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ObjectiveTrimetazidine may have beneficial effects on left ventricular (LV) function in patients with systolic heart failure. The authors assessed whether long-term addition of trimetazidine to conventional treatment could improve, along with LV function, resting whole body energy metabolism in patients with chronic systolic heart failure.DesignSingle blind randomised study.SettingUniversity Hospital.Patients44 patients with systolic heart failure receiving full medical treatment.InterventionsIndirect calorimetry and two-dimensional echocardiography at baseline and after 3 months.Main outcome measuresWhole body resting energy expenditure (REE), percentage of predicted REE, LV ejection fraction (EF), NYHA class, quality of life.ResultsTrimetazidine increased EF compared with conventional therapy alone (from 35±8% to 42±11% vs from 35±7% to 36±6%; p=0.02, analysis of variance for repeated measures). NYHA class and quality of life also improved compared with conventional therapy (p<0.0001). REE (from 1677±264 to 1580±263 kcal/day) and percentage of predicted REE (based on the Harris–Benedict equation: from 114±10% to 108±9%) decreased in the trimetazidine group, but not in the control group (REE from 1679±304 to 1690±337 kcal/day and percentage of predicted REE from 113±12% to 115±14%). The variation was different between groups (p=0.03 and 0.023, respectively).ConclusionsIn patients with systolic heart failure, improvement in functional class and LV function induced by middle-term trimetazidine therapy is paralleled by a reduction in whole body REE. The beneficial cardiac effects of trimetazidine may be also mediated by a peripheral metabolic effect.

IntroductionIncreasing severity of impairment of left ventricular systolic dysfunction (LVSD) in patients with chronic heart failure (CHF) is associated with higher mortality. However, the relation between temporal changes in LVSD severity and long-term clinical outcome is unknown. MethodsPatients with CHF defined as the presence of compatible symptoms and either at least moderate LVSD or NTproBNP >125 ng/L were enrolled. LVSD was qualitatively assessed as: none, mild, moderate, and severe. Echocardiography was performed at baseline and 12 months. The primary endpoint was all-cause mortality. Cox proportional hazard models were used to assess the relation between changes in LVSD and outcome. Hazard ratios (HR) are reported with 95% confidence intervals (CI).Results At baseline, 170 (11%) had no, 231 (16%) mild, 633 (43%) moderate and 453 (30%) severe LVSD. Amongst patients with either moderate or severe LVSD at baseline, 40% had improvement in function at 12 months (figure 1). Amongst patients with no LVSD at baseline, only 14% had deterioration of function. During subsequent median follow up of 2773 days, 868 patients died. Worsening of LVSD was associated with increasing all-cause mortality in patients with moderate LVSD and severe LVSD at baseline (figure 2), but this was not significant after adjustment for covariables (table 1). Improvement of LVSD was independently associated with better survival in patients with moderate LVSD at baseline (HR 0.72 (95% CI: 0.53–0.98, p = 0.04).Abstract 108 Table 1Adjusted and unadjusted hazard ratios for all-cause mortality in patients with heart failure according to whether LVSD worsened or improved. *Corrected for age, sex, NTproBNP, NYHA class, systolic blood pressure, heart rate, heart rhythm, IHD, loop diuretic, ACEi or ARB, beta-blocker, MRA, and creatinine. Abbreviations: angiotensin converting enzyme inhibitor (ACEi); angiotensin receptor blocker (ARB); confidence interval (CI); hazard ratio (HR); left ventricular systolic dysfunction (LVSD); mineralocorticoid receptor antagonist (MRA); New York Heart Association (NYHA)Abstract 108 Figure 1Stability of left ventricular systolic dysfunction (LVSD). Change of the severity of LVSD assessed by echocardiography at baseline and one year. Continuous data presented as N and percentages (%)Abstract 108 Figure 2Kaplan–Meier curves for all-cause mortality in patients with heart failure by change in the severity of left ventricular systolic dysfunction (LVSD) stratified by baseline LVSD. Differences between groups were evaluated using the log-rank testConclusionGreater severity of LVSD at baseline is associated with increasing likelihood of improvement. Amongst patients with moderate LVSD, improvement in LVSD is independently associated with survival.Conflict of InterestFunded by the National Institute for Health Research

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

BackgroundSickle cell disease (SCD) is an inherited haemoglobinopathy characterised by recurrent vaso-occlusive crises and chronic haemolytic anaemia. Amongst the cardiac complications related to SCD, left ventricular systolic dysfunction (LVSD) is an uncommon, poorly characterised, but life-threatening complication.PurposeTo characterise using cardiac MRI (CMR) the varying phenotypes of LVSD complicating SCD.MethodsWe conducted a retrospective evaluation of 20 SCD patients with LVSD (LVEF <55%) identified by transthoracic echocardiography (TTE), who were attending a specialist cardiology-haemoglobinopathy clinic between April-December 2023. We excluded patients who had not had a CMR [n=4], with normal LV function on CMR [n=4] and alternative explanation for LVSD [n=1]. We collected demographics, clinical data and imaging data from TTE and CMR, including ventricular dimensions and function, presence of Late Gadolinium Enhancement (LGE) and parametric mapping (T1, T2, T2*). ResultsThe data of 11 patients are shown in tables 1 and 2. We identified 3 different phenotypes of LVSD: non-ischaemic dilated cardiomyopathy (NI-DCM) [n=8], ischaemic dilated cardiomyopathy (I-DCM) [n=2] and iron-overload cardiomyopathy [n=1]. Figure 1 shows CMR imaging of selected patients from each subgroup.Significant co-morbidities in the NI-DCM cohort included hypertension (HTN) (50%) and renal impairment (25%). We identified significant LV dilatation, elevated T1 values and high rates of non-ischaemic LGE in this subgroup. Despite high ferritin levels, there was no cardiac iron overload, however 75% (n=6) had liver iron overload.In the I-DCM cohort, we identified two patients with extensive myocardial infarcts seen on CMR, severe LV dilatation and significant LV impairment but no epicardial coronary artery disease on cardiac CT.Finally, we identified one patient with iron-overload cardiomyopathy (cardiac T2* 7 ms, T1 598 ms) and severe LVSD. She had been on regular top-up transfusions for more than 10 years, with poor chelation compliance. Rapid deterioration of LV function was noted between TTE and CMR dates.DiscussionRecognised, common cardiac complications in adults with SCD include LV diastolic dysfunction in the setting of chronic anaemia, usually resulting in LV dilatation and eccentric hypertrophy. Our NI-DCM group may present a late consequence of these pathophysiologic changes, in the setting of HTN and CKD which have previously been reported to be associated with LVSD. Interestingly, we identified significant LV fibrosis (high T1, LGE) which has not been previously reported in SCD. We describe two patients with ischaemic cardiomyopathy with no epicardial coronary disease, likely due to microvascular infarction. One patient succumbed to heart failure 3 years from diagnosis, the other being considered for device therapy. These outcomes highlight the dire consequences of this complication. Finally, we describe a patient with severe LVSD and severe cardiac iron overload. Iron overload cardiomyopathy is exceedingly rare in SCD (<3%), however remains an important consideration in patients with unexplained LVSD in the context of recurrent transfusions and poor compliance with chelation and can result in rapid deterioration and mortality if untreated. ConclusionTo our knowledge, this descriptive study is the first one to characterise the aetiology of LVSD in SCD. Despite a small patient cohort, we have identified 3 different phenotypes with NI-DCM being the most common. We emphasise the vital role CMR in phenotyping LVSD in SCD and we believe this study supports the undertaking of prospective studies to further delineate the underlying pathophysiology of these very serious complications of SCD.Abstract 161 Table 1 Non-ischaemic dilated cardiomyopathy (n=8) Ischaemic cardiomyopathy (n=2) Iron overload (n=1) Demographics and clinical data Age, years 41 +/- 15 61 +/- 9 37 CKD stage 3–5,% 25% 50% 0 Hypertension,% 50% 100% 0% Ferritin, mcg/L 1965 +/-1605 (n=6) 1268 +/- 600 9098 Transfusion (exchange/top -up),% 38% 50% 100% SCD modifying treatment,% 25% 0% 0 Echocardiographic data LVEF,% 45 +-5.7 24 +-7 46 LVIDD, cm 6.0 +- 0.5 (n=7) 6.3 +-0.3 4.9 LA, cm 4.3 +-0.9 (n=7) 4.7 +-0.3 3.5 TR Vmax, m/s 2.7 +-0.4 (n=6) 3.4 (n=1) 2.9 Abstract 161 Table 2 Non-ischaemic dilated cardiomyopathy (n=8) Ischaemic cardiomyopathy (n=2) Iron overload (n=1) Cardiac MRI data LVEF,% 48.4 +- 4.7 36.5 +-4.5 31 LVEDVi, ml/m2 155.5 +-31.5 250.5 +-28.5 71 LVESVi, ml/m2 81 +-20.5 178.5 +-10.5 49 LA, cm2 [<30 cm2] 32.8 +-6.6 40 +-5 18 T1, ms [970–1050 ms] 1082.5 +-59.4 1072 (n=1) 598 T2, ms [40–51 ms] 54 +-2.1 (n=4) 49 (n=1) n/a T2* heart, ms [>20 ms] 40.5 +-6.4 32 (n=1) 7 T2* liver, ms [>17 ms] 13.1 +- 9.1 4.8 (n=1) 1.2 Late Gadolinium Enhancement,% 60% 100% n/a ECV,% 26.2 +-3.1 (n=5) 31.5 +-1.5 n/a Abstract 161 Figure 1Conflict of InterestNone

Background Myocardial dysfunction may contribute to the haemodynamic instability which accompanies sepsis, and may result in circulatory failure. There is no association between systolic dysfunction (SD) and mortality in septic patients and there is conflicting evidence regarding the effects of diastolic dysfunction (DD) on mortality in septic patients. Methods We conducted a systematic review and meta-analysis to investigate DD and mortality in septic patients. We included studies conducted in this patient population which investigated the association between DD reported according to tissue Doppler imaging (TDI) criteria and mortality, using the longest reported follow-up. As a secondary endpoint, we evaluated the association between SD and mortality according to the results reported by the retrieved studies. Results We included seven studies in our meta-analysis with 636 septic patients, 48 % of them were found to have DD. We found a significant association between DD and mortality (RR 1.82, 95 % CI 1.12–2.97, p  = 0.02). This finding remained valid in a further analysis which including an older study reporting DD without TDI criteria. Five studies reported data on SD for a total of 581 patients, 29.6 % of them with SD. No association was found between SD and mortality (RR 0.93, 95 % CI 0.62–1.39, p  = 0.73). Looking at subgroups, there was a trend towards higher mortality comparing isolated DD or combined SD–DD vs normal heart function ( p  = 0.10 and p  = 0.05, respectively). Conclusions Diastolic dysfunction is common in septic patients and it is associated with mortality. Systolic dysfunction is less common and is not associated with mortality in this group of patients.

Background We analysed the effect of ivabradine on outcomes in heart failure (HF) patients on recommended background therapies with heart rates ≥75 bpm and <75 bpm in the SHIFT trial. A cut-off value of ≥75 bpm was chosen by the EMEA for approval for the use of ivabradine in chronic heart failure. Methods The SHIFT population was divided by baseline heart rate ≥75 or <75 bpm. The effect of ivabradine was analysed for primary composite endpoint (cardiovascular death or HF hospitalization) and other endpoints. Results In the ≥75 bpm group, ivabradine reduced primary endpoint (HR 0.76, 95 % CI 0.68–0.85, P  < 0.0001), all-cause mortality (HR 0.83, 95 % CI, 0.72–0.96, P   =  0.0109), cardiovascular mortality (HR 0.83, 95 % CI, (0.71–0.97, P   =  0.0166), HF death (HR 0.61, 95 % CI, 0.46–0.81, P  < 0.0006), and HF hospitalization (HR 0.70, 95 % CI, 0.61–0.80, P  < 0.0001). Risk reduction depended on heart rate after 28 days, with the best protection for heart rates <60 bpm or reductions >10 bpm. None of the endpoints was significantly reduced in the <75 bpm group, though there were trends for risk reductions in HF death and hospitalization for heart rate <60 bpm and reductions >10 bpm. Ivabradine was tolerated similarly in both groups. Conclusion The effect of ivabradine on outcomes is greater in patients with heart rate ≥75 bpm with heart rates achieved <60 bpm or heart rate reductions >10 bpm predicting best risk reduction. Our findings emphasize the importance of identification of high-risk HF patients by high heart rates and their treatment with heart rate-lowering drugs such as ivabradine.

For patients with nonischemic cardiomyopathy (NICM), current guidelines recommend implantable cardioverter defibrillators (ICD) when left ventricular ejection fraction (LVEF) is ≤35%, but the DANISH trial failed to confirm that ICDs reduced all-cause mortality for such patients. Circumstantial evidence suggests that scar on CMR is predictive of sudden and arrhythmic death in this population. The presence of myocardial scar identified by cardiac magnetic resonance imaging (CMR) in patients with NICM and an LVEF ≤35% might identify patients at higher risk of sudden arrhythmic death, for whom an ICD is more likely to reduce all-cause mortality. The BRITISH trial is a prospective, multicenter, randomized controlled trial aiming to enrol 1,252 patients with NICM and an LVEF ≤35%. Patients with a nonischemic scar on CMR will be randomized to either: (1) ICD, with or without cardiac resynchronization (CRT-D), or (2) implantable loop recorder (ILR) or cardiac resynchronization (CRT-P). Patients who are screened for the trial but are found not to be eligible, predominantly due to an absence of scar or those who decline to be randomized will be enrolled in an observational registry. The primary endpoint is all-cause mortality, which we plan to assess at 3 years after the last participant is randomized. Secondary endpoints include clinical outcomes, appropriate and inappropriate device therapies, symptom severity and well-being, device-related complications, and analysis of the primary endpoint by subgroups with other risk markers. The BRITISH trial will assess whether the use of CMR-defined scar to direct ICD implantation in patients with NICM and an LVEF ≤35% is associated with a reduction in mortality.

Chronic limb-threatening ischemia (CLTI), the severest stage of peripheral artery disease, frequently necessitates amputation. In CLTI patients, heart failure with reduced ejection fraction (HFrEF) markedly raises mortality risk, with increased peripheral vascular resistance contributing to this exacerbation. This investigation aimed to assess the impact of major amputation (MA) on the cardiovascular (CV) prognosis in CLTI patients with HFrEF by lowering peripheral vascular resistance. Conducting a retrospective, observational analysis at a single center, a total of 60 patients with CLTI and HFrEF (EF < 50%) who underwent endovascular therapy (EVT) at our institution were assessed. We compared CV outcomes in CLTI patients with HFrEF who received MA (n = 17) to those who did not (n = 43) after undergoing EVT. During the follow-up period, which median 641 (IQR: 245 to 1,734) days post-EVT, a composite primary endpoint of CV death or hospitalization for HF was observed. During the study period, 19 patients (32%) were admitted for HF or died as a consequence of CV events. Kaplan-Meier analysis revealed a significantly reduced incidence of the primary endpoint in the MA cohort (log-rank test: p = 0.035). Adjustments for age and sex showed MA was significantly linked to improved CV prognosis (HR: 0.19; 95% confidence interval: 0.04 to 0.87). A nonsignificant trend toward decreased overall mortality was noted in the MA group, with infections being the predominant cause of death across both groups. In conclusion, in CLTI patients with HFrEF, MA might be linked to reduced CV events, proposing it as a potential definitive strategy for improving CV outcomes in this high-risk population.

Cardiac point-of-care ultrasound (POCUS) can evaluate for systolic and diastolic dysfunction to inform care in the Emergency Department (ED). However, accurate assessment can be limited by user experience. Artificial intelligence (AI) has been proposed as a model to increase the accuracy of cardiac POCUS. However, there is limited evidence of the accuracy of AI in the clinical environment. The objective of this study was to determine the diagnostic accuracy of AI for identifying systolic and diastolic dysfunction compared with expert reviewers. This was a prospective, observational study of adult ED patients aged ≥45 years with risk factors for systolic and diastolic dysfunction. Ultrasound fellowship-trained physicians used an ultrasound machine with existing AI software and obtained parasternal long axis, parasternal short axis, and apical 4-chamber views of the heart. Systolic dysfunction was defined as ejection fraction (EF) < 50 % in at least two views using visual assessment or E-point septal separation >10 mm. Diastolic dysfunction was defined as an E:A < 0.8, or ≥ 2 of the following: septal e' < 7 cm/s or lateral e' < 10 cm/s, E:e' > 14, or left atrial volume > 34 mL/m2. AI was subsequently used to measure EF, E, A, septal e', and lateral e' velocities. The gold standard was systolic or diastolic dysfunction as assessed by two independent physicians with discordance resolved via consensus. We performed descriptive statistics (mean ± standard deviation) and calculated the sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-) of the AI in determining systolic and diastolic dysfunction with 95 % confidence interval (CI). Subgroup analyses were performed by body mass index (BMI). We enrolled 220 patients, with 11 being excluded due to inadequate images, resulting in 209 patients being included in the study. Mean age was 60 ± 9 years, 51.7 % were women, and the mean BMI was 31 ± 8.1 mg/kg2. For assessing systolic dysfunction, AI was 85.7 % (95 %CI 57.2 % to 98.2 %) sensitive and 94.8 % (95 %CI 90.6 % to 97.5 %) specific with a LR+ of 16.4 (95 %CI 8.6 to 31.1) and LR- of 0.15 (95 % CI 0.04 to 0.54). For assessing diastolic dysfunction, AI was 91.9 % (95 %CI 85.6 % to 96.0 %) sensitive and 94.2 % (95 %CI 87.0 % to 98.1 %) specific with a LR+ of 15.8 (95 %CI 6.7 to 37.1) and a LR- of 0.09 (0.05 to 0.16). When analyzed by BMI, results were similar except for lower sensitivity in the BMI ≥ 30 vs BMI < 30 (100 % vs 80 %). When compared with expert assessment, AI had high sensitivity and specificity for diagnosing both systolic and diastolic dysfunction.

Screening for left ventricular systolic dysfunction (LVSD), defined as reduced left ventricular ejection fraction (LVEF), deserves renewed interest as the medical treatment for the prevention and progression of heart failure improves. We aimed to review the updated literature to outline the potential and caveats of using artificial intelligence–enabled electrocardiography (AIeECG) as an opportunistic screening tool for LVSD.We searched PubMed and Cochrane for variations of the terms “ECG,” “Heart Failure,” “systolic dysfunction,” and “Artificial Intelligence” from January 2010 to April 2022 and selected studies that reported the diagnostic accuracy and confounders of using AIeECG to detect LVSD.Out of 40 articles, we identified 15 relevant studies; eleven retrospective cohorts, three prospective cohorts, and one case series. Although various LVEF thresholds were used, AIeECG detected LVSD with a median AUC of 0.90 (IQR from 0.85 to 0.95), a sensitivity of 83.3% (IQR from 73 to 86.9%) and a specificity of 87% (IQR from 84.5 to 90.9%). AIeECG algorithms succeeded across a wide range of sex, age, and comorbidity and seemed especially useful in non-cardiology settings and when combined with natriuretic peptide testing. Furthermore, a false-positive AIeECG indicated a future development of LVSD. No studies investigated the effect on treatment or patient outcomes.This systematic review corroborates the arrival of a new generic biomarker, AIeECG, to improve the detection of LVSD. AIeECG, in addition to natriuretic peptides and echocardiograms, will improve screening for LVSD, but prospective randomized implementation trials with added therapy are needed to show cost-effectiveness and clinical significance.