Gut microbiota‐dependent trimethylamine N‐oxide and cardiovascular outcomes in patients with prior myocardial infarction: A nested case control study from the PEGASUS‐TIMI 54 trial

Background Trimethylamine N‐oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor. Methods and Results PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin ‐ Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow‐up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case‐control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs‐TnT [high‐sensitivity troponin T], hs‐CRP [high‐sensitivity C‐reactive protein], NT‐proBNP [N‐terminal‐pro‐B‐type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06–1.93, P trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28–3.96, P trend=0.003) and stroke (OR 2.68, 95% CI, 1.39–5.17, P trend<0.001). After adjustment for clinical factors, the association persisted for cardiovascular death (ORadj 1.89, 95% CI, 1.03–3.45, P trend=0.027) and stroke (ORadj 2.01, 95% CI, 1.01–4.01, P trend=0.022), but was slightly attenuated after adjustment for cardiovascular biomarkers (cardiovascular death: ORadj 1.74, 95% CI, 0.88–3.45, P trend=0.079; and stroke: ORadj 1.82, 95% CI, 0.88–3.78, P trend=0.056). The reduction in MACE with ticagrelor was consistent across TMAO quartiles (P interaction=0.92). Conclusions Among patients with prior myocardial infarction, higher TMAO levels were associated with cardiovascular death and stroke but not with recurrent myocardial infarction. The efficacy of ticagrelor was consistent regardless of TMAO levels. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: PEGASUS‐TIMI 54, NCT01225562

Thermodynamics and Universality for Mean Field Quantum Spin Glasses

We study aspects of the thermodynamics of quantum versions of spin glasses. By means of the Lie-Trotter formula for exponential sums of operators, we adapt methods used to analyze classical spin glass models to answer analogous questions about quantum models.Comment: 17 page

Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: Prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial

Aims Statins reduce cardiovascular risk in patients with acute coronary syndrome (ACS) and normal-to-moderately impaired renal function. It is not known whether proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors provide similar benefit across a range of renal function. We determined whether effects of the PCSK9 inhibitor alirocumab to reduce cardiovascular events and death after ACS are influenced by renal function. ................................................................................................................................................................................................... Methods ODYSSEY OUTCOMES compared alirocumab with placebo in patients with recent ACS and dyslipidaemia despite and results intensive statin treatment. Estimated glomerular filtration rate (eGFR) &lt;30 mL/min/1.73 m was exclusionary. In 18 918 patients, baseline eGFR was 82.8 ± 17.6 mL/min/1.73 m , and low-density lipoprotein cholesterol (LDL-C) was 92 ± 31 mg/dL. At 36 months, alirocumab decreased LDL-C by 48.5% vs. placebo but did not affect eGFR (P = 0.65). Overall, alirocumab reduced risk of the primary outcome (coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization) with fewer deaths. There was no interaction between continuous eGFR and treatment on the primary outcome or death (P = 0.14 and 0.59, respectively). Alirocumab reduced primary outcomes in patients with eGFR &gt;_90 mL/min/1.73 m (n = 7470; hazard ratio 0.784, 95% confidence interval 0.670–0.919; P = 0.003) and 60 to &lt;90 (n = 9326; 0.833, 0.731–0.949; P = 0.006), but not in those with eGFR &lt; 60 (n = 2122; 0.974, 0.805–1.178; P = 0.784). Adverse events other than local injection-site reactions were similar in both groups across all categories of eGFR. ................................................................................................................................................................................................... Conclusions In patients with recent ACS, alirocumab was associated with fewer cardiovascular events and deaths across the range of renal function studied, with larger relative risk reductions in those with eGFR &gt; 60 mL/min/1.73 m 2 2 2 2The trial was funded by Sanofi and Regeneron Pharmaceuticals, Inc

The effect of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across baseline blood pressure categories: Analysis of the LEADER and SUSTAIN 6 trials

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P =.06 for MACE; P =.14 for nephropathy) or semaglutide (P =.40 for MACE; P =.27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP

Integrating coronary atherosclerosis burden and progression with coronary artery disease risk factors to guide therapeutic decision making (vol 136, page 260, 2023)

Cardiolog

Twenty Year Trends and Sex Differences in Young Adults Hospitalized with Acute Myocardial Infarction: The ARIC Community Surveillance Study

Background: Sex differences are known to exist in the management of older patients presenting with acute myocardial infarction (AMI). Few studies have examined the incidence and risk factors of AMI among young patients, or whether clinical management differs by sex. Methods: The Atherosclerosis Risk in Communities (ARIC) Surveillance study conducts hospital surveillance of AMI in 4 US communities (MD MN, MS and NC). AMI was classified by physician review, using a validated algorithm. Medications and procedures were abstracted from the medical record. Our study population was limited to young patients aged 35 to 54 years. Results: From 1995 to 2014, 28 732 weighted hospitalizations for AMI were sampled among patients aged 35 to 74 years. Of these, 8737 (30%) were young. The annual incidence of AMI hospitalizations increased for young women but decreased for young men. The overall proportion of AMI admissions attributable to young patients steadily increased, from 27% in 1995 to 1999 to 32% in 2010 to 2014 (P for trend=0.002), with the largest increase observed in young women. History of hypertension (59% to 73%, P for trend<0.0001) and diabetes mellitus (25% to 35%, P for trend<0.0001) also increased among young AMI patients. Compared to young men, young women presenting with AMI were more often black and had a greater comorbidity burden. In adjusted analyses, young women had a lower probability of receiving lipid-lowering therapies (relative risk [RR]=0.87; 95% confidence interval [CI], 0.80-0.94), nonaspirin antiplatelets (RR=0.83; 95% CI, 0.75-0.91), beta blockers (RR=0.96; 95% CI, 0.91-0.99), coronary angiography (RR=0.93; 95% CI, 0.86-0.99) and coronary revascularization (RR = 0.79; 95% CI, 0.71-0.87). However, 1-year all-cause mortality was comparable for women versus men (HR=1.10; 95% CI, 0.83-1.45). Conclusions: The proportion of AMI hospitalizations attributable to young patients increased from 1995 to 2014 and was especially pronounced among women. History of hypertension and diabetes among young patients admitted with AMI increased over time as well. Compared with young men, young women presenting with AMI had a lower likelihood of receiving guideline-based AMI therapies. A better understanding of factors underlying these changes is needed to improve care of young patients with AMI

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine ‘sick day’ guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies

Fifteen-year trends in management and outcomes of non–ST-segment–elevation myocardial infarction among black and white patients: The ARIC community surveillance study, 2000–2014

Background—Standardization of evidence-based medical therapies has improved outcomes for patients with non–ST-segment– elevation myocardial infarction (NSTEMI). Although racial differences in NSTEMI management have previously been reported, it is uncertain whether these differences have been ameliorated over time. Methods and Results—The ARIC (Atherosclerosis Risk in Communities) Community Surveillance study conducts hospital surveillance of acute myocardial infarction in 4 US communities. NSTEMI was classified by physician review, using a validated algorithm. From 2000 to 2014, 17 755 weighted hospitalizations for NSTEMI (patient race: 36% black, 64% white) were sampled by ARIC. Black patients were younger (aged 60 versus 66 years), more often female (45% versus 38%), and less likely to have medical insurance (88% versus 93%) but had more comorbidities. Black patients were less often administered aspirin (85% versus 92%), other antiplatelet therapy (45% versus 60%), b-blockers (85% versus 88%), and lipid-lowering medications (68% versus 76%). After adjustments, black patients had a 24% lower probability of receiving nonaspirin antiplatelets (relative risk: 0.76; 95% confidence interval, 0.71–0.81), a 29% lower probability of angiography (relative risk: 0.71; 95% confidence interval, 0.67–0.76), and a 45% lower probability of revascularization (relative risk: 0.55; 95% confidence interval, 0.50–0.60). No suggestion of a changing trend over time was observed for any NSTEMI therapy (P values for interaction, all >0.20). Conclusions—This longitudinal community surveillance of hospitalized NSTEMI patients suggests black patients have more comorbidities and less likelihood of receiving guideline-based NSTEMI therapies, and these findings persisted across the 15-year period. Focused efforts to reduce comorbidity burden and to more consistently implement guideline-directed treatments in this high-risk population are warranted