Treatment with recombinant Sirt1 rewires the cardiac lipidome and rescues diabetes-related metabolic cardiomyopathy.

BACKGROUND: Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. METHODS: db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/ + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. RESULTS: rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36, Acox3, Pparg, Ncoa3, and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. CONCLUSIONS: In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development.

Twitter promotion is associated with higher citation rates of cardiovascular articles: the ESC Journals Randomized Study.

The association between the dissemination of scientific articles on Twitter and online visibility (as assessed by the Altmetric Score) is still controversial, and the impact on citation rates has never been rigorously addressed for cardiovascular medicine journals using a randomized design. The ESC Journals Study randomized 695 papers published in the ESC Journal Family (March 2018-May 2019) for promotion on Twitter or to a control arm (with no active tweeting from ESC channels) and aimed to assess whether Twitter promotion was associated with an increase in citation rates (primary endpoint) and of the Altmetric Score. This is the final analysis including 694 articles (one paper excluded due to retraction). After a median follow-up of 994 days (interquartile range: 936-1063 days), Twitter promotion of articles was associated with a 1.12 (95% confidence interval: 1.08-1.15) higher rate of citations, and this effect was independent of the type of article. Altmetric Attention Score and number of users tweeting were positive predictors for the number of citations. A social media strategy of Twitter promotion for cardiovascular medicine papers seems to be associated with increased online visibility and higher numbers of citations.

Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes.

BACKGROUND: Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS). MATERIALS AND METHODS: Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides. RESULTS: Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation). CONCLUSIONS: Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS.

International Expert Consensus Document on Takotsubo Syndrome (Part II): Diagnostic Workup, Outcome, and Management.

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

International Expert Consensus Document on Takotsubo Syndrome (Part I): Clinical Characteristics, Diagnostic Criteria, and Pathophysiology.

Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes.

RATIONALE: Hyperglycemic memory may explain why intensive glucose control has failed to improve cardiovascular outcomes in patients with diabetes. Indeed, hyperglycemia promotes vascular dysfunction even after glucose normalization. However, the molecular mechanisms of this phenomenon remain to be elucidated. OBJECTIVE: The present study investigated the role of mitochondrial adaptor p66(Shc) in this setting. METHODS AND RESULTS: In human aortic endothelial cells (HAECs) exposed to high glucose and aortas of diabetic mice, activation of p66(Shc) by protein kinase C ßII (PKCßII) persisted after returning to normoglycemia. Persistent p66(Shc) upregulation and mitochondrial translocation were associated with continued reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and apoptosis. We show that p66(Shc) gene overexpression was epigenetically regulated by promoter CpG hypomethylation and general control nonderepressible 5-induced histone 3 acetylation. Furthermore, p66(Shc)-derived ROS production maintained PKCßII upregulation and PKCßII-dependent inhibitory phosphorylation of endothelial nitric oxide synthase at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia. Moreover, p66(Shc) activation accounted for the persistent elevation of the advanced glycated end product precursor methylglyoxal. In vitro and in vivo gene silencing of p66(Shc), performed at the time of glucose normalization, blunted ROS production, restored endothelium-dependent vasorelaxation, and attenuated apoptosis by limiting cytochrome c release, caspase 3 activity, and cleavage of poly (ADP-ribose) polymerase. CONCLUSIONS: p66(Shc) is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets.

Lack of protective role of HDL-C in patients with coronary artery disease undergoing elective coronary artery bypass grafting.

AIMS: Primary prevention studies have confirmed that high-density lipoprotein cholesterol (HDL-C) levels are strongly associated with reduced cardiovascular events. However, recent evidence suggests that HDL-C functionality may be impaired under certain conditions. In the present study, we hypothesize that HDL-C may lose their protective role in the secondary prevention of coronary artery disease (CAD). METHODS AND RESULTS: A consecutive series of 1548 patients undergoing isolated first-time elective CABG at one institution between 2004 and 2009 was studied. According to the ATPIII criteria, pre-operative HDL-C values were used to identify patients with high (Group A) vs. low HDL-C (Group B). To eliminate biased estimates, a propensity score model was built and two cohorts of 1:1 optimally matched patients were obtained. Cumulative survival and major adverse cardiovascular events (MACE) were analysed by means of Kaplan-Meier method. Cox proportional-hazards regression models were used to identify independent predictors of MACE and death. Propensity matching identified two cohorts of 502 patients each. At a median follow-up time of 32 months, there were 44 out of 502 (8.8%) deaths in Group A and 36 out of 502 deaths in Group B (7.2%, HR 1.19; P = 0.42). MACE occurred in 165 out of 502 (32.9%) in Group A and 120 out of 502 (23.9%) in Group B (P = 0.04). Regression analysis showed that pre-operative HDL-C levels were not associated with reduced but rather increased MACE occurrence during follow-up (HR 1.43, P = 0.11). CONCLUSION: Higher HDL-C levels are not associated with reduced risk of vascular events in CAD patients undergoing CABG. Our findings may support efforts to improve HDL-C functionality instead of increasing their levels.

Caffeic acid phenethyl ester inhibits endothelial tissue factor expression.

Caffeic acid phenethyl ester (CAPE) is a component of honeybee hives with various beneficial properties. Tissue factor (TF), the key trigger of thrombosis, is expressed in human endothelial cells. This study was designed to investigate whether CAPE modulates TF expression in human aortic endothelial cells (HAECs). Western blots and real-time polymerase chain reactions were performed. CAPE (10(-7)-10(-5) M) inhibited tumor necrosis factor (TNF)-α induced endothelial TF protein expression by 2.1-fold at 10(-5) M (p<0.0001). Similarly, TF surface activity was reduced (p<0.02). In contrast, TF mRNA expression, TF promoter activity, and mitogen-activated protein (MAP) kinase activation remained unaltered. In conclusion, CAPE inhibits TF protein expression and activity at the posttranscriptional level thereby exhibiting anti-thrombotic potential.

Association between self-reported motivation to quit smoking with effectiveness of smoking cessation intervention among patients hospitalized for acute coronary syndromes in Switzerland.

Guidelines recommend brief smoking cessation interventions for hospitalized smokers reporting low motivation-to-quit. However, an intensive smoking cessation intervention may improve smoking cessation for these smokers. We conducted a secondary analysis of a pre-post interventional study that tested the efficacy of a proactive approach systematically offering intensive smoking cessation intervention to all hospitalized smokers with acute coronary syndrome (ACS) compared to a reactive approach offering it only to smokers willing to quit. We analyzed data from one study site in Switzerland, which recorded motivation-to-quit smoking at study inclusion between 08.2009 and 02.2012. The primary outcome was smoking cessation at 1- and 5-year. We tested for interaction by participant's motivation-to-quit score (low vs. high motivation), and calculated multivariable adjusted risk ratios (RR), stratified by motivation score. We obtained motivation scores for 230 smokers. Follow-up was 94% (217/230) at 1-year and 68% (156/230) at 5-year. Among participants with low motivation to quit, 19% of smokers in the reactive phase had quit at 1 year compared to 50% of smokers in the proactive phase (multivariable adjusted RR = 2.85, 95%CI:0.91-8.91). Among highly motivated smokers, rates did not differ between phases: 48% vs. 49% (multivariable adjusted RR = 1.02, 95%CI:0.75-1.39, p-value for interaction between motivation-to-quit categories = 0.10). At 5-year follow-up, the point estimates were similar. While our study has limitations inherent to the study design and sample size, we found that a proactive approach to offer systematic smoking cessation counseling for smokers with ACS reporting low motivation to quit was associated with higher smoking cessation rates at 1 year.

A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study.

AIMS: Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size. METHODS AND RESULTS: In 454 patients undergoing PCI, acetylcholine (10(-6) to 10(-4) M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30-60 mg/day and followed for 18-24 months. Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns. CONCLUSION: The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volume.

Prognostic values of fasting hyperglycaemia in non-diabetic patients with acute coronary syndrome: A prospective cohort study.

BACKGROUND: Controversy remains regarding the prevalence of hyperglycaemia in non-diabetic patients hospitalised with acute coronary syndrome and its prognostic value for long-term outcomes. METHODS AND RESULTS: We evaluated the prevalence of hyperglycaemia (defined as fasting glycaemia ⩾10 mmol/l) among patients with no known diabetes at the time of enrolment in the prospective Special Program University Medicine-Acute Coronary Syndromes cohort, as well as its impact on all-cause death, myocardial infarction, stroke and incidence of diabetes at one year. Among 3858 acute coronary syndrome patients enrolled between December 2009-December 2014, 709 (18.4%) had known diabetes, while 112 (3.6%) of non-diabetic patients had hyperglycaemia at admission. Compared with non-hyperglycaemic patients, hyperglycaemic individuals were more likely to present with ST-elevation myocardial infarction and acute heart failure. At discharge, hyperglycaemic patients were more frequently treated with glucose-lowering agents (8.9% vs 0.66%, p<0.001). At one-year, adjudicated all-cause death was significantly higher in non-diabetic patients presenting with hyperglycaemia compared with patients with no hyperglycaemia (5.4% vs 2.2%, p=0.041) and hyperglycaemia was a significant predictor of one-year mortality (adjusted hazard ratio 2.39, 95% confidence interval 1.03-5.56). Among patients with hyperglycaemia, 9.8% had developed diabetes at one-year, while the corresponding proportion among patients without hyperglycaemia was 1.8% (p<0.001). In multivariate analysis, hyperglycaemia at presentation predicted the onset of treated diabetes at one-year (odds ratio 4.15, 95% confidence interval 1.59-10.86; p=0.004). CONCLUSION: Among non-diabetic patients hospitalised with acute coronary syndrome, a fasting hyperglycaemia of ⩾10 mmol/l predicted one-year mortality and was associated with a four-fold increased risk of developing diabetes at one year.

Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort.

BACKGROUND: The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS. METHODS: A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation. RESULTS: The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68). CONCLUSIONS: After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.

Renal nerve ablation reduces blood pressure in resistant hypertension: Long-term clinical outcomes in a single-center experience.

Approximately 10% of patients with hypertension have resistant hypertension, even if adequate pharmacological therapy is established. In this regard, renal nerve ablation (RNA) could represent a valid alternative treatment option. In a retrospective analysis with a follow-up of 6, 12, and 24 months, the authors investigated the efficacy and safety of catheter-based renal artery ablation in 57 patients undergoing RNA with multiple renal nerve ablation in both renal arteries. In addition to medical antihypertensive therapy (4.2 ± 1.4 drugs per patient), RNA using three different ablation systems was performed in patients with confirmed resistant hypertension (systolic blood pressure >140 mm Hg in spite of three drugs including a diuretic). The primary end point was the change in office ambulatory systolic blood pressure from baseline to 6, 12, and 24 months of follow-up after RNA. The primary safety end point was the change in plasma creatinine levels after 12 and 24 months compared with baseline. The mean office systolic blood pressure at baseline was 167.6 ± 22.4 and after 6, 12, and 24 months averaged 143.5 ± 21.1 (P < .05), 141.1 ± 21.1 (P < .05), and 139.4 ± 19.6 mm Hg (P < .05) respectively, with an average of 15.1 ± 5.3 nerve ablations performed. No significant changes in plasma creatinine levels were observed at 12 months (P = .421) and at 24 months (P = .217). There were no complications after RNA nor any relevant adverse vascular, renal, or cardiovascular events observed except in one patient in whom a covered stent had to be placed at the femoral puncture site. In this study, in all patients with resistant hypertension, RNA, if performed adequately in the number of ablations and energy delivery, is an efficient and safe treatment option to lower office and 24-hour blood pressure. Whether these blood pressure-lowering effects will lead to a reduction of cardiovascular morbidity and mortality will require further studies.

Hyperglycaemia-induced epigenetic changes drive persistent cardiac dysfunction via the adaptor p66Shc.

AIMS: Hyperglycaemia-induced reactive oxygen species (ROS) are key mediators of cardiac dysfunction. Intensive glycaemic control (IGC) has failed to reduce risk of heart failure in patients with diabetes but the underlying mechanisms remain to be elucidated. The present study investigates whether epigenetic regulation of the pro-oxidant adaptor p66Shc contributes to persistent myocardial dysfunction despite IGC. METHODS AND RESULTS: p66Shc expression was increased in the heart of diabetic mice, and 3-week IGC by slow-release insulin implants did not revert this phenomenon. Sustained p66Shc upregulation was associated with oxidative stress, myocardial inflammation and left ventricular dysfunction, as assessed by conventional and 2D speckle-tracking echocardiography. In vivo gene silencing of p66Shc, performed during IGC, inhibited ROS production and restored cardiac function. Furthermore, we show that dysregulation of methyltransferase DNMT3b and deacetylase SIRT1 causes CpG demethylation and histone 3 acetylation on p66Shc promoter, leading to persistent transcription of the adaptor. Altered DNMT3b/SIRT1 axis in the diabetic heart was explained by upregulation of miR-218 and miR-34a. Indeed, in human cardiomyocytes exposed to high glucose, inhibition of these miRNAs restored the expression of DNMT3b and SIRT1 and erased the adverse epigenetic signatures on p66Shc promoter. Consistently, reprogramming miR-218 and miR-34a attenuated persistent p66Shc expression and ROS generation. CONCLUSIONS: In diabetic left ventricular dysfunction, a complex epigenetic mechanism linking miRNAs and chromatin modifying enzymes drives persistent p66Shc transcription and ROS generation. Our results set the stage for pharmacological targeting of epigenetic networks to alleviate the clinical burden of diabetic cardiomyopathy.