Search

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Introduction:Adrenomedullin (ADM) is a free circulating peptide that regulates endothelial barrier function and vascular tone. Here, we sought to study the relationship of adrenomedullin in combination with lactate and the risk of death in patients with out-of-hospital cardiac arrest (OHCA) of non-traumatic origin.Methods:Mid-regional pro-ADM (MR-proADM) concentrations were measured in OHCA patients after successful ROSC on admission. The outcome of interest was all-cause death. Patients were characterized by quartiles (Q) of MR-proADM and lactate concentrations. Cox models were adjusted for age, sex, shockable rhythm, bystander resuscitation, and baseline eGFR.Results:A total of 232 patients were included in the present study (28% women, 67 years, SAPS II score 80). In total, 132 patients (56.9%) died, and 24 patients had an unfavorable neurologic outcome (i.e., a CPC score of 3-4). The median MR-proADM and lactate levels were 1.4 nmol/L (IQR 0.8 to 2.8 nmol/L) and 4.8 mmol/L (IQR 2.8 to 7.4 mmol/L), respectively. MR-proADM concentrations correlated weakly with lactate levels (r=0.23, P<0.001). High (Q4) versus low (Q1-Q3) MR-proADM concentration was associated with an increased rate of death at 28 days (45.4% vs. 75.9%; P<0.001; Fig A). After multivariable adjustment (including baseline lactate levels), higher MR-proADM levels were significantly associated with an increased risk of death (Q4 vs. Q1-Q3: adjusted HR 1.84, 95% CI 1.21 to 2.77; adjusted HR for 1 unit increase in standardized biomarker 1.55, 95% CI 1.28 to 1.86). The combination of high MR-proADM and high lactate (Q4) concentration identified patients at particularly elevated risk (adjusted HR 3.99; 95% CI 1.67-9.56; Fig B).Conclusions:Higher MR-proADM concentration are associated with an increased risk of death in patients with OHCA of non-traumatic origin. The combination of high MR-proADM and high lactate levels identifies patients at distinctly elevated risk.

Background:Patients with hypertrophic cardiomyopathy (HCM) frequently have diastolic dysfunction (DD) characterized by elevated filling pressures. Speckle-tracking analysis of the left atrium (LA) is an imaging tool for quantifying DD, however, its value in HCM is not well established.Methods.Transthoracic echocardiographic images of consecutive HCM patients with a septal thickness ≥15 mm and no aberrant loading conditions at an academic tertiary care center were evaluated. Peak atrial longitudinal strain (PALS) was determined by averaging the atrial strain over all segments in the 4- and 2-chamber views (Figure).Results.Among 205 HCM patients, 108 patients (52 years, 40% female) had sinus rhythm and sufficient image quality to be included. The median interventricular wall thickness was 20 mm (IQR 17-23), the relative wall thickness ratio was 0.65 mm (IQR 0.46-0.87), and the LV mass index was 164.0 g/m2(IQR 131.5-188.5). The mean PALS was 18.5% (± 8.8%) and did not differ between men and women. PALS significantly (all p <0.05) correlated with septal thickness (r=-0.31), LA volume index (r=-0.60), E/A ratio (r=-0.25), E/E’ (r=-0.63), systolic pulmonary pressure (r=-0.31), and high sensitivity troponin-T levels (r=-0.43). Moreover, PALS correlated with resting gradients in patients with relevant LV outflow tract obstruction (n=53 [49%]; r=-0.29). Among patients who underwent cardiac magnetic resonance imaging (81%), PALS was significantly correlated with LA ejection fraction (r=0.59) and late gadolinium enhancement of the total LV mass (r=-0.42). In addition, PALS was the only echocardiographic parameter reflecting DD that was significantly associated with the presence of LGE (Odds Ratio 0.93, 95%CI 0.88-0.99).Conclusion.PALS is a useful tool for quantifying DD in HCM patients and is associated with the presence of LGE. Future research will need to evaluate its significance in early identification of HCM patients at risk of sudden cardiac death.

Background:Aspirin is the most frequently used antiplatelet monotherapy for secondary prevention in patients with established ASCVD. Trials comparing monotherapy with a P2Y12i versus aspirin have shown variable results.Methods:Medline, Embase, & Cochrane Central databases were searched to identify RCTs comparing monotherapy with a P2Y12i versus aspirin for secondary prevention in patients with established ASCVD (ischemic stroke, coronary, or peripheral artery disease). The primary outcome of interest was major adverse cardiac events (MACE). Secondary outcomes were myocardial infarction (MI), stroke, all-cause mortality, & major bleeding. The DerSimonian and Laird random-effects model was used to calculate risk ratios (RR) & the corresponding 95% confidence interval (CI). Heterogeneity among studies was assessed using the Higgins I2value.Results:9 eligible RCTs (5 with clopidogrel & 4 with ticagrelor) with 62,336 patients were included in our analyses. Monotherapy with P2Y12i significantly reduced the risk of MACE by 11% (0.89, 95% CI 0.84 - 0.95, I2=0), & MI by 19% (0.81, 95% CI 0.71 - 0.92, I2=0) as compared with aspirin monotherapy (Figure). There was no significant difference in the risk of stroke (0.85, 95% CI 0.73-1.01), & all-cause mortality (1.01, 95% CI 0.92 - 1.11) between the 2 treatment groups. There was no significant difference in the risk of major bleeding with P2Y12i monotherapy as compared with aspirin (0.97, 95% CI 0.66 - 1.43, I2=0). Results were consistent irrespective of the P2Y12i.Conclusion:P2Y12i monotherapy is associated with a significant reduction in atherothrombotic events as compared with aspirin alone without an increased risk of major bleeding.

Introduction:Atrial fibrillation (AF) and atrial flutter (AFL) are associated with diabetes and its comorbidities including hypertension, obesity, and heart failure (HF). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) 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 (T2D). We therefore hypothesized that SGLT2i may reduce the risk of AF/AFL.Methods:DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin in 17160 patients with T2D and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events using Cox and negative binomial models, respectively. AF events were identified using a MedDRA preferred term search (?Atrial Fibrillation?, ?Atrial Flutter?) in the safety database.Results:Dapagliflozin reduced the risk of incident AF/AFL by 19% (264 versus 325 events; hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009, Fig A). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL (n=1116): HR 0.79, 95% CI 0.58 to 1.09, No AF/AFL: HR 0.81, 95% CI 0.67 to 0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.78, 95% CI 0.62 to 0.99) versus MRF (HR 0.83, 95% CI 0.66 to 1.04; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55 to 1.11, No HF: HR 0.81, 95% CI 0.68 to 0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Dapagliflozin also reduced the total number of AF/AFL events (337 versus 432; rate ratio 0.77, 95% CI 0.64 to 0.92, P=0.005; Fig B).Conclusions:Dapagliflozin appears to reduce both incident AF/AFL as well as the total number of AF/AFL events in patients with T2D. This effect was consistent regardless of the patients? prior history of AF, ASCVD, or HF.

Introduction:Dapagliflozin reduced the risk of the composite of cardiovascular death or hospitalization for heart failure (CVD/HHF) in patients (pts) with type 2 diabetes (T2D) in DECLARE-TIMI 58. We hypothesized that cardiac biomarkers may help to identify pts who are at higher baseline risk and thus may benefit more from treatment with SGLT2i.Aim:To evaluate the association of baseline hsTnT and NT-proBNP levels with CVD/HHF and with the magnitude of benefit with dapagliflozin.Methods:This was a prespecified biomarker study from DECLARETIMI 58, a randomized, double-blind, placebo-controlled CV outcomes trial of dapagliflozin in pts with. Baseline NT-proBNP and hsTnT levels were measured in the TIMI Biomarker Core Laboratory in 14,565 pts (median follow-up 4.2 y). Patients were stratified by baseline biomarker levels. Relative risk ratios using hazard ratios and absolute risk reductions using Kaplan-Meier event rates at 4 years with dapagliflozin were calculated for CVD/HHF within biomarker quartiles.Results:The median baseline NT-proBNP and hsTnT levels were 75 pg/mL (IQR 35-165) and 10.2 pg/mL (IQR 6.9-15.5), respectively. Patients with higher levels of NT-proBNP and hsTnT had higher KM event rates of CVD/HHF (Q4 vs Q1: NT-proBNP: 13.7% vs 1.0%; hsTnT: 11.8% vs 1.4%; P-trend <0.001). Dapagliflozin consistently reduced the relative risk of CVD/HHF regardless of baseline NT-proBNP (P INT 0.72) or hsTnT quartiles (P INT 0.93). However, given their higher baseline risk, pts with elevated levels of NT-proBNP and/or hsTnT tended to derive even greater absolute risk reduction with dapagliflozin [ARR in Q4 for NT-proBNP 2.9% (NNT 35); hsTnT 2.4% (NNT 42)] [Figure].Conclusions:Patients with higher NT-proBNP or hsTnT levels are at increased risk of CV death and HHF. Dapagliflozin reduced the risk of CV death/HHF irrespective of NT-proBNP and hsTnT levels, with greater absolute risk reductions seen in pts with higher baseline biomarker levels.

Introduction:Sodium glucose transporter 2 inhibitors (SGLT2i) reduce the risk of major adverse cardiovascular events (MACE), including myocardial infarction (MI), in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). In DECLARE-TIMI 58, this benefit was seen in patients with ASCVD and particularly in those ones with prior MI. The effect of SGLT2i in reducing MIs of different types and sizes has not previously been reported.Hypothesis:In patients with T2DM and prior MI, dapagliflozin consistently reduces recurrent MI events across a range of infarct types & sizes.Methods:This was a pre-specified sub-analysis from DECLARE-TIMI 58, which randomized 17,160 patients with T2DM to dapagliflozin 10 mg vs. placebo, of whom, 3584 had a history of prior MI at enrollment. All MI events were prospectively adjudicated and classified according to: (1) Universal Definition types 1-5, (2) the presenting electrocardiogram (STEMI vs. NSTEMI), and (3) size based on peak troponin [as multiples of the upper limit of normal (ULN)]. Cox proportional hazards model was used to generate HR and 95 % CI.Results:From the total incident MIs (489) in patients with prior MI from DECLARE-TIMI 58, 316 (65%) were type 1 MIs and 403 (82%) were NSTEMI. From those with biomarkers available (456), 241 (53%) had peak troponin ? 10 X ULN. Besides reducing recurrent MI (HR 0.78; 95 % CI 0.63-0.95; p = 0.016), dapagliflozin appeared to favorably affect the risk of both type 1 (HR 0.80; 95 % CI 0.63-1.02) and type 2 (HR 0.64; 95 % CI 0.42-0.97) MIs. There also appeared to be a favorable reduction across all ranges of infarct sizes based on peak troponin (Figure).Conclusions:In patients with T2DM and prior MI, dapagliflozin consistently reduced recurrent MI across the spectrum of different infarct sizes and types, including those ones caused by a myocardial oxygen supply/demand mismatch. The mechanisms that explain reductions in MI with SGLT2i remain to be determined.

Background:We previously observed early aspirin (ASA) use after orthotopic heart transplantation (OHT) to be associated with lower rates of moderate to severe cardiac allograft vasculopathy (CAV). Antibody-mediated rejection (AMR) and acute cellular rejection (ACR) are important risk factors for CAV. As ASA has anti-inflammatory and antithrombotic actions, 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 (N=120) were categorized by the presence of early ASA use post-transplant (ASA treatment >6 months in the first year) and the presence of ACR and/or AMR during 5-year follow-up. 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 angiographic moderate/severe CAV (International Society for Heart and Lung Transplantation grade ? 2) was investigated and interaction tested with rejection status.Results:Patients with rejection (N=77) were younger and less likely hypertensive with no imbalance in aspirin use. Patients with both AMR and ACR had higher rates of CAV >2 at 5 years than those with either isolated AMR or ACR or no rejection (24.0 vs 14.9 v 5.3%; ptrend=0.028). Among patients with rejection, ASA therapy was associated with significantly lower rates of CAV >2 (3.3 vs 30.1%; p=0.001; HRadj0.07; 95% CI 0.01-0.52; Fig.), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs 5.3%; p=0.900; pinteraction=0.094).Conclusions:Early ASA use after OHT was associated with lower rates of moderate to severe CAV among patients with allograft rejection. This observation supports the need for a prospective randomized evaluation of ASA therapy after heart transplantation.