Slayman Obeid

Gut microbiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors

Aims Systemic levels of trimethylamine N-oxide (TMAO), a pro-atherogenic and pro-thrombotic metabolite produced from gut microbiota metabolism of dietary trimethylamine (TMA)-containing nutrients such as choline or carnitine, predict incident cardiovascular event risks in stable primary and secondary prevention subjects. However, the prognostic value of TMAO in the setting of acute coronary syndromes (ACS) remains unknown. Methods and results We investigated the relationship of TMAO levels with incident cardiovascular risks among sequential patients presenting with ACS in two independent cohorts. In the Cleveland Cohort, comprised of sequential subjects (n = 530) presenting to the Emergency Department (ED) with chest pain of suspected cardiac origin, an elevated plasma TMAO level at presentation was independently associated with risk of major adverse cardiac events (MACE, including myocardial infarction, stroke, need for revascularization, or death) over the ensuing 30-day (4th quartile (Q4) adjusted odds ratio (OR) 6.30, 95% confidence interval (CI), 1.89-21.0, P < 0.01) and 6-month (Q4 adjusted OR 5.65, 95%CI, 1.91-16.7; P < 0.01) intervals. TMAO levels were also a significant predictor of the long term (7-year) mortality (Q4 adjusted HR 1.81, 95%CI, 1.04-3.15; P < 0.05). Interestingly, TMAO level at initial presentation predicted risk of incident MACE over the near-term (30 days and 6 months) even among subjects who were initially negative for troponin T (< 0.1 ng/mL) (30 days, Q4 adjusted OR 5.83, 95%CI, 1.79-19.03; P < 0.01). The prognostic value of TMAO was also assessed in an independent multicentre Swiss Cohort of ACS patients (n = 1683) who underwent coronary angiography. Trimethylamine N-oxide again predicted enhanced MACE risk (1-year) (adjusted Q4 hazard ratios: 1.57, 95% CI, 1.03-2.41; P <0.05). Conclusion Plasma TMAO levels among patients presenting with chest pain predict both near- and long-term risks of incident cardiovascular events, and may thus provide clinical utility in risk stratification among subjects presenting with suspected ACS.

ECG Criteria to Differentiate Between Takotsubo (Stress) Cardiomyopathy and Myocardial Infarction

Background ECG criteria differentiating Takotsubo cardiomyopathy (TTC) from mainly anterior myocardial infarction (MI) have been suggested; however, this was in small patient populations. Methods and Results Twelve‐lead admission ECGs of consecutive 200 TTC and 200 MI patients were compared in dichotomized groups based on the presence or absence of ST‐elevation MI (STEMI versus STE‐TTC and non‐ST elevation MI versus non ST‐elevation‐TTC). When comparing STEMI and STE‐TTC, ST‐elevation in –aVR was characteristic of STE‐TTC with a sensitivity/specificity of 43% and 95%, positive predictive value (PPV) 91%, and a negative predictive value (NPV) 62% (P<0.001); when ST‐elevation in –aVR is accompanied by ST‐elevation in inferior leads, sensitivity/specificity were 14% and 98% (PPV was 89% and NPV 52%) (P=0.001), and 12% and 100% when associated with ST‐elevation in anteroseptal leads (PPV 100%, NPV 52%) (P<0.001). On the other hand, STEMI was characterized by ST‐elevation in aVR (sensitivity/specificity of 31% and 95% P<0.001, PPV 85% and NPV 59%) and ST‐depression in V2‐V3‐V4 (sensitivity/specificity of 24% and 100% P<0.001, PPV 100% and NPV 76%). When comparing non‐ST elevation MI and non ST‐elevation‐TTC, T‐inversion in leads I‐aVL‐V5‐V6 had a sensitivity/specificity of 17% and 97% for non ST‐elevation‐TTC (PPV 83% and NPV 55%) (P<0.001), and ST‐elevation in –aVR with T‐inversion in any lead was also specific for non ST‐elevation‐TTC (sensitivity/specificity of 8% and 100%, PPV 100% and NPV 53%) (P=0.006). In non‐ST elevation MI patients, the presence of ST‐depression in V2‐V3 was specific (sensitivity/specificity of 11% and 99%, PPV 91% and NPV 51%) (P=0.01). Conclusions ECG on admission can differentiate between TTC and acute MI, with high specificity and positive predictive value. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01947621.

From Eisenhower’s heart attack to modern management: a true success story!

It was on 23 September 1955 when the President of the USA Dwight D. Eisenhower took a day off and was playing golf at Cherry Hills Country Club. During the game, Ike, as the Americans called him, complained of what he considered to be indigestion. The President’s personal physician, Dr Howard Snyder, took the symptoms for a gastrointestinal problem and waited 10 h before referring Eisenhower to a hospital. In the medical history of the President, Dr Snyder noted that he gave Eisenhower amyl nitrate for the chest pain and morphine against pain. Thanks to a solid dose of morphine, Eisenhower fell into a deep sleep and did not wake until the next morning. His angina, however, persisted and finally an electrocardiograph (ECG) was organized from another hospital—today considered a necessity that should be available within minutes of symptom onset. The ECG recorded an anterolateral acute myocardial infarction with STsegment elevations. Only at this point, i.e. >24 h after his symptom onset, was Eisenhower hospitalized. Wall Street reacted in panic and shares plummeted; eventually, the Dow Jones had lost 6% or US

Intracardiac versus transesophageal echocardiography for left atrial appendage occlusion with watchman.

14 billon—and for good reasons: at that time the mortality of an acute myocardial infarction was huge, probably between 30% and 40%, even for those who were able to reach a hospital; indeed, more than half of them died or ended up in severe heart failure with a grim midterm outlook. Indeed, in the 1950s, not many diagnostic tools or any effective therapy were available. Although the clinical presentation of an acute myocardial infarction was known to most clinicians, not many were aware of the variety of symptoms with which an infarction may present. Indeed, in Eisenhower’s case, the initial presentation was atypical. Furthermore, an ECG was not commonly available, cardiac enzymes had not been introduced as diagnostic tests, nor was echocardiography or coronary angiography at hand for emergency physicians or cardiologists. Also, the treatment of acute myocardial infarction was really only ‘tender loving care’, i.e. nitroglycerin and morphine for pain relief. Defibrillation was only introduced by Paul M. Zoll in his seminal paper ‘Determination of ventricular fibrillation by externally applied electric countershock’ in the New England Journal of Medicine a year later and implemented into coronary care units in the early 1960s by Bernard Lown. Aspirin was well known and used by many, ever since Felix Hoffmann had produced it at Bayer Chemicals in Germany in 1897, but it was exclusively used for pain and fever. Only when Sir John Vane showed in 1971 that aspirin also inhibits platelet aggregation was it considered years later for patients with acute myocardial infarction. Also, in Eisenhower’s time, beta-blockers had not yet been developed; Sir James Black who won the Nobel Prize in 1988 for his discovery of propranolol had not even started his research at ICI laboratories. Finally, Akiro Endo’s work in the 1970s led to the discovery of statins, i.e. HMG-coenzyme A reductase inhibitors that were proven to be effective in such patients almost 20 years later in 1992 when the 4S trial was published. Lastly, it took several decades until inhibitors of the P2Y12 receptor such as ticlopidine, clopidogrel, prasugrel, or even ticagrelor were introduced into clinical practice. The most important step, however, was timely and effective revascularization. Although streptokinase and later tissue plasminogen activators provided some benefit, it required a bold step by a pioneer of cardiology to make this more effective: indeed, 40 years ago, i.e. on 16 September 1977, Andreas R. Grüntzig at the University Hospital in Zurich performed his seminal procedure in a patient with a proximal stenosis of the left anterior descending coronary artery with his self-made balloon. Although he opened the door to interventional cardiology, it took more than two decades until balloon angioplasty started to be used to treat patients with acute ST-segment elevation myocardial infarction or STEMI. Later, the introduction of stents improved the results of primary percutaneous coronary

Midregional Proadrenomedullin Improves Risk Stratification beyond Surgical Risk Scores in Patients Undergoing Transcatheter Aortic Valve Replacement.

Background: Left atrial appendage occlusion (LAAO) is mostly performed by transesophageal echocardiography (TEE) guidance. Intracardiac echocardiography (ICE) may be an alternative imaging modality for LAAO that precludes the need for general anesthesia or sedation.

SYNTAX score II in patients with coronary artery disease undergoing percutaneous mitral repair with the MitraClip

Background Conventional surgical risk scores lack accuracy in risk stratification of patients undergoing transcatheter aortic valve replacement (TAVR). Elevated levels of midregional proadrenomedullin (MR-proADM) levels are associated with adverse outcome not only in patients with manifest chronic disease states, but also in the general population. Objectives We investigated the predictive value of MR-proADM for mortality in an unselected contemporary TAVR population. Methods We prospectively included 153 patients suffering from severe aortic stenosis who underwent TAVR from September 2013 to August 2014. This population was compared to an external validation cohort of 205 patients with severe aortic stenosis undergoing TAVR. The primary endpoint was all cause mortality. Results During a median follow-up of 258 days, 17 out of 153 patients who underwent TAVR died (11%). Patients with MR-proADM levels above the 75th percentile (≥ 1.3 nmol/l) had higher mortality (31% vs. 4%, HR 8.9, 95% CI 3.0–26.0, P < 0.01), whereas patients with EuroSCORE II scores above the 75th percentile (> 6.8) only showed a trend towards higher mortality (18% vs. 9%, HR 2.1, 95% CI 0.8–5.6, P = 0.13). The Harrell’s C-statistic was 0.58 (95% CI 0.45–0.82) for the EuroSCORE II, and consideration of baseline MR-proADM levels significantly improved discrimination (AUC = 0.84, 95% CI 0.71–0.92, P = 0.01). In bivariate analysis adjusted for EuroSCORE II, MR-proADM levels ≥1.3 nmol/l persisted as an independent predictor of mortality (HR 9.9, 95% CI (3.1–31.3), P <0.01) and improved the model’s net reclassification index (0.89, 95% CI (0.28–1.59). These results were confirmed in the independent validation cohort. Conclusions Our study identified MR-proADM as a novel predictor of mortality in patients undergoing TAVR. In the future, MR-proADM should be added to the commonly used EuroSCORE II for better risk stratification of patients suffering from severe aortic stenosis.

Safety and efficacy profile of bioresorbable-polylactide-polymer-biolimus-A9-eluting stents versus durable-polymer-everolimus- and zotarolimus-eluting stents in patients with acute coronary syndrome.

BACKGROUND Percutaneous mitral valve repair (PMVR) using the MitraClip™ system has become a valuable alternative in patients with severe mitral regurgitation (MR) and high surgical risk. We sought to evaluate the prognostic value of the SYNTAX II score (SSII) in patients with concomitant coronary artery disease (CAD) undergoing a Mitraclip procedure. METHODS In seventy-five consecutive patients who underwent PMVR at the University Heart Center Zürich and the Cardiocentro Ticino, the SSSII was calculated at baseline. Clinical endpoints comprised of all-cause mortality, mitral valve surgery due to failure of PMVR or reoperation, hospitalization for congestive heart failure, heart transplantation and the composite of all four endpoints. RESULTS Patients were followed for a median of 271days. And were divided in tertiles of SSII: SSII low ≤46.5 (n=25), SSII mid 46.6-54.4 (n=25) and SSII high ≥54.5 (n=25). Patients in the highest SSII tertile had a lower left ventricular ejection fraction (33% vs. 40% vs. 53%) with a higher log-BNP (3.6 vs. 3.45 vs. 3.16) when compared to SSII mid and SSII low, respectively. However, the anatomical syntax score (SS) did not differ significantly within the tertiles (9.1±6.3 (SSII Low) vs 9.5±7.6 (SSII Mid) vs 10.2±6.7(SSII High), p=0.837). The primary endpoint occurred in 33% of patients (n=25). By multivariate analysis patients in the high SSII tertile (OR=6.12, 95% confidence interval, [CI] 1.45-25.86, p=0.014) and patients with a history of MI (OR=3.57, 95% confidence interval, [CI] 1.17-10.88, p=0.025) were at significantly higher risk of experiencing adverse events. Furthermore, in a combined outcome ROC curve analysis, the SSII showed good discrimination with an AUC of 0.73, p=0.001. A cutoff SSII >49 has been identified to have a sensitivity of 83% and specificity of 53% with approximately 45% of the patients experiencing an event during follow-up. CONCLUSION Using SSII in CAD patients undergoing PMVR is feasible and of prognostic significance hence widening its clinical utility in valvular heart disease.

Percutaneous retrieval of an endothelialized AMPLATZER cardiac plug from the abdominal aorta 6 months after embolization

Comparative data on long‐term safety and efficacy of bioresorbable‐polymer‐BES versus durable‐polymer‐EES/ZES in ACS setting have hitherto been lacking. We sought to assess the safety and efficacy of bioresorbable‐polymer‐biolimus‐A9‐eluting stents (BES) compared with thin‐strut‐durable‐polymer‐everolimus‐ and zotarolimus‐eluting stents (EES/ZES) in patients with acute coronary syndrome (ACS) undergoing PCI.

Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk

A 56-year-old, asymptomatic patient with a history of coronary artery disease, previously treated percutaneously and permanent atrial fibrillation with the CHA2DS2-Vasc-score of 3, arrived at our hospital for a routine transoesophageal echocardiography (TEE) control, 6 months after the implantation of 24-mm-AMPLATZER-Cardiac-Plug (ACP). The left atrial appendage (LAA) had been initially implanted to reduce the risk …

Real-world procedural and 30-day outcome using the Portico transcatheter aortic valve prosthesis: A large single center cohort

Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7-3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0-4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota-dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota-dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo.