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Heart Failure Reviews Sep 2023Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials... (Review)
Review
Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor-neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium-glucose co-transporter 2 inhibitor.
Topics: Humans; Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Heart Failure; Mineralocorticoid Receptor Antagonists; Neprilysin; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume
PubMed: 37311917
DOI: 10.1007/s10741-023-10325-2 -
European Heart Journal Aug 2023The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in...
AIMS
The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA).
METHODS AND RESULTS
A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6-51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66-0.89), P < .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) >40% [HR 0.75 (95% CI 0.63-0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45-0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs.
CONCLUSION
Conventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.
Topics: Humans; Stroke Volume; Retrospective Studies; Angiotensin-Converting Enzyme Inhibitors; Ventricular Function, Left; Prospective Studies; Angiotensin Receptor Antagonists; Heart Failure; Adrenergic beta-Antagonists
PubMed: 37216684
DOI: 10.1093/eurheartj/ehad347 -
Therapeutic Advances in Neurological... 2023Duchenne muscular dystrophy (DMD) is a devastating disease that results in life-limiting complications such as loss of skeletal muscle function as well as respiratory... (Review)
Review
Duchenne muscular dystrophy (DMD) is a devastating disease that results in life-limiting complications such as loss of skeletal muscle function as well as respiratory and cardiac complications. Advanced therapeutics in pulmonary care have significantly reduced respiratory complication-related mortality, making cardiomyopathy the main determinant factor of survival. While there are multiple therapies such as the use of anti-inflammatory drugs, physical therapy, and ventilatory assistance targeted toward delaying the disease progression in DMD, a cure remains elusive. In the last decade, several therapeutic approaches have been developed to improve patient survival. These include small molecule-based therapy, micro-dystrophin gene delivery, CRISPR-mediated gene editing, nonsense readthrough, exon skipping, and cardiosphere-derived cell therapy. Associated with the specific benefits of each of these approaches are their individual risks and limitations. The variability in the genetic aberrations leading to DMD also limits the widespread use of these therapies. While numerous approaches have been explored to treat DMD pathophysiology, only a handful have successfully advanced through the preclinical stages. In this review, we summarize the currently approved as well as the most promising therapeutics undergoing clinical trials aimed toward treating DMD with a focus on its cardiac manifestations.
PubMed: 37425427
DOI: 10.1177/17562864231182934 -
International Journal of Molecular... Jul 2023Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many... (Review)
Review
Bradykinin (BK) metabolism and its receptors play a central role in drug-induced angioedema (AE) without urticaria through increased vascular permeability. Many cardiovascular and diabetic drugs may cause BK-mediated AE. Angiotensin-converting enzyme inhibitors (ACEIs) and neprilysin inhibitors impair BK catabolism. Dipeptidyl peptidase-IV (DPP-IV) inhibitors reduce the breakdown of BK and substance P (SP). Moreover, angiotensin receptor blockers, thrombolytic agents, and statins may also induce BK-mediated AE. Understanding pathophysiological mechanisms is crucial for preventing and treating drug-induced AE.
Topics: Humans; Angioedema; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Dipeptidyl-Peptidase IV Inhibitors; Fibrinolytic Agents
PubMed: 37511409
DOI: 10.3390/ijms241411649 -
International Journal of Molecular... Oct 2023In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine... (Review)
Review
In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.
Topics: Humans; Neprilysin; Tetrazoles; Angiotensin Receptor Antagonists; Heart Failure; Angiotensin-Converting Enzyme Inhibitors; Drug Combinations; Renin-Angiotensin System; Natriuretic Peptides; Aminobutyrates; Biphenyl Compounds
PubMed: 37895150
DOI: 10.3390/ijms242015472 -
Journal of the American College of... Mar 2024The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described.
OBJECTIVES
Data from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum.
METHODS
The PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial.
RESULTS
The pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72).
CONCLUSIONS
In patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634).
Topics: Aged; Female; Humans; Male; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Drug Combinations; Enalapril; Heart Failure; Stroke Volume; Tetrazoles; Valsartan; Ventricular Function, Left; Double-Blind Method
PubMed: 38508844
DOI: 10.1016/j.jacc.2024.01.027 -
Frontiers in Bioscience (Landmark... Jul 2023Pharmacotherapy is the cornerstone treatment for patients with heart failure (HF) that uses drugs targeting the renin-angiotensin-aldosterone system (RAAS), including... (Review)
Review
Pharmacotherapy is the cornerstone treatment for patients with heart failure (HF) that uses drugs targeting the renin-angiotensin-aldosterone system (RAAS), including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan. This article reviews the pathophysiology of the RAAS and the neurohormonal changes seen in patients with HF as well as the targets and the mode of action of these drugs. We also assess the role of ACE in ventricular remodeling and summarize the main evidence for the use of ACE-related drugs in HF patients.
PubMed: 37525924
DOI: 10.31083/j.fbl2807150 -
Korean Journal of Neurotrauma Sep 2023Chronic subdural hematoma (CSDH) is a commonly encountered disease in the field of neurosurgery, typically resulting from head trauma. Several medical treatments have... (Review)
Review
Chronic subdural hematoma (CSDH) is a commonly encountered disease in the field of neurosurgery, typically resulting from head trauma. Several medical treatments have been introduced to manage patients with CSDH though surgical drainage is the main strategy to manage symptomatic patients. This review is aimed to meticulously examine contemporary pharmacological approaches, based on a thorough understanding of CSDH pathophysiology. Finally, the review offers a glance into future perspectives to enhance the management of CSDH.
PubMed: 37840605
DOI: 10.13004/kjnt.2023.19.e47 -
PloS One 2023Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Diabetic kidney disease (DKD) is a health burden of rising importance. Slowing progression to end stage kidney disease is the main goal of drug treatment. The aim of this analysis is to compare drug treatments of DKD by means of a systemic review and a network meta-analysis.
METHODS
We searched Medline, CENTRAL and clinicaltrials.gov for randomized, controlled studies including adults with DKD treated with the following drugs of interest: single angiotensin-converting-enzyme-inhibitor or angiotensin-receptor-blocker (single ACEi/ARB), angiotensin-converting-enzyme-inhibitor and angiotensin-receptor-blocker combination (ACEi+ARB combination), aldosterone antagonists, direct renin inhibitors, non-steroidal mineralocorticoid-receptor-antagonists (nsMRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). As primary endpoints, we defined: overall mortality and end-stage kidney disease, as secondary endpoints: renal composite outcome and albuminuria and as safety endpoints: acute kidney injury, hyperkalemia and hypotension. Under the use of a random effects model, we computed the overall effect estimates using the statistic program R4.1 and the corresponding package "netmeta". Risk of bias was assessed using the RoB 2 tool and the quality of evidence of each pairwise comparison was rated according to GRADE (Grading of Recommendations Assessment, Development and Evaluation).
RESULTS
Of initial 3489 publications, 38 clinical trials were found eligible, in total including 42346 patients. Concerning the primary endpoints overall mortality and end stage kidney disease, SGLT2i on top of single ACEi/ARB compared to single ACEi/ARB was the only intervention significantly reducing the odds of mortality (OR 0.81, 95%CI 0.70-0.95) and end-stage kidney disease (OR 0.69, 95%CI 0.54-0.88). The indirect comparison of nsMRA vs SGLT2i in our composite endpoint suggests a superiority of SGLT2i (OR 0.60, 95%CI 0.47-0.76). Concerning safety endpoints, nsMRA and SGLT2i showed benefits compared to the others.
CONCLUSIONS
As the only drug class, SGLT2i showed in our analysis beneficial effects on top of ACEi/ARB treatment regarding mortality and end stage kidney disease and by that reconfirmed its position as treatment option for diabetic kidney disease. nsMRA reduced the odds for a combined renal endpoint and did not raise any safety concerns, justifying its application.
Topics: Adult; Humans; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Angiotensin Receptor Antagonists; Network Meta-Analysis; Sodium-Glucose Transporter 2 Inhibitors; Kidney Failure, Chronic; Angiotensins; Diabetes Mellitus
PubMed: 37917640
DOI: 10.1371/journal.pone.0293183 -
Antiviral Research Jul 2023Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with...
Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.
Topics: Humans; Mice; Animals; SARS-CoV-2; COVID-19; Captopril; Myocytes, Cardiac; Angiotensin-Converting Enzyme Inhibitors; Inflammation; Apoptosis
PubMed: 37207821
DOI: 10.1016/j.antiviral.2023.105636