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1.
Role of ranolazine in heart failure: From cellular to clinic perspective.
Kaplan, A, Amin, G, Abidi, E, Altara, R, Booz, GW, Zouein, FA
European journal of pharmacology. 2022;:174787
Abstract
Ranolazine was approved by the US Food and Drug Administration as an antianginal drug in 2006, and has been used since in certain groups of patients with stable angina. The therapeutic action of ranolazine was initially attributed to inhibitory effects on fatty acids metabolism. As investigations went on, however, it developed that the main beneficial effects of ranolazine arise from its action on the late sodium current in the heart. Since late sodium currents were discovered to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure, ranolazine has in some way been tested either directly or indirectly on heart failure in numerous experimental and clinical studies. As the heart continuously remodels following any sort of severe injury, the inhibition by ranolazine of the underlying mechanisms of cardiac remodeling including ion disturbances, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal impairment are discussed, along with unresolved issues. A projection of pathologies targeted by ranolazine from cellular level to clinical is provided in this review.
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2.
Race, Ancestry, and Risk: Targeting Prevention to Address Heart Failure Disparities.
Youmans, QR, Lloyd-Jones, DM, Khan, SS
Circulation. Heart failure. 2022;(1):e008741
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3.
Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis.
Gronda, E, Lopaschuk, GD, Arduini, A, Santoro, A, Benincasa, G, Palazzuoli, A, Gabrielli, D, Napoli, C
Canadian journal of physiology and pharmacology. 2022;(2):93-106
Abstract
Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.
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4.
The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review.
Zhang, R, Sun, X, Li, Y, He, W, Zhu, H, Liu, B, Zhang, A
Journal of cardiovascular pharmacology and therapeutics. 2022;:10742484211058681
Abstract
Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.
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5.
Nocturnal Hypertension and Heart Failure: Mechanisms, Evidence, and New Treatments.
Kario, K, Williams, B
Hypertension (Dallas, Tex. : 1979). 2021;(3):564-577
Abstract
Heart failure (HF) is a common condition with an increasing prevalence. Despite a variety of evidence-based treatments for patients with HF with reduced ejection fraction, morbidity and mortality rates remain high. Furthermore, there are currently no treatments that have yet been shown to reduce complication and death rates in patients who have HF with preserved ejection fraction. Hypertension is a common comorbidity in patients with HF, contributing to disease development and prognosis. For example, hypertension is closely associated with the development of left ventricular hypertrophy, which an important precursor of HF. In particular, nighttime blood pressure (BP) appears to be an important, modifiable risk factor. Both nighttime BP and an abnormal circadian pattern of nighttime BP dipping have been shown to predict development of HF and the occurrence of cardiovascular events, independent of office BP. Key mechanisms for this association include sodium handling/salt sensitivity and increased sympathetic activation. These pathogenic mechanisms are targeted by several new treatment options, including sodium-glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and renal denervation. All of these could form part of antihypertensive strategies designed to control nighttime BP and contribute to the goal of achieving perfect 24-hour BP management. Nevertheless, additional research is needed to determine the effects of reducing nighttime BP and improving the circadian BP profile on the rate of HF, other cardiovascular events, and mortality.
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6.
Physical activity and the risk of heart failure: a systematic review and dose-response meta-analysis of prospective studies.
Aune, D, Schlesinger, S, Leitzmann, MF, Tonstad, S, Norat, T, Riboli, E, Vatten, LJ
European journal of epidemiology. 2021;(4):367-381
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Abstract
Although physical activity is an established protective factor for cardiovascular diseases such as ischemic heart disease and stroke, less is known with regard to the association between specific domains of physical activity and heart failure, as well as the association between cardiorespiratory fitness and heart failure. We conducted a systematic review and meta-analysis of prospective observational studies to clarify the relations of total physical activity, domains of physical activity and cardiorespiratory fitness to risk of heart failure. PubMed and Embase databases were searched up to January 14th, 2020. Summary relative risks (RRs) were calculated using random effects models. Twenty-nine prospective studies (36 publications) were included in the review. The summary RRs for high versus low levels were 0.77 (95% CI 0.70-0.85, I2 = 49%, n = 7) for total physical activity, 0.74 (95% CI 0.68-0.81, I2 = 88.1%, n = 16) for leisure-time activity, 0.66 (95% CI 0.59-0.74, I2 = 0%, n = 2) for vigorous activity, 0.81 (95% CI 0.69-0.94, I2 = 86%, n = 3) for walking and bicycling combined, 0.90 (95% CI 0.86-0.95, I2 = 0%, n = 3) for occupational activity, and 0.31 (95% CI 0.19-0.49, I2 = 96%, n = 6) for cardiorespiratory fitness. In dose-response analyses, the summary RRs were 0.89 (95% CI 0.83-0.95, I2 = 67%, n = 4) per 20 MET-hours per day of total activity and 0.71 (95% CI 0.65-0.78, I2 = 85%, n = 11) per 20 MET-hours per week of leisure-time activity. Nonlinear associations were observed in both analyses with a flattening of the dose-response curve at 15-20 MET-hours/week for leisure-time activity. These findings suggest that high levels of total physical activity, leisure-time activity, vigorous activity, occupational activity, walking and bicycling combined and cardiorespiratory fitness are associated with reduced risk of developing heart failure.
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7.
A Fluid Challenge Test for the Diagnosis of Occult Heart Failure.
D'Alto, M, Badesch, D, Bossone, E, Borlaug, BA, Brittain, E, Humbert, M, Naeije, R
Chest. 2021;(2):791-797
Abstract
A right heart catheterization with measurements of pulmonary artery wedge pressure (PAWP) may be necessary for the diagnosis of left heart failure as a cause of pulmonary hypertension or unexplained dyspnea. Diagnostic cutoff values are a PAWP of ≥ 15 mm Hg at rest or a PAWP of ≥ 25 mm Hg during exercise. However, accurate measurement of PAWP can be challenging and heart failure may be occult. Left heart catheterization, with measurement of left ventricular end-diastolic pressure, may also be indecisive. Measurements are then best repeated in stress conditions. Exercise is an option, but the equipment is not universally available, and interpretation can be difficult in patients with wide respiratory pressure swings. An alternative is offered by a fluid challenge. Studies have gathered data supporting infusion of 500 mL or 7 mL/kg saline and a PAWP of 18 mm Hg as a diagnostic cutoff. The procedure is simple and does not take much catheterization laboratory time. Combining echocardiography with invasive measurements may increase the diagnostic accuracy of diastolic dysfunction. Cardiac output after a fluid challenge may be of prognostic relevance.
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8.
CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction.
McDonald, M, Virani, S, Chan, M, Ducharme, A, Ezekowitz, JA, Giannetti, N, Heckman, GA, Howlett, JG, Koshman, SL, Lepage, S, et al
The Canadian journal of cardiology. 2021;(4):531-546
Abstract
In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.
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9.
Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium.
Kretzschmar, T, Wu, JMF, Schulze, PC
International journal of molecular sciences. 2021;(3)
Abstract
Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.
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10.
The Optimal Timing of Primary Prevention Implantable Cardioverter-Defibrillator Referral in the Rapidly Changing Medical Landscape.
Wong, JA, Roberts, JD, Healey, JS
The Canadian journal of cardiology. 2021;(4):644-654
Abstract
The use of implantable cardioverter-defibrillators (ICDs) significantly reduces the risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Current guidelines, which are based on seminal clinical trials published nearly 2 decades ago, recommend that patients be on optimal medical therapy for HF for a minimum of 3 months before referral for prophylactic ICD. This waiting period allows for left ventricular reverse remodelling and improvement in HF symptoms, which may render primary prevention ICD implantation unnecessary. However, medical therapy for HFrEF has significantly evolved since the publication of these landmark trials. Given the plethora of medical therapy options now available for HFrEF, it is appropriate to reassess the duration of this waiting period. In the present review, we examine the landmark randomised trials in primary prevention of sudden cardiac death in patients with HFrEF, summarise the novel medical therapies (sacubitril-valsartan, sodium-glucose cotransporter 2 inhibitors, ivabradine, vericiguat, and omecamtiv mecarbil) that have emerged since the publication of those trials, discuss the optimal timing of ICD referral, and review subtypes of nonischemic cardiomyopathy where timing of ICD insertion is guided by alternative criteria. With the steps now needed to optimise medical therapy for HFrEF, in terms of both classes of drugs and doses of each agent, it can easily take up to 6 months to achieve optimisation. Following that, waiting periods of 3 months for ischemic cardiomyopathy and 6 months for nonischemic cardiomyopathy may be required to allow adequate reverse remodelling before reevaluating for ICD implantation.