Influence of renin-angiotensin-aldosterone system inhibitors on plasma levels of angiotensin-converting enzyme 2

Concern has been raised that treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the expression of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2, and lead to an increased risk of death from SARS-CoV-2. We aimed to address this concern by evaluating the in vivo relationship of treatment with ACE inhibitors and angiotensin receptor blockers (ARB) with circulating plasma concentrations of ACE2 in a large cohort of patients with established cardiovascular disease (n = 1864) or cardiovascular risk factors (n = 2144) but without a history of heart failure.; Angiotensin-converting enzyme 2 was measured in 4008 patients (median age 68, 33% women, 31% on ACE-inhibitors, 31% on ARB) using the SOMAscan proteomic platform (SomaLogic Inc, Colorado, USA). Plasma concentration of ACE2 was comparable in 1250 patients on ACE inhibitors (mean 5.99) versus patients without ACE inhibitors (mean 5.98, P = 0.54). Similarly, plasma concentration of ACE2 was comparable in 1260 patients on ARB (mean 5.99) versus patients without ARB (mean 5.98, P = 0.50). Plasma concentration of ACE2 was comparable in 2474 patients on either ACE inhibitors or ARB (mean 5.99) versus patients without ACE inhibitors or ARB (mean 5.98, P = 0.31). Multivariable quantile regression model analysis confirmed the lack of association between treatment with ACE inhibitors or ARB and ACE2 concentrations. Body mass index showed the only positive association with ACE2 plasma concentration (effect 0.015, 95% confidence interval 0.002 to 0.028, P = 0.024).; In a large cohort of patients with established cardiovascular disease or cardiovascular risk factors but without heart failure, ACE inhibitors and ARB were not associated with higher plasma concentrations of ACE2

Gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and cardiovascular risk in patients with suspected functionally relevant coronary artery disease (fCAD)

Trimethylamine N-oxide (TMAO) has been associated with cardiovascular outcomes. However, the diagnostic value of TMAO and its precursors have not been assessed for functionally relevant coronary artery disease (fCAD) and its prognostic potential in this setting needs to be evaluated.; Among 1726 patients with suspected fCAD serum TMAO, and its precursors betaine, choline and carnitine, were quantified using liquid chromatography tandem mass spectrometry. Diagnosis of fCAD was performed by myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography blinded to marker concentrations. Incident all-cause death, cardiovascular death (CVD) and myocardial infarction (MI) were assessed during 5-years follow-up.; Concentrations of TMAO, betaine, choline and carnitine were significantly higher in patients with fCAD versus those without (TMAO 5.33 μM vs 4.66 μM, p < 0.001); however, diagnostic accuracy was low (TMAO area under the receiver operating curve [AUC]: 0.56, 95% CI [0.53-0.59], p < 0.001). In prognostic analyses, TMAO, choline and carnitine above the median were associated with significantly (p < 0.001 for all) higher cumulative events for death and CVD during 5-years follow-up. TMAO remained a significant predictor for death and CVD even in full models adjusted for renal function (HR = 1.58 (1.16, 2.14), p = 0.003; HR = 1.66 [1.07, 2.59], p = 0.025). Prognostic discriminative accuracy for TMAO was good and robust for death and CVD (2-years AUC for CVD 0.73, 95% CI [0.65-0.80]).; TMAO and its precursors, betaine, choline and carnitine were significantly associated with fCAD, but with limited diagnostic value. TMAO was a strong predictor for incident death and CVD in patients with suspected fCAD.; NCT01838148

Incremental Value of Biomarkers in the Diagnosis of Functionally Relevant Coronary Artery Disease and the Prognosis of Adverse Cardiovascular Outcomes

Summary The most common of heart diseases is coronary artery disease (CAD). Atherosclerosis is the underlying cause of CAD, which leads to plaque formation through an orchestrated inflammatory process. Consequently, blood and oxygen flow to the heart become limited. This can lead to chest pain and potentially a heart attack. CAD make up the largest portion of deaths caused by cardiovascular diseases, which are the leading cause of death world-wide. These numbers are inclining as the prevalence of cardiovascular risk factors, such as diabetes mellitus, obesity and lack of physical exercise are on the rise. However, according to the WHO, 75% of major adverse cardiac events (MACE) related to CAD can be prevented if the right interventions are incorporated. Therefore, the early and accurate detection of especially functional relevant CAD (fCAD), defined as exercise-induced myocardial ischemia, belongs to most important tasks in modern medicine. The current gold-standard for the non-invasive detection of CAD are cardiac imaging techniques. These imaging modalities, however, are not widely available in all health care settings and carry along an array of challenges: they require specialist referral, are costly and associated with rare, but potentially serious adverse events including radiation-induced cancer. Therefore, it is of great interest and importance to find alternatives in guiding the diagnosis of CAD. Biomarkers, being intrinsically minimally-invasive, bearing less risks and comparably cheap, may combat those issues that are related to imaging techniques. While current guidelines, however, suggest multiple biomarkers to help understanding the influence of co-morbidities on CAD and to estimate cardiovascular risk factors, to date, there is still no biomarker that can be recommended for the diagnosis of CAD. Therefore, it is important to search for and evaluate novel biomarkers that may facilitate the diagnosis of CAD, assess their incremental value and to evaluate their prognostic value on adverse cardiovascular outcomes. In the frame of the Basel VIII study, patients with suspected fCAD referred to the University Hospital of Basel for rest/stress cardiac imaging were recruited. Biomarkers were measured in those patients and the clinical utility of those markers was assessed by evaluating the diagnostic and prognostic value of those biomarkers with the aim to facilitate detection of fCAD. Finally, we see that the biomarkers analysed in this PhD project display a prognostic value for adverse cardiovascular outcomes, it remains a challenging task to find suitable biomarkers for the diagnosis of fCAD

Potential of Acrylamide Formation, Sugars, and Free Asparagine in Potatoes: A Comparison of Cultivars and Farming Systems

Glucose, fructose, sucrose, free asparagine, and free glutamine were analyzed in 74 potato samples from 17 potato cultivars grown in 2002 at various locations in Switzerland and different farming systems. The potential of these potatoes for acrylamide formation was measured with a standardized heat treatment. These potentials correlated well with the product of the concentrations of reducing sugars and asparagine. Glucose and fructose were found to determine acrylamide formation. The cultivars showed large differences in their potential of acrylamide formation which was primarily related to their sugar contents. Agricultural practice neither influenced sugars and free asparagine nor the potential of acrylamide formation. It is concluded that acrylamide contents in potato products can be substantially reduced primarily by selecting cultivars with low concentrations of reducing sugars

Artificial intelligence to improve ischemia prediction in Rubidium Positron Emission Tomography—a validation study

Background: Patients are referred to functional coronary artery disease (CAD) testing based on their pre-test probability (PTP) to search for myocardial ischemia. The recommended prediction tools incorporate three variables (symptoms, age, sex) and are easy to use, but have a limited diagnostic accuracy. Hence, a substantial proportion of non-invasive functional tests reveal no myocardial ischemia, leading to unnecessary radiation exposure and costs. Therefore, preselection of patients before ischemia testing needs to be improved using a more predictive and personalised approach. Aims: Using multiple variables (symptoms, vitals, ECG, biomarkers), artificial intelligence–based tools can provide a detailed and individualised profile of each patient. This could improve PTP assessment and provide a more personalised diagnostic approach in the framework of predictive, preventive and personalised medicine (PPPM). Methods: Consecutive patients (n = 2417) referred for Rubidium-82 positron emission tomography were evaluated. PTP was calculated using the ESC 2013/2019 and ACC 2012/2021 guidelines, and a memetic pattern–based algorithm (MPA) was applied incorporating symptoms, vitals, ECG and biomarkers. Five PTP categories from very low to very high PTP were defined (i.e., &lt; 5%, 5–15%, 15–50%, 50–85%, &gt; 85%). Ischemia was defined as summed difference score (SDS) = 2. Results: Ischemia was present in 37.1%. The MPA model was most accurate to predict ischemia (AUC: 0.758, p &lt; 0.001 compared to ESC 2013, 0.661; ESC 2019, 0.673; ACC 2012, 0.585; ACC 2021, 0.667). Using the &lt; 5% threshold, the MPA’s sensitivity and negative predictive value to rule out ischemia were 99.1% and 96.4%, respectively. The model allocated patients more evenly across PTP categories, reduced the proportion of patients in the intermediate (15–85%) range by 29% (ACC 2012)–51% (ESC 2019), and was the only tool to correctly predict ischemia prevalence in the very low PTP category. Conclusion: The MPA model enhanced ischemia testing according to the PPPM framework: 1)The MPA model improved individual prediction of ischemia significantly and could safely exclude ischemia based on readily available variables without advanced testing (“predictive”).2)It reduced the proportion of patients in the intermediate PTP range. Therefore, it could be used as a gatekeeper to prevent patients from further unnecessary downstream testing, radiation exposure and costs (“preventive”).3)Consequently, the MPA model could transform ischemia testing towards a more personalised diagnostic algorithm (“personalised”)

Using High-Sensitivity Cardiac Troponin for the Exclusion of Inducible Myocardial Ischemia in Symptomatic Patients: A Cohort Study.

Background The optimal noninvasive method for surveillance in symptomatic patients with stable coronary artery disease (CAD) is unknown. Objective To apply a novel approach using very low concentrations of high-sensitivity cardiac troponin I (hs-cTnI) for exclusion of inducible myocardial ischemia in symptomatic patients with CAD. Design Prospective diagnostic cohort study. (ClinicalTrials.gov: NCT01838148). Setting University hospital. Patients 1896 consecutive patients with CAD referred with symptoms possibly related to inducible myocardial ischemia. Measurements Presence of inducible myocardial ischemia was adjudicated using myocardial perfusion imaging with single-photon emission computed tomography, as well as coronary angiography and fractional flow reserve measurements where available. Staff blinded to adjudication measured circulating hs-cTn concentrations. An hs-cTnI cutoff of 2.5 ng/L, derived previously in mostly asymptomatic patients with CAD, was assessed. Predefined target performance criteria were at least 90% negative predictive value (NPV) and at least 90% sensitivity for exclusion of inducible myocardial ischemia. Sensitivity analyses were based on measurements with an hs-cTnT assay and an alternative hs-cTnI assay with even higher analytic sensitivity (limit of detection, 0.1 ng/L). Results Overall, 865 patients (46%) had inducible myocardial ischemia. The hs-cTnI cutoff of 2.5 ng/L provided an NPV of 70% (95% CI, 64% to 75%) and a sensitivity of 90% (CI, 88% to 92%) for exclusion of inducible myocardial ischemia. No hs-cTnI cutoff reached both performance characteristics predefined as targets. Similarly, using the alternative assays for hs-cTnI or hs-cTnT, no cutoff achieved the target performance: hs-cTnT concentrations less than 5 ng/L yielded an NPV of 66% (CI, 59% to 72%), and hs-cTnI concentrations less than 2 ng/L yielded an NPV of 68% (CI, 62% to 74%). Limitation Data were generated in a large single-center diagnostic study using central adjudication. Conclusion In symptomatic patients with CAD, very low hs-cTn concentrations, including hs-cTnI concentrations less than 2.5 ng/L, do not generally allow users to safely exclude inducible myocardial ischemia. Primary Funding Source European Union, Swiss National Science Foundation, Kommission für Technologie und Innovation (Innosuisse), Swiss Heart Foundation, Cardiovascular Research Foundation Basel, University of Basel, University Hospital Basel, Roche, Abbott, and Singulex

Clinical utility of circulating interleukin-6 concentrations in the detection of functionally relevant coronary artery disease.

BACKGROUND Inflammation plays a major role in the pathogenesis of coronary artery disease (CAD). METHODS We hypothesized, that quantifying inflammation by measuring circulating interleukin-6 concentrations help in the diagnosis and/or prediction of functionally relevant CAD. Among consecutive patients with symptoms suggestive of CAD, functionally relevant CAD was adjudicated in two domains: first, diagnosis according to myocardial perfusion single photon emission tomography (MPI-SPECT) and coronary angiography; second, cardiovascular death and all-cause death during 2-years follow-up. Adjudication was done blinded to the interleukin-6 concentrations. RESULTS Among 1553 patients, symptoms were adjudicated to be causally related to CAD in 43% (665/1553). Interleukin-6 concentrations were higher in patients with functionally relevant CAD as compared to those without (1.56 pg/mL versus 1.30 pg/mL, p < 0.001), but overall had only low-to-modest diagnostic accuracy (area under the curve [AUC]: 0.57, 95%CI 0.55-0.61) and were no independent predictor of functionally relevant CAD after multivariable adjustment (p = 0.068). Interleukin-6 concentrations had moderate-to-high accuracy in the prediction of cardiovascular death (AUC 0.75, 95%CI 0.69-0.82) and all-cause death (AUC 0.72, 95%CI 0.66-0.78) at 2-years, and remained a significant predictor after multivariable adjustment (p < 0.001). Compared to patients with interleukin-6 concentrations below the median (1.41 pg/mL), patients with concentrations above the median had a significantly higher cumulative incidence of cardiovascular death (1% vs. 4%, log-rank p < 0.001) and all-cause death (2% vs. 8%, log-rank p < 0.001) at 2 years. CONCLUSION Interleukin-6 concentrations are strong and independent predictors of cardiovascular death and all-cause death