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Left ventricular ejection fraction (LVEF) ≤ 40% is a well-established risk factor for mortality after acute coronary syndromes (ACS). However, the long-term prognostic impact of mildly reduced ejection fraction (EF) (LVEF 41-49%) after ACS remains less clear.This was a retrospective study enrolling patients admitted with ACS included in a single-centre databank. LVEF was assessed by echocardiography during index hospitalization. Patients were divided in the following categories according to LVEF: normal (LVEF ≥ 50%), mildly reduced (LVEF 41-49%), and reduced (LVEF ≤ 40%). The endpoint of interest was all-cause death after hospital discharge. A multivariable Cox model was used to adjust for confounders. A total of 3200 patients were included (1952 with normal EF, 375 with mildly reduced EF, and 873 with reduced EF). The estimated cumulative incidence rates of mortality at 10 years for patients with normal, mildly reduced, and reduced EF were 24.8%, 33.5%, and 41.3%, respectively. After adjustments, the presence of reduced EF was associated with higher mortality compared with normal EF [adjusted hazard ratio (HR) 1.64; 95% confidence interval (CI) 1.36-1.96; P 0.001], as was mildly reduced EF compared with normal EF (adjusted HR 1.33; 95% CI 1.05-1.68; P = 0.019). The presence of reduced EF was not associated with a statistically significantly higher mortality compared with mildly reduced EF (adjusted HR 1.23; 95% CI 0.96-1.57; P = 0.095).In patients with ACS, mildly reduced EF measured in the acute phase was associated with higher long-term mortality compared with patients with normal EF. These data emphasize the importance of anti-remodelling therapies for ACS patients who have LVEF in the mildly reduced range.

OBJECTIVE In patients with moderate to severe albuminuric kidney disease, sodium–glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk. RESEARCH DESIGN AND METHODS In the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to RESULTS Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38–0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001). CONCLUSIONS Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

ZusammenfassungDiabetes mellitus (DM) stellt eine wichtige Komorbidität bei Patienten mit Herzinsuffizienz dar, die maßgeblich die Prognose der Patienten determiniert. Von entscheidender Bedeutung zur Verbesserung der Prognose dieser Hochrisiko-Patienten ist daher eine frühzeitige Diagnostik und differenzierte medikamentöse Therapie mit Ausschöpfung aller möglichen Therapieoptionen und Absetzen potenziell schädlicher Substanzen. Das gemeinsame Positionspapier der Deutschen Gesellschaft für Kardiologie (DGK) und der Deutschen Diabetes Gesellschaft (DDG) fasst die vorhandene wissenschaftliche Evidenz zusammen und gibt Empfehlungen, was bei der Diagnose und Therapie der Herzinsuffizienz und des DM zu beachten ist, um die Prognose zu verbessern.

Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms. Here we evaluated reactivation of parvovirus B19 and several viruses of the herpes family in patients with long-COVID syndrome, how vaccination affected viral interference, and how virus reactivation influenced clinical conditions. Clinical and laboratory data on 252 consecutive patients (97 vaccinated and 155 non-vaccinated) were recorded between April 2021–May 2022 (median 243 days post-COVID-19 infection). Viral IgG and IgM titers were compared between vaccinated or non-vaccinated patients, and age and sex-matched healthy controls. Vaccination was associated with significantly less frequent fatigue and multiorgan symptoms (P < 0.001), significantly less cumulative IgM positivity of the investigated viruses, significantly lower plasma levels of IgG subfractions 2 and 4, and significantly lower quantitative Cytomegalovirus (CMV) IgG, CMV IgM, and EBV IgM titers. These results indicate that anti-SARS-CoV2 vaccination interrupts viral crosstalk in patients with long-COVID syndrome. (ClinicalTrials.gov Identifier: NCT05398952)

Aims Adrenomedullin (ADM) is a free-circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of ADM in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA). Methods and results Mid-regional pro-adrenomedullin (MR-proADM) and lactate concentrations were measured in patients with OHCA who survived at least 24 h after the return of spontaneous circulation. The outcome of interest was all-cause death. Patients were characterized by the quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, simplified acute physiology score II (SAPS II), and estimated glomerular filtration rate (eGFR). A total of 232 patients were included in the present study (28% women, 67 years, SAPS II 80). The median MR-proADM and lactate levels at 24 h were 1.4 nmol/L [interquartile range (IQR) 0.8–2.8 nmol/L] and 1.8 mmol/L (IQR 1.3–3.4 mmol/L), respectively. Mid-regional pro-adrenomedullin concentrations correlated weakly with lactate levels (r = 0.36, P < 0.001). High (Q4) vs. low (Q1–Q3) MR-proADM concentrations were significantly associated with an increased rate of death at 28 days (75.9 vs. 45.4%; P < 0.001). After multivariable adjustment (including lactate levels at 24 h), higher MR-proADM levels were significantly associated with an increased risk of death [Q4 vs. Q1–Q3: adjusted hazard ratio (adj-HR) 1.67, 95% confidence interval (CI) 1.12–2.50; adj-HR for a 1-unit increase in a standardized biomarker 1.44, 95% CI 1.19–1.73]. This relationship remained significant even after further adjustment for baseline NT-proBNP and high-sensitivity troponin T levels. The combination of high MR-proADM and high lactate (Q4) concentrations identified patients at a particularly elevated risk (adj-HR 3.50; 95% CI 1.92–6.39). Conclusion Higher MR-proADM concentrations are associated with an increased risk of death in patients with OHCA, and the combination of high MR-proADM and lactate levels identifies patients at a distinctly elevated risk.

ImportanceSodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.ObjectiveTo assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).Design, setting, and participantsThis secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (InterventionsDapagliflozin vs placebo.Main outcomes and measuresThe dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.ResultsAt baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.Conclusions and relevanceThe effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.Trial registrationClinicalTrials.gov Identifier: NCT01730534.

Supplemental Digital Content is available in the text., Background: Female sex is an independent risk factor for stroke and systemic embolic events in patients with atrial fibrillation. This study aimed to examine the efficacy and safety profile of edoxaban in women versus men. Methods: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) randomly assigned 21 105 patients (8040 women) with atrial fibrillation and CHADS2 score ≥2 either to a higher-dose edoxaban regimen, a lower-dose edoxaban regimen, or warfarin. The primary end points of the trial were the composite of stroke or systemic embolic events (efficacy), and International Society on Thrombosis and Haemostasis–defined major bleeding (safety). Results: In comparison with men, women were older, had lower body weight, were more likely to have hypertension and renal dysfunction, but less likely to smoke, drink alcohol, or have diabetes or coronary artery disease. Pretreatment endogenous factor Xa activity was significantly higher in women than in men (92.5% versus 86.1%, P

ObjectivesThis study aimed to estimate and compare the prevalence of the virus-specific antibodies against the SARS-CoV-2 nucleoprotein antigen (anti-SARS-CoV-2 N) in healthcare workers and an all-comer paediatric and adult patient population.Design, setting and participantsA longitudinal study enrolling healthcare professionals and concurrent serial cross-sectional studies of unselected all-comer patients were conducted at an Austrian academic medical centre. Healthcare workers were tested at enrolment and after 1, 2, 3, 6 and 12 months. The cross-sectional studies in patients were conducted at three time periods, which roughly coincided with the times after the first, second and third wave of SARS-CoV-2 in Austria (ie, 24 August–7 September 2020; 8–22 February 2021 and 9–23 November 2021). Anti-SARS-CoV-2 N antibodies were measured using a sandwich electrochemiluminescence assay (Roche).ResultsIn total, 2735 and 9275 samples were measured in 812 healthcare workers (median age: 40 years, 78% female) and 8451 patients (median age: 55 years, 52% female), respectively. Over the entire study period, anti-SARS-CoV-2 N antibodies were detected in 98 of 812 healthcare workers, resulting in a seroprevalence of 12.1% (95% CI 10.0% to 14.5%), which did not differ significantly (p=0.63) from that of the all-comer patient population at the end of the study period (407/3184; 12.8%, 95% CI 11.7% to 14.0%). The seroprevalence between healthcare workers and patients did not differ significantly at any time and was 1.5-fold to 2-fold higher than the number of confirmed cases in Austria throughout the pandemic. In particular, there was no significant difference in the seroprevalence between paediatric and adult patients at any of the tested time periods.ConclusionThroughout the pandemic, healthcare staff and an adult and paediatric all-comer patient population had similar exposure to SARS-CoV-2.Trial registration numberClinicalTrials.gov Identifier:NCT04407429.

AIMS Dapagliflozin reduced the risk of the composite of cardiovascular (CV) death or hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus in DECLARE-TIMI 58. We hypothesized that baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels would help identify patients who are at higher baseline risk and we describe the treatment effects of dapagliflozin in patients according to their baseline NT-proBNP and hsTnT levels. METHODS AND RESULTS This was a pre-specified biomarker study from DECLARE-TIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Clinical Trials Laboratory in 14 565 patients. Among the included patients, 9143 patients (62.8%) were male, 1464 (10.1%) had a history of heart failure and the mean age was 63.9 years. The median baseline NT-proBNP and hsTnT levels were 75 pg/mL [interquartile range (IQR) 35-165] and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher NT-proBNP and hsTnT quartiles had higher rates of CV death/HHF (Q4 vs. Q1: NT-proBNP: 4-year Kaplan-Meier event rates 13.7% vs. 1.0%; hsTnT: 11.8% vs. 1.4%; P-trend

Aim To compare the efficacy and safety of P2Y12 inhibitor or aspirin monotherapy for secondary prevention in patients with atherosclerotic cardiovascular disease (ASCVD). Methods and results Medline, Embase, and Cochrane Central databases were searched to identify randomized trials comparing monotherapy with a P2Y12 inhibitor versus aspirin for secondary prevention in patients with ASCVD (cardiovascular, cerebrovascular, or peripheral artery disease). The primary outcome was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, and major bleeding. A random-effects model was used to calculate risk ratios (RR) and the corresponding 95% confidence interval (CI) and heterogeneity among studies was assessed using the Higgins I2 value. A total of 9 eligible trials (5 with clopidogrel and 4 with ticagrelor) with 61 623 patients were included in our analyses. Monotherapy with P2Y12 inhibitors significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84–0.95, I2 = 0%) and MI by 19% (0.81, 95% CI 0.71–0.92, I2 = 0%) compared with aspirin monotherapy. There was no significant difference in the risk of stroke (0.85, 95% CI 0.73–1.01), or all-cause mortality (1.01, 95% CI 0.92–1.11). There was also no significant difference in the risk of major bleeding with P2Y12 inhibitor monotherapy compared with aspirin (0.94, 95% CI 0.72–1.22, I2 = 42.6%). Results were consistent irrespective of the P2Y12 inhibitor used. Conclusion P2Y12 inhibitor monotherapy for secondary prevention is associated with a significant reduction in atherothrombotic events compared with aspirin alone without an increased risk of major bleeding.

Background: Patients with prior percutaneous coronary intervention (PCI) are at high residual risk for multiple types of coronary events within and beyond the stented lesion. This risk might be mitigated by more intensive LDL-C (low-density lipoprotein cholesterol)-lowering beyond just with statin therapy. Methods: FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) randomized 27 564 patients with stable atherosclerotic disease on statin to the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab or placebo with a median follow-up of 2.2 years. The end points of interest were major adverse cardiovascular events (MACE; a composite of cardiovascular death, myocardial infarction, stroke, unstable angina or coronary revascularization), and major coronary events (a composite of coronary heart death, myocardial infarction, or coronary revascularization). We compared the risk of MACE and the magnitude of relative and absolute risk reductions with evolocumab in patients with and without prior PCI. Results: Seventeen thousand seventy-three patients had prior PCI. In the placebo arm, those with prior PCI had higher rates of MACE (13.2% versus 8.3%; hazard ratio [HR] adj 1.61 [95% CI, 1.42–1.84]; P adj , 1.72 [95% CI, 1.49–1.99]; P P interaction 0.51; major coronary events: HR, 0.82 [0.75–0.90] versus HR, 0.88 [0.75–1.04]; P interaction 0.42). Absolute risk reductions for MACE were 2.0% versus 0.9% ( P interaction 0.14) and for major coronary events 2.0% versus 0.7% ( P interaction 0.045). In those with prior PCI, the effect of evolocumab on coronary revascularization (HR, 0.76 [0.69–0.85]) was directionally consistent across types of revascularization procedures: coronary artery bypass grafting (HR, 0.71 [0.54–0.94]); any PCI (HR, 0.77 [0.69–0.86]); PCI for de novo lesions (HR, 0.76 [0.66–0.88]); and PCI for stent failure or graft lesions (HR, 0.76 [0.63–0.91]). Conclusions: Evolocumab reduces the risk of MACE in patients with prior PCI including the risk of coronary revascularization, with directionally consistent effects across several types of revascularization procedures, including coronary artery bypass grafting and PCI for stent or graft failure. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.

To compare the efficacy and safety of P2YMedline, Embase, and Cochrane Central databases were searched to identify randomized trials comparing monotherapy with a P2YP2Y

Background: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. Methods: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. Results: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97–1.56], P =0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21–2.12], P =0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 – 2.03], P =0.0058), and limb adverse events (adjusted HR, 8.37, P P -interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P -interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90–1.26]) and amputation (HR, 1.09 [95% CI, 0.84–1.40]), with no significant interactions by a history of PAD versus not ( P -interactions=0.30 and 0.093, respectively). Conclusions: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

Highlights •T2DM, HF, and CKD are closely intertwined. •SGLT2i exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects. •SGLT2i reduce inflammation, oxidative stress, fibrosis, intraglomerular hypertension, and sympathetic nervous system activation, and may improve mitochondrial function and myocardial efficiency. •Cardiologists, diabetologists, nephrologists, and primary care physicians should be familiar with this drug class.

Background Diabetes and heart failure (HF) promote atrial fibrillation (AF) and are associated with an increased risk of adverse cardiovascular (CV) events in patients with AF. Because of effective anticoagulation options, AF patients are now more likely to develop HF than a stroke or a systemic embolic event. Appropriate risk stratification of patients with AF should therefore not only consider the risk for stroke but also for HF events. Methods Patients with AF admitted to a tertiary academic center between 01/2005 and 07/2019 were identified through a search of electronic health records. The primary outcome of interest was CV death or hospitalization for HF (HHF). We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, hypertension, smoking, C-reactive protein, and LDL-C. To select the most informative variables and overcome the limitations of stepwise regression procedures, we performed a least absolute shrinkage and selection operator logistic regression in a model that incorporated diabetes, HF, NT-proBNP, and the covariates for adjustment in combination with 10-fold cross-validation. Results In total, 7,412 patients (median age 70 years, 39.7% female) were included in the present analysis and followed over a median of 4.6 years. Both diabetes (Adjusted (Adj.) hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.55 to 2.25) and HF (Adj. HR 2.57, 95% CI 2.22 to 2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared to patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all-cause death. There was a robust relationship between CV death/HHF and NT-proBNP (Adj. HR for 1-unit increase in standardized log-transformed biomarker 1.86, 95% CI 1.67 to 2.07). NT-proBNP showed good discriminatory performance (AUC 0.78, 95% CI 0.77–0.80), and the addition of NT-proBNP to the covariates used for adjustment resulted in a significant AUC improvement (Δ=0.04, P Conclusion These findings suggest that the influence of diabetes and HF expand beyond the risk of stroke and systemic embolic events to CV death/HHF in an unselected AF patient population. NT-proBNP may provide improved risk assessment in AF patients. Funding Acknowledgement Type of funding sources: None. Figure 1. Forest Plot

OBJECTIVE Heart failure (HF) is an impactful complication of type 2 diabetes mellitus (T2DM). We aimed to develop and validate a risk score for hospitalization for HF (HHF) incorporating biomarkers and clinical factor(s) in patients with T2DM. RESEARCH DESIGN AND METHODS We derived a risk score for HHF using clinical data, high-sensitivity troponin T (hsTnT), and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) from 6,106 placebo-treated patients with T2DM in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53). Candidate variables were assessed using Cox regression. The strongest indicators of HHF risk were included in the score using integer weights. The score was externally validated in 7,251 placebo-treated patients in DECLARE-TIMI 58 (Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis in Myocardial Infarction 58). The effect of dapagliflozin on HHF was assessed by risk category in DECLARE-TIMI 58. RESULTS The strongest indicators of HHF risk were NT-proBNP, prior HF, and hsTnT (each P < 0.001). A risk score using these three variables identified a gradient of HHF risk (P-trend CONCLUSIONS We developed and validated a risk score for HHF in T2DM that incorporated NT-proBNP, prior HF, and hsTnT. The risk score identifies patients at higher risk of HHF who derive greater absolute benefit from dapagliflozin.

Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear.In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days.A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups.Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

OBJECTIVE Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk. RESEARCH DESIGN AND METHODS DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to 300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to RESULTS Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to 300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35–1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480). CONCLUSIONS In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.

Background Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. Methods Patients receiving OHT at a single center 2004-2010 (n = 120) were categorized by early ASA use post-transplant (ASA use for > 6 months in the first year) and the presence of biopsy-defined acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) during 5 year followup. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. Results Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3 vs 30.1%; p = 0.001; HRadj 0.07; 95% CI 0.01-0.52) whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs 5.3%; p = 0.90; HRadj 1.26; 95% CI 0.08-20.30; pinteraction = 0.09). Conclusions Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection. This article is protected by copyright. All rights reserved.

Biomarkers that reflect hemodynamic stress, inflammation, extracellular matrix remodeling, angiogenesis, and endothelial dysfunction may improve risk stratification and add valuable pathobiological insight in patients with out-of-hospital cardiac arrest (OHCA). In total, 120 patients with OHCA who survived at least 48 h after return of spontaneous circulation were consecutively included in the present analysis. Concentrations of 30 biomarkers were measured simultaneously using a multi-panel biomarker assay. Cox regression models were adjusted for age, sex, estimated glomerular filtration rate, lactate concentration, bystander resuscitation, initial cardiac rhythm, and type of targeted temperature management. Overall, 57 patients (47.5%) had a favorable neurological outcome (Cerebral Performance Category ≤ 2) at 30 days, while palliative care was initiated in 49 patients (40.8%), and 52 patients (43.3%) died. After correction for multiple testing with Bonferroni-Holm, 8 biomarkers (including Angiopoietin-2, Procalcitonin, Resistin, IL-4Rα, MMP-8, TNFα, Renin, and IL-1α) were significantly associated with all-cause death. After multivariable adjustment, only angiopoietin-2 (Adjusted (Adj) hazard ratio (HR) per 1-unit increase in standardized biomarker concentrations 1.52 (95% CI 1.16–1.99)) and renin (Adj HR 1.32 (95% CI 1.06–1.65) remained independently associated with an increased risk of death. The discriminatory performance indicated good performance for angiopoietin-2 (area under the curve (AUC): 0.75 (95% CI 0.66–0.75) and was significantly higher (P = 0.011) as compared with renin (AUC: 0.60, 95% CI 0.50–0.60). In conclusion, angiopoietin-2 was significantly associated with all-cause mortality in patients with OHCA who survived the first 48 h and may prove to be useful for risk stratification of these patients.

Background Plasma omega‐3 polyunsaturated fatty acids (ω3‐PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established. Methods and Results Baseline plasma ω3‐PUFA composition (α‐linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case‐cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event‐free subjects as controls from MERLIN‐TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST‐Elevation‐Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non–ST‐segment–elevation ‐acute coronary syndrome. After inverse‐probability‐weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long‐chain ω3‐PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68–0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55–0.97). Long‐chain ω3‐PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27–0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16–0.56). An attenuated relationship was seen for α‐linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74–1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67–1.25). No significant relationship was observed between any ω3‐PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post‐acute coronary syndrome ventricular tachycardia. Conclusions In patients after non–ST‐segment–elevation‐acute coronary syndrome, plasma long‐chain ω3‐PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids. Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00099788.

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45–0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76–1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66–1.17]) and those without HF (HR, 0.88 [95% CI, 0.74–1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43–0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62–0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34–0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89–1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86–1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P =0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88–1.13; P =0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81–1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65–1.00; P =0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72–1.00; P =0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Patients with type 2 diabetes mellitus have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function. After several large cardiovascular outcome trials with mostly neutral results, 2 studies of the sodium–glucose co-transporter 2 inhibitors (SGLT2is), empagliflozin and canagliflozin, reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred. These findings prompted several analyses to elucidate the mechanisms of action of SGLT2is and have initiated several large clinical trials in patients with HF without type 2 diabetes mellitus. This review summarizes known and possible mechanisms that contribute to these salutary effects of SGLT2is. Also discussed is the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs.

Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.

Introduction: Biomarkers of hemodynamic stress and myocardial injury are associated with the risk of CV death & heart failure in patients with atherosclerotic vascular disease (ASCVD). Here we explore the association between cardiac biomarkers and ASCVD outcomes in patients with type 2 diabetes (T2DM). Methods: This was a nested biomarker study in DECLARETIMI 58, a randomized, blinded, placebo-controlled trial of dapagliflozin in T2DM and either multiple risk factors (MRF, ~60%) or established ASCVD (~40%). The relationship between baseline NT-proBNP and hsTnT levels (TIMI Biomarker Laboratory, n=14,565) and the composite of myocardial infarction, ischemic stroke, and CV death (MACE), was modeled within the placebo arm using Cox models adjusted for age, sex, race, smoking, baseline eGFR, BMI, T2DM duration, insulin use, history of CAD, MI, ischemic stroke, PAD, HF, dyslipidemia & hypertension. Interaction testing was applied to assess the effect of dapagliflozin according to baseline biomarker value. Results: NT-proBNP and hsTnT were significantly associated with MACE (Adjusted hazard ratio (aHR) per 1-SD in log-transformed biomarker, NT-proBNP: aHR 1.62; hsTnT aHR 1.59). The magnitude of the relationship was similar in patients with ASCVD (NT-proBNP aHR 1.60; hsTnT aHR 1.62) and MRF (NT-proBNP aHR 1.62; hsTnT: aHR 1.51) [Fig A] . Moreover, both biomarkers remained independently associated with MACE when combined in the multivariable model (NT-proBNP aHR 1.46, hsTnT aHR 1.39). The risk of MACE by baseline biomarker level and stratified by treatment arm is shown in Fig B. Conclusions: In patients with T2DM both with and without ASCVD, higher baseline NT-proBNP or hsTnT levels identified patients at increased risk of MACE. The difference in MACE rates between dapagliflozin and placebo tended to be more pronounced in ASCVD patients with higher baseline or NT-proBNP or hsTnT levels.

Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to

This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length60 mm) or coronary artery bypass grafting surgery (CABG).In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Aims Concomitant atrial fibrillation (AF) and diabetes mellitus (DM) increases the risk of stroke and systemic embolic events (SEE). This meta-analysis assessed the benefit/risk balance of non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin, and explored whether there was effect modification by DM or heterogeneity in outcomes between NOACs in patients with and without DM. Methods and results We performed a meta-analysis of 58 634 patients from four Phase 3 trials of NOAC vs. warfarin in patients with AF, comparing the primary outcomes of efficacy and safety and six other secondary outcomes in patients stratified by the presence of DM. Interaction testing was used to assess for heterogeneity of treatment effects. A meta-regression was performed to evaluate the influence of baseline characteristics. NOACs reduced the risk of stroke/SEE in 18 134 patients with DM [hazard ratio (HR) 0.80; 95% confidence interval (CI) (0.69–0.93), I2 3.90] to a similar degree as in 40 500 patients without DM [HR 0.82; 95% CI (0.74–0.91), I2 16.33; P-int 0.81]. There was no effect modification of DM on the relative reduction with NOACs vs. warfarin in major bleeding (DM: 0.95, 95% CI 0.75–1.20, I2 43.83; no DM: 0.83, 95% CI 0.55–1.24; I2 87.90; P-int 0.37). Intracranial haemorrhage (HRs 0.51 and 0.47, P-int 0.70) and cardiovascular death (HRs 0.87 and 0.90, P-int 0.70) were significantly reduced by NOACs in the presence or absence of DM. Conclusion Non-vitamin K antagonist oral anticoagulants are more effective and safer than warfarin in AF patients with or without DM. Absent contraindications, NOACs should be the anticoagulation treatment choice in patients with diabetes.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58–1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67–0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66–1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62–0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55–1.11]; No HF: HR, 0.81 [95% CI, 0.68–0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A 1c , body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64–0.92]; P =0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr∆end) and held them in an environmental chamber with 10% FiO2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.