Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure: A Meta-Analysis of Randomized Clinical Trials.
Kumar Kris,Kheiri Babikir,Simpson Timothy F,Osman Mohammed,Rahmouni Hind
The American journal of medicine
BACKGROUND:We aimed to conduct this study with the goal of further clarifying the role of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with preexisting heart failure with reduced ejection fraction with or without diabetes and to leverage increased sample size and power to evaluate clinically important secondary safety and efficacy outcomes. METHODS:This meta-analysis was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcome was a composite of cardiovascular death or heart failure hospitalization. Secondary outcomes included the individual components of the primary outcome; major adverse cardiovascular events (defined as a composite of cardiovascular death, myocardial infarction, stroke), any death, myocardial infarction, or stroke, along with adverse events such as volume depletion, acute kidney injury, adverse events leading to drug discontinuation, amputation, and severe hypoglycemia. Other outcomes included the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score and changes in N-terminal pro-hormone BNP (NT-proBNP). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for dichotomous variables and weighted difference (MD) and 95% CI for continuous variables. RESULTS:Compared with placebo, SGLT2i use was associated with a significant reduction of cardiovascular death or heart failure hospitalization (HR = 0.74; 95% CI = 0.66-0.82; P <0.01), heart failure hospitalization (HR = 0.69; 95% CI = 0.57-0.84; P <0.01), cardiovascular death (HR = 0.79; 95% CI = 0.68-0.92; P <0.01), and any death (HR = 0.80; 95% CI = 0.70-0.92; P <0.01). CONCLUSIONS:SGLT2i was associated with a decreased risk of clinically relevant cardiovascular death, heart failure hospitalization, and heart failure symptoms with similar rates of adverse events.
Allicin improves the function of cardiac microvascular endothelial cells by increasing PECAM-1 in rats with cardiac hypertrophy.
Shi Pilong,Cao Yonggang,Gao Jingquan,Fu Bowen,Ren Jing,Ba Lina,Song Chao,Qi Hanping,Huang Wei,Guan Xueying,Sun Hongli
Phytomedicine : international journal of phytotherapy and phytopharmacology
OBJECTIVE:Cardiac microvascular damage is significantly associated with the development of cardiac hypertrophy (CH). Researchers found that allicin could inhibit CH, but the relationship between cardiac microvessel and the inhibition of allicin on CH has not been reported. We aimed to investigate the effect of allicin on the function of cardiac microvascular endothelial cells (CMECs) in CH rat. MATERIALS AND METHODS:The hemodynamic parameters were measured by BL-420F biological function experimental system and the indicators of the ventricular structure and function were measured by echocardiographic system. MTT assay was performed to assess the cell viability. Nitrite detection was performed to detect nitric oxide content. The morphology and molecular characteristics were detected by electron micrographs, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR), western blot. Wound healing experiment, analysis of tube formation and shear adaptation were performed to assess CMECs migration ability, angiogenesis and shear-responsiveness respectively. RESULT:Our findings have identified that microvascular density was decreased by observing the expression of platelet endothelial cell adhesion molecule-1 (PECAM-1) in CH rats. Interestingly, allicin improved the distribution and expression of PECAM-1. Meanwhile, allicin enhanced the migration and angiogenesis ability of CMECs, activated PECAM-1-PI3K-AKT-eNOS signaling pathway, however, the role of allicin was disappear after PECAM-1 was silenced. Allicin decreased the expression of caspase-3 and receptor interacting protein 3 (RIP3), inhibited necroptosis, and increased the levels of Angiopoietin-2 (Ang-2) and platelet-derived growth factor receptor-β (PDGFR-β). Under 10 dyn/cm condition, allicin advanced the modification ability of CMECs's shear-adaptation by activating PECAM-1. CONCLUSION:Allicin provided cardioprotection for CH rats by improving the function of CMECs through increasing the expression of PECAM-1.
Epicardial fat in heart failure patients with mid-range and preserved ejection fraction.
van Woerden Gijs,Gorter Thomas M,Westenbrink B Daan,Willems Tineke P,van Veldhuisen Dirk J,Rienstra Michiel
European journal of heart failure
AIMS:Adipose tissue and inflammation may play a role in the pathophysiology of patients with heart failure (HF) with mildly reduced or preserved ejection fraction. We therefore investigated epicardial fat in patients with HF with preserved (HFpEF) and mid-range ejection fraction (HFmrEF), and related this to co-morbidities, plasma biomarkers and cardiac structure. METHODS AND RESULTS:A total of 64 HF patients with left ventricular ejection fraction >40% and 20 controls underwent routine cardiac magnetic resonance examination. Epicardial fat volume was quantified on short-axis cine stacks covering the entire epicardium and was related to clinical correlates, biomarkers associated with inflammation and myocardial injury, and cardiac function and contractility on cardiac magnetic resonance. HF patients and controls were of comparable age, sex and body mass index. Total epicardial fat volume was significantly higher in HF patients compared to controls (107 mL/m vs. 77 mL/m , P <0.0001). HF patients with atrial fibrillation and/or type 2 diabetes mellitus had more epicardial fat than HF patients without these co-morbidities (116 vs. 100 mL/m , P =0.03, and 120 vs. 97 mL/m , P =0.001, respectively). Creatine kinase-MB, troponin T and glycated haemoglobin in patients with HF were positively correlated with epicardial fat volume (R =0.37, P =0.006; R =0.35, P =0.01; and R =0.42, P =0.002, respectively). CONCLUSION:Heart failure patients had more epicardial fat compared to controls, despite similar body mass index. Epicardial fat volume was associated with the presence of atrial fibrillation and type 2 diabetes mellitus and with biomarkers related to myocardial injury. The clinical implications of these findings are unclear, but warrant further investigation.
Inflammatory Cytokines and Chemokines as Therapeutic Targets in Heart Failure.
Hanna Anis,Frangogiannis Nikolaos G
Cardiovascular drugs and therapy
Heart failure exhibits remarkable pathophysiologic heterogeneity. A large body of evidence suggests that regardless of the underlying etiology, heart failure is associated with induction of cytokines and chemokines that may contribute to the pathogenesis of adverse remodeling, and systolic and diastolic dysfunction. The pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6 have been extensively implicated in the pathogenesis of heart failure. Inflammatory cytokines modulate phenotype and function of all myocardial cells, suppressing contractile function in cardiomyocytes, inducing inflammatory activation in macrophages, stimulating microvascular inflammation and dysfunction, and promoting a matrix-degrading phenotype in fibroblasts. Moreover, cytokine-induced growth factor synthesis may exert chronic fibrogenic actions contributing to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). In addition to their role in adverse cardiac remodeling, some inflammatory cytokines may also exert protective actions on cardiomyocytes under conditions of stress. Chemokines, such as CCL2, are also upregulated in failing hearts and may stimulate recruitment of pro-inflammatory leukocytes, promoting myocardial injury, fibrotic remodeling, and dysfunction. Although experimental evidence suggests that cytokine and chemokine targeting may hold therapeutic promise in heart failure, clinical translation remains challenging. This review manuscript summarizes our knowledge on the role of TNF-α, IL-1, IL-6, and CCL2 in the pathogenesis of heart failure, and discusses the promises and challenges of targeted anti-cytokine therapy. Dissection of protective and maladaptive cellular actions of cytokines in the failing heart, and identification of patient subsets with overactive or dysregulated myocardial inflammatory responses are required for design of successful therapeutic approaches.
Irisin: linking metabolism with heart failure.
Li Jiamin,Xie Susu,Guo Lei,Jiang Jun,Chen Han
American journal of translational research
The heart is an organ with extremely high energy expenditure, and cardiac performance is consistent with its metabolic level. Under pathological situations, the heart adjusts its metabolic pattern through mitochondrial regulation and substrate selection to maintain energy homeostasis. Heart failure is associated with impaired cardiac energy production, transduction or utilization. Reduced exercise tolerance, skeletal muscle dystrophy and even cardiac cachexia are commonly found in patients with advanced heart failure. Irisin is a newly identified myokine and is mainly secreted by skeletal muscles after exercise. Irisin regulates metabolism and plays essential roles in the development of metabolic diseases. The heart is another abundant source of irisin synthesis and secretion other than skeletal muscle. However, the functions of irisin in the heart have not been completely elucidated. This review introduces the current understanding of the physiological role of irisin, alteration of irisin levels in heart failure, possible mechanisms of irisin in metabolic remodeling and cardiac hypertrophy, and perspectives of irisin serving as a novel target in the management of heart failure.
Epidemiology of heart failure.
Groenewegen Amy,Rutten Frans H,Mosterd Arend,Hoes Arno W
European journal of heart failure
The heart failure syndrome has first been described as an emerging epidemic about 25 years ago. Today, because of a growing and ageing population, the total number of heart failure patients still continues to rise. However, the case mix of heart failure seems to be evolving. Incidence has stabilized and may even be decreasing in some populations, but alarming opposite trends have been observed in the relatively young, possibly related to an increase in obesity. In addition, a clear transition towards heart failure with a preserved ejection fraction has occurred. Although this transition is partially artificial, due to improved recognition of heart failure as a disorder affecting the entire left ventricular ejection fraction spectrum, links can be made with the growing burden of obesity-related diseases and with the ageing of the population. Similarly, evidence suggests that the number of patients with heart failure may be on the rise in low-income countries struggling under the double burden of communicable diseases and conditions associated with a Western-type lifestyle. These findings, together with the observation that the mortality rate of heart failure is declining less rapidly than previously, indicate we have not reached the end of the epidemic yet. In this review, the evolving epidemiology of heart failure is put into perspective, to discern major trends and project future directions.
Risk Factors for Heart Failure in the Community: Differences by Age and Ejection Fraction.
Chamberlain Alanna M,Boyd Cynthia M,Manemann Sheila M,Dunlay Shannon M,Gerber Yariv,Killian Jill M,Weston Susan A,Roger Véronique L
The American journal of medicine
BACKGROUND:Differences in comorbid conditions in patients with heart failure compared with population controls, and whether differences exist by type of heart failure or age, have not been well documented. METHODS:The prevalence of 17 chronic conditions were obtained in 2643 patients with incident heart failure from 2000 to 2013 and controls matched 1:1 on sex and age from Olmsted County, Minnesota. Logistic regression determined associations of each condition with heart failure. RESULTS:Among 2643 matched pairs (mean age 76.2 years, 45.6% men), the comorbidities with the largest attributable risk of heart failure were arrhythmia (48.7%), hypertension (28.4%), and coronary artery disease (33.9%); together these explained 73.0% of heart failure. Similar associations were observed for patients with reduced and preserved ejection fraction, with the exception of hypertension. The risk of heart failure attributable to hypertension was 2-fold higher in patients with heart failure with preserved ejection fraction (38.7%) than in patients with heart failure with reduced ejection fraction (17.8%). Hypertension, coronary artery disease, arrhythmia, and diabetes were more strongly associated with heart failure in younger (≤75 years) compared to older (>75 years) persons. CONCLUSIONS:Patients with heart failure have a higher prevalence of many chronic conditions than controls. Similar associations were observed in patients with reduced and preserved ejection fraction, with the exception of hypertension, which was more strongly associated with heart failure with preserved ejection fraction. Finally, some cardiometabolic risk factors were more strongly associated with heart failure in younger persons, highlighting the importance of optimizing prevention and treatment of risk factors and, in particular, cardiometabolic risk factors.
Interleukin-16 promotes cardiac fibrosis and myocardial stiffening in heart failure with preserved ejection fraction.
Tamaki Shunsuke,Mano Toshiaki,Sakata Yasushi,Ohtani Tomohito,Takeda Yasuharu,Kamimura Daisuke,Omori Yosuke,Tsukamoto Yasumasa,Ikeya Yukitoshi,Kawai Mari,Kumanogoh Atsushi,Hagihara Keisuke,Ishii Ryohei,Higashimori Mitsuru,Kaneko Makoto,Hasuwa Hidetoshi,Miwa Takeshi,Yamamoto Kazuhiro,Komuro Issei
BACKGROUND:Chronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process. METHODS AND RESULTS:An analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension. CONCLUSION:Our data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.
Drugs That Ameliorate Epicardial Adipose Tissue Inflammation May Have Discordant Effects in Heart Failure With a Preserved Ejection Fraction as Compared With a Reduced Ejection Fraction.
Journal of cardiac failure
Heart failure with a preserved ejection fraction (HFpEF) and heart failure with a reduced ejection fraction (HFrEF) have distinctive pathophysiologies, and thus, therapeutic approaches to the 2 disorders should differ. Neurohormonal activation drives the progression of HFrEF, and neurohormonal antagonists are highly effective in HFrEF, but not in HFpEF. Conversely, a broad range of chronic systemic inflammatory or metabolic disorders cause an expansion and inflammation of epicardial adipose tissue; the secretion of adipocytokines may lead to microvascular dysfunction and fibrosis of the underlying myocardium, which (if the left atrium is affected) may lead to atrial fibrillation (AF) and (if the left ventricle is affected) may lead to HFpEF. Anti-inflammatory drugs (such as statins and anticytokine agents) can ameliorate epicardial adipose tissue dysfunction. Statins appear to ameliorate the development of atrial myopathy (both experimentally and clinically), and in randomized controlled trials, they reduce the incidence of new-onset and recurrent AF and decrease the risk of heart failure with the features of HFpEF; yet, they have no benefits in HFrEF. Similarly, anticytokine agents appear to prevent heart failure in patients with or prone to HFpEF, but adversely affect HFrEF. Several antihyperglycemic agents also reduce epicardial fat mass and inflammation, but this benefit may be offset by additional actions to cause sodium retention and neurohormonal activation. Thiazolidinediones have favorable effects on experimental AF and HFpEF, but their antinatriuretic actions negate these benefits, and they worsen the clinical course of HFrEF. Glucagon-like peptide-1 receptor agonists also ameliorate AF and HFpEF in laboratory models, but their positive inotropic and chronotropic effects may be deleterious in HFrEF. By contrast, metformin and sodium-glucose cotransporter 2 inhibitors alleviate epicardial adipose tissue dysfunction and may reduce the risk of AF and HFpEF; yet, they may have additional actions to promote cardiomyocyte survival that are useful in HFrEF. The concordance of the benefits of anti-inflammatory and antihyperglycemic drugs on AF and HFpEF (but not on HFrEF) supports the paradigm that epicardial adipose tissue is a central pathogenetic mechanism and therapeutic target for both AF and HFpEF in patients with chronic systemic inflammatory or metabolic diseases.
Identification of novel pheno-groups in heart failure with preserved ejection fraction using machine learning.
Hedman Åsa K,Hage Camilla,Sharma Anil,Brosnan Mary Julia,Buckbinder Leonard,Gan Li-Ming,Shah Sanjiv J,Linde Cecilia M,Donal Erwan,Daubert Jean-Claude,Mälarstig Anders,Ziemek Daniel,Lund Lars
Heart (British Cardiac Society)
OBJECTIVE:Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups ('phenogroups') based on clinical and echocardiogram data using machine learning, and to compare clinical characteristics, proteomics and outcomes across the phenogroups. METHODS:We applied model-based clustering to 32 echocardiogram and 11 clinical and laboratory variables collected in stable condition from 320 HFpEF outpatients in the Karolinska-Rennes cohort study (56% female, median 78 years (IQR: 71-83)). Baseline proteomics and the composite end point of all-cause mortality or heart failure (HF) hospitalisation were used in secondary analyses. RESULTS:We identified six phenogroups, for which significant differences in the prevalence of concomitant atrial fibrillation (AF), anaemia and kidney disease were observed (p<0.05). Fifteen out of 86 plasma proteins differed between phenogroups (false discovery rate, FDR<0.05), including biomarkers of HF, AF and kidney function. The composite end point was significantly different between phenogroups (log-rank p<0.001), at short-term (100 days), mid-term (18 months) and longer-term follow-up (1000 days). Phenogroup 2 was older, with poorer diastolic and right ventricular function and higher burden of risk factors as AF (85%), hypertension (83%) and chronic obstructive pulmonary disease (30%). In this group a third experienced the primary outcome to 100 days, and two-thirds to 18 months (HR (95% CI) versus phenogroups 1, 3, 4, 5, 6: 1.5 (0.8-2.9); 5.7 (2.6-12.8); 2.9 (1.5-5.6); 2.7 (1.6-4.6); 2.1 (1.2-3.9)). CONCLUSIONS:Using machine learning we identified distinct HFpEF phenogroups with differential characteristics and outcomes, as well as differential levels of inflammatory and cardiovascular proteins.
Heart Rate-Induced Myocardial Ca Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction.
Silverman Daniel N,Rambod Mehdi,Lustgarten Daniel L,Lobel Robert,LeWinter Martin M,Meyer Markus
Journal of the American Heart Association
Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca overload caused by increased myocardial Na levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension. Methods and Results In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left-sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end-diastolic pressure in both groups (controls -4.3±4.1 mm Hg versus patients with HFpEF -8.5±6.0 mm Hg, =0.08). Pacing also reduced LV end-diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls -15%±14% versus patients with HFpEF -32%±11%, =0.009). Coronary venous [Ca] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na] did not change. Conclusions Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca retention.