86%

Developmental Changes in the ECG of a Hamster Model of Muscular Dystrophy and Heart Failure

Hampton¹,

Kale²,

McCue³

et al. 2012

Front. Pharmacol.

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Aberrant autonomic signaling is being increasingly recognized as an important symptom in neuromuscular disorders. The δ-sarcoglycan-deficient BIO TO-2 hamster is recognized as a good model for studying mechanistic pathways and sequelae in muscular dystrophy and heart failure, including autonomic nervous system (ANS) dysfunction. Recent studies using the TO-2 hamster model have provided promising preclinical results demonstrating the efficacy of gene therapy to treat skeletal muscle weakness and heart failure. Methods to accelerate preclinical testing of gene therapy and new drugs for neuromuscular diseases are urgently needed. The purpose of this investigation was to demonstrate a rapid non-invasive screen for characterizing the ANS imbalance in dystrophic TO-2 hamsters. Electrocardiograms were recorded non-invasively in conscious ∼9-month old TO-2 hamsters (n = 10) and non-myopathic F1B control hamsters (n = 10). Heart rate was higher in TO-2 hamsters than controls (453 ± 12 bpm vs. 311 ± 25 bpm, P < 0.01). Time domain heart rate variability, an index of parasympathetic tone, was lower in TO-2 hamsters (12.2 ± 3.7 bpm vs. 38.2 ± 6.8, P < 0.05), as was the coefficient of variance of the RR interval (2.8 ± 0.9% vs. 16.2 ± 3.4%, P < 0.05) compared to control hamsters. Power spectral analysis demonstrated reduced high frequency and low frequency contributions, indicating autonomic imbalance with increased sympathetic tone and decreased parasympathetic tone in dystrophic TO-2 hamsters. Similar observations in newborn hamsters indicate autonomic nervous dysfunction may occur quite early in life in neuromuscular diseases. Our findings of autonomic abnormalities in newborn hamsters with a mutation in the δ-sarcoglycan gene suggest approaches to correct modulation of the heart rate as prevention or therapy for muscular dystrophies.

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Section: Discussionsupporting

confidence: 86%

Developmental Changes in the ECG of a Hamster Model of Muscular Dystrophy and Heart Failure

Hampton¹,

Kale²,

McCue³

et al. 2012

Front. Pharmacol.

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“…It is known that sympathetic activation plays a crucial pathogenetic role in the development and progression of heart failure and markers of its function, such as heart rate variability, represent independent predictors of patients' outcome. According to the analysis of heart rate variability, istaroxime prevented the disturbance of autonomic tone by preserving the parasympathetic activity [19], expanding previous reports showing that istaroxime did not affect heart rate [15,16]. In addition, an improvement of coronary flow reserve was also documented [19].…”

mentioning

confidence: 62%

“…A subsequent analysis of the HORIZON-HF data focused on left ventricular diastolic function, as evaluated by pressure-volume analysis and tissue Doppler imaging of the lateral mitral annulus [22]; istaroxime reduced diastolic stiffness, as shown by the pressurevolume analysis, increased the early diastolic wave tissue Doppler velocity (E') and reduced the E/E' ratio. The current study by Lo Giudice et al [19] on one hand fills in a spectrum of animal trials on istaroxime and on the other stresses the lack of adequate clinical testing of this agent, which prevents its potential clinical use in a field in which effective drugs are noticeably missing.…”

mentioning

confidence: 89%

“…In the present issue of the Journal, this very group of investigators reports further on the long-term effects of oral istaroxime on the same cardiomyopathic hamsters they used before [19]. Compared to animals that received a vehicle, oral istaroxime administered for 16 weeks was followed by an improvement of left ventricular geometry and function.…”

mentioning

confidence: 92%

“…According to the analysis of heart rate variability, istaroxime prevented the disturbance of autonomic tone by preserving the parasympathetic activity [19], expanding previous reports showing that istaroxime did not affect heart rate [15,16]. In addition, an improvement of coronary flow reserve was also documented [19]. These two latter findings are of particular importance given the fact that two main drawbacks of classical inotropes are the detrimental effects of sympathetic activation, including tachycardia and arrhythmogenesis, as well as the myocardial ischemia resulting from the increase of myocardial oxygen demand [5].…”

mentioning

confidence: 99%

See 2 more Smart Citations

Istaroxime: Is the Remedy Better than the Disease?

Farmakis

Filippatos

2011

Cardiovasc Drugs Ther

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Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials

Ahmad

Miller

McCullough

et al. 2019

European J of Heart Fail

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Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti‐hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long‐term use in heart failure. The focus of this state‐of‐the‐art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients.

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Chronic Istaroxime Improves Cardiac Function and Heart Rate Variability in Cardiomyopathic Hamsters

Abstract: Chronic istaroxime improves cardiac function and heart rate variability in Bio TO.2 Syrian hamster model of progressive heart failure.

Cited by 9 publications

References 28 publications

Developmental Changes in the ECG of a Hamster Model of Muscular Dystrophy and Heart Failure

Developmental Changes in the ECG of a Hamster Model of Muscular Dystrophy and Heart Failure

Istaroxime: Is the Remedy Better than the Disease?

Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials

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