Association of β-Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients With Heart Failure With a Preserved Ejection Fraction

Silverman, Daniel N.; Plante, Timothy B; Infeld, Margaret; Callas, Peter W.; Juraschek, Stephen P.; Dougherty, Geoffrey; Meyer, Markus

doi:10.1001/jamanetworkopen.2019.16598

Cited by 108 publications

(76 citation statements)

References 55 publications

(142 reference statements)

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“…Beta-blockers are a class of drugs that are widely used in the treatment of cardiovascular diseases (CVDs) such as hypertension and myocardial infarction (MI) [1][2][3]. Propranolol (nonselective β receptor blocker) and atenolol (β 1 selective Beta-blockers) are among the beta-blocker drugs used in the treatment of many CVDs [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

2020

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Propranolol and atenolol are known as β receptor blocker drugs. These drugs are used to treat some heart diseases. There are controversies in the relationship between the use of beta-blocker drugs and the level of reactive oxygen species (ROS). Mitochondria as one of the most important sources of ROS are considered as one of the targets of drug-induced cardiotoxicity. The aim of this study was to evaluate the effects of propranolol and atenolol on mitochondria isolated from the heart. To achieve this aim, several markers of mitochondrial and cellular toxicity were evaluated. The key results of this study are the increased ROS level, collapse in mitochondrial membrane potential (MMP), mitochondrial swelling and cytochrome c release as well as disruption of respiratory chain complex II in mitochondria in isolated heart mitochondria after exposure to propranolol and atenolol. The results indicate an increase in caspase-3 activity and a decrease in the ATP level in cardiomyocytes after exposure to propranolol and atenolol. The underlying mechanisms of propranolol and atenolol induced cardiotoxicity may be associated with alterations in mitochondrial function, oxidative stress, and changes in the mitochondrial membrane.

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Section: Introductionmentioning

confidence: 99%

Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

2020

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“…From epidemiological perspective, patients with HFpEF are usually older, predominantly females and with high prevalence of other cardiovascular comorbid conditions such as atrial fibrillation, hypertension, and renal dysfunction which in the end contribute to reduced exercise tolerance, and may explain the high proportion (ranging from 50% to 60%) of beta‐blockers prescription in HFpEF patients . Nevertheless, emerging evidence suggests that pharmacological heart rate lowering is not beneficial in patients with preserved ejection fraction . In this regard, the proposed pathophysiological mechanism of pharmacological heart rate lowering in HFpEF patients is the prolongation of the filling of the cardiac chambers, which increases filling pressures, left ventricular diastolic wall stress and central arterial pressures …”

Section: Discussionmentioning

confidence: 99%

“…A recent meta‐analysis suggests a clinically beneficial effect of beta‐blockers in patients with HF and left ventricular ejection fraction ≥40%; however, the evidence to those with left ventricular ejection fraction >50% is limited . Recently, a recent secondary study from TOPCAT showed that for patients with an EF of 50% or greater, beta‐blocker use was associated with an increased risk of HF hospitalizations but not CVD mortality . However, no prior randomized clinical trial has explored the effects of beta‐blocker withdrawal on functional capacity in HFpEF patients with documented ChI.…”

Section: Discussionmentioning

confidence: 99%

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Beta‐blockers withdrawal in patients with heart failure with preserved ejection fraction and chronotropic incompetence: Effect on functional capacity rationale and study design of a prospective, randomized, controlled trial (The Preserve‐HR trial)

Palau

Seller²,

Domínguez

et al. 2020

Clinical Cardiology

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Background: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and multifactorial. Chronotropic incompetence (ChI) has emerged as a crucial pathophysiological mechanism. Beta-blockers, drugs with negative chronotropic effects, are commonly used in HFpEF, although current evidence does not support its routine use in these patients. Hypothesis: We postulate beta-blockers may have deleterious effects in HFpEF andChI. This work aims to evaluate the short-term effect of beta-blockers withdrawal on functional capacity assessed by the maximal oxygen uptake (peakVO2) in patients with HFpEF and ChI.Methods: This is a prospective, crossover, randomized (1:1) and multicenter study.After randomization, the clinical and cardiac rhythm will be continuously registered for 30 days. PeakVO2 is assessed by cardiopulmonary exercise testing (CPET) at 15 and 30 days in both groups. Secondary endpoints include quality of life, cognitive, and safety assessment. Patients with stable HFpEF, functional class New York Heart Association (NYHA) II-III, chronic treatment with beta-blockers, and ChI will be Abbreviations: ChI, chronotropic incompetence; CPET, cardiopulmonary exercise testing; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NYHA, New York Heart Association; PeakVO2, peak exercise oxygen uptake; QoL, quality of life.Patricia Palau and Julia Seller contributed equally to this study.

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“…HFpEF accounts for ~50% of HF cases, a proportion that is predicted to increase yearly relative to HFrEF (4). Numerous drugs treat HFrEF; no approved therapies target HFpEF, and clinical trials with several classes of drugs, including reninangiotensin-aldosterone inhibitors, produced no clinical benefits (5)(6)(7)(8). The HFpEF syndrome is characterized by endothelial dysfunction, hypertension, impaired relaxation and contractile reserve, ventricular stiffening and fibrosis (2,9).…”

Section: Condensed Abstractmentioning

confidence: 99%

Synthetic Growth Hormone-Releasing Hormone Agonist as Novel Treatment for Heart Failure with Preserved Ejection Fraction

Dulce

Kanashiro‐Takeuchi

Takeuchi

et al. 2020

Preprint

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25Heart failure with preserved ejection fraction (HFpEF) is characterized by a myocardium 26 with impaired relaxation, fibrosis and ventricular stiffness. Despite the rapidly increasing 27 prevalence of HFpEF, no effective therapies have emerged. Here we show that a potent 28 synthetic agonist of growth hormone-releasing hormone (GHRH-A) both prevents and reverses 29 the HFpEF phenotype generated in mice through continuous infusion of angiotensin-II (Ang-II). 30Animals treated with Ang-II had diastolic dysfunction, and isolated cardiomyocytes (ex vivo) 31 exhibited incomplete relaxation, depressed contractile responses and altered myofibrillar protein 32 phosphorylation. Calcium handling mechanisms were disturbed in cardiomyocytes from mice 33 with HFpEF. The GHRH-A MR-356 prevented the development of the pathological phenotype 34 and reversed the phenotype in vivo and ex vivo in mice with established HFpEF. Taken together 35 these findings indicate that the GHRH receptor signaling pathway represents a new molecular 36 target to counteract HFpEF-associated cardiomyocytye dysfunction by targeting myofilament 37 phosphorylation. Accordingly, activation of the GHRH receptor with potent synthetic GHRH 38 agonists may provide a novel therapeutic approach to management of HFpEF syndrome. 39 40 41 42 Heart failure (HF) remains a leading cause of death worldwide and is associated with two 43 general clinical variants -heart failure with reduced ejection fraction (HFrEF), characterized by 44 systolic dysfunction, and heart failure with preserved ejection fraction (HFpEF), predominantly 45 due to diastolic dysfunction 1-3 . HFpEF accounts for ~50% of HF cases, a proportion that is 46 predicted to increase at about 1% per year relative to HFrEF 4, 5 . Whereas there are numerous 47 approved and guideline supported drugs for HFrEF, there are no approved therapies targeting 48 HFpEF, and numerous clinical trials with several classes of drugs have failed to produce clinical 49 benefits 6-10 . The HFpEF syndrome is characterized by endothelial dysfunction, hypertension, 50 impaired relaxation and contractile reserve, ventricular stiffening and fibrosis 2, 11, 12 . The 51 underlying molecular mechanisms of HFpEF are poorly understood due to its diverse etiology, 52 which in most cases involves multi-organ pathological conditions 13-15 . Importantly, current 53 therapeutic strategies fail to stop the progression of HFpEF 6, 8, 16-18 , creating a healthcare crisis 54 due to the unmet therapeutic need for HFpEF patients 19, 20 . 55 The development of new potent synthetic growth hormone-releasing hormone agonists 56 (GHRH-As) and their application in different models of myocardial injury (either ischemic 21-25 57 or non-ischemic 26 ) demonstrates the effectiveness of myocardial GHRH receptors (GHRHRs) 58 activation to reduce fibrosis or hypertrophy, respectively, and improve cardiac performance 22-26 . 59 The signaling of GHRHR extends beyond the hypothalamic-pituitary axis 27 as the GHRHRs are 60 present on cardiomyocytes 22, 23 ...

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Association of β-Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients With Heart Failure With a Preserved Ejection Fraction

Cited by 108 publications

References 55 publications

Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

Toxicity of Atenolol and Propranolol on Rat Heart Mitochondria

Beta‐blockers withdrawal in patients with heart failure with preserved ejection fraction and chronotropic incompetence: Effect on functional capacity rationale and study design of a prospective, randomized, controlled trial (The Preserve‐HR trial)

Synthetic Growth Hormone-Releasing Hormone Agonist as Novel Treatment for Heart Failure with Preserved Ejection Fraction

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