High-Sensitivity Cardiac Troponin Assays: Ready for Prime Time!

Rapid and accurate triage of patients presenting with chest pain to an emergency department (ED) is critical to prevent ED overcrowding and unnecessary resource use in individuals at low risk of acute myocardial infarction (AMI) and to efficiently and effectively guide patients at high risk to definite therapy. The use of biomarkers for rule-out or rule-in of suspected AMI has evolved substantially over the last several decades. Previously well-established biomarkers have been replaced by cardiac troponin (cTn). High-sensitivity cTn (hs-cTn) assays represent the newest generation of cTn assays and offer tremendous advantages, including improved sensitivity and precision. Still, implementation of these assays in the United States lags behind several other areas of the world. Within this educational review, we discuss the evolution of biomarker testing for detection of myocardial injury, address the specifics of hs-cTn assays and their recommended use within triage algorithms, and highlight potential challenges in their use. Ultimately, we focus on implementation strategies for hs-cTn assays, as they are now clearly ready for prime time.

Pharmacologic modulation of intracellular Na+ concentration with ranolazine impacts inflammatory response in humans and mice.

Changes in Ca2+ influx during proinflammatory stimulation modulates cellular responses, including the subsequent activation of inflammation. Whereas the involvement of Ca2+ has been widely acknowledged, little is known about the role of Na+. Ranolazine, a piperazine derivative and established antianginal drug, is known to reduce intracellular Na+ as well as Ca2+ levels. In stable coronary artery disease patients (n = 51) we observed reduced levels of high-sensitive C-reactive protein (CRP) 3 mo after the start of ranolazine treatment (n = 25) as compared to the control group. Furthermore, we found that in 3,808 acute coronary syndrome patients of the MERLIN-TIMI 36 trial, individuals treated with ranolazine (1,934 patients) showed reduced CRP values compared to placebo-treated patients. The antiinflammatory effects of sodium modulation were further confirmed in an atherosclerotic mouse model. LDL-/- mice on a high-fat diet were treated with ranolazine, resulting in a reduced atherosclerotic plaque burden, increased plaque stability, and reduced activation of the immune system. Pharmacological Na+ inhibition by ranolazine led to reduced express of adhesion molecules and proinflammatory cytokines and reduced adhesion of leukocytes to activated endothelium both in vitro and in vivo. We demonstrate that functional Na+ shuttling is required for a full cellular response to inflammation and that inhibition of Na+ influx results in an attenuated inflammatory reaction. In conclusion, we demonstrate that inhibition of Na+-Ca2+ exchange during inflammation reduces the inflammatory response in human endothelial cells in vitro, in a mouse atherosclerotic disease model, and in human patients.

When cardiovascular medicines should be discontinued.

An integral component of the practice of medicine is focused on the initiation of medications, based on clinical practice guidelines and underlying trial evidence, which usually test the addition of novel medications intended for life-long use in short-term clinical trials. Much less attention is given to the question of medication discontinuation, especially after a lengthy period of treatment, during which patients age gets older and diseases may either progress or new diseases may emerge. Given the paucity of data, clinical practice guidelines offer little to no guidance on when and how to deprescribe cardiovascular medications. Such decisions are often left to the discretion of clinicians, who, together with their patients, express concern of potential adverse effects of medication discontinuation. Even in the absence of adverse effects, the continuation of medications without any proven effect may cause harm due to drug-drug interactions, the emergence of polypharmacy, and additional preventable spending to already strained health systems. Herein, several cardiovascular medications or medication classes are discussed that in the opinion of this author group should generally be discontinued, either for the prevention of potential harm, for a lack of benefit, or for the availability of better alternatives.

Drug development for major chronic health conditions-aligning with growing public health needs: Proceedings from a multistakeholder think tank.

The global pharmaceutical industry portfolio is skewed towards cancer and rare diseases due to more predictable development pathways and financial incentives. In contrast, drug development for major chronic health conditions that are responsible for a large part of mortality and disability worldwide is stalled. To examine the processes of novel drug development for common chronic health conditions, a multistakeholder Think Tank meeting, including thought leaders from academia, clinical practice, non-profit healthcare organizations, the pharmaceutical industry, the Food and Drug Administration (FDA), payors as well as investors, was convened in July 2022. Herein, we summarize the proceedings of this meeting, including an overview of the current state of drug development for chronic health conditions and key barriers that were identified. Six major action items were formulated to accelerate drug development for chronic diseases, with a focus on improving the efficiency of clinical trials and rapid implementation of evidence into clinical practice.

Effect of albiglutide on cardiovascular outcomes in older adults: A post hoc analysis of a randomized controlled trial.

AIM: To analyse the effects of albiglutide, a glucagon-like peptide 1 receptor agonist, on cardiovascular outcomes in older adults aged ≥65 years with type 2 diabetes and cardiovascular disease who participated in the Harmony Outcomes trial (NCT02465515). MATERIALS AND METHODS: We conducted a post hoc analysis of the primary endpoint of the Harmony Outcomes trial-time to first occurrence of a major adverse cardiovascular event-in subgroups of participants aged <65 and ≥65 years and <75 and ≥75 years at baseline. Hazard ratios and 95% confidence intervals (CIs) were generated using Cox proportional hazards regression. RESULTS: The analysis population included 9462 Harmony Outcomes participants, including 4748 patients ≥65 and 1140 patients ≥75 years at baseline. Hazard ratios for the prevention of major adverse cardiovascular events were 0.66 (95% CI, 0.53-0.82) in persons <65 and 0.86 (95% CI, 0.71-1.04) in those ≥65 years (age interaction p = .07), and 0.78 (95% CI, 0.67-0.91) in <75 and 0.70 (95% CI, 0.48-1.01) in ≥75 year age groups (interaction p = .6). When analysed as a continuous variable, age did not modify the effect of albiglutide on the primary endpoint. CONCLUSIONS: This post hoc analysis adds to the body of literature showing that glucagon-like peptide 1 receptor agonists added to standard type 2 diabetes therapy safely reduce the incidence of cardiovascular events in older adults with established cardiovascular disease. In this analysis, the risk-benefit profile was similar between younger and older age groups treated with albiglutide.

Moderna COVID-19 vaccine was linked to myocarditis or myopericarditis at 28 d (4.2 events/100 000 persons).

SOURCE CITATION: Husby A, Hansen JV, Fosbøl E, et al. SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study. BMJ. 2021;375:e068665. 34916207.

In older persons at risk for dementia, a multidomain approach reduced stroke and transient ischemic attack.

SOURCE CITATION: Lehtisalo J, Rusanen M, Solomon A, et al. Effect of a multi-domain lifestyle intervention on cardiovascular risk in older people: the FINGER trial. Eur Heart J. 2022. [Epub ahead of print.] 35051281.

In older men, an invitation for comprehensive CV screening did not reduce death at 5.6 y.

SOURCE CITATION: Lindholt JS, Søgaard R, Rasmussen LM, et al. Five-year outcomes of the Danish Cardiovascular Screening (DANCAVAS) trial. N Engl J Med. 2022;387:1385-94. 36027560.

Landiolol for refractory tachyarrhythmias in the intensive care unit: case reports.

Tachyarrhythmias are common complications of critically ill patients treated on intensive care units. Landiolol is an ultra-short acting beta-blocker with a very high beta1-selectivity. Therefore, landiolol effectively reduces heart rate with only minimal negative effects on blood pressure and inotropy. This article describes two cases of successful treatment of supraventricular and ventricular tachycardias with landiolol in critically ill patients.

The prognostic value of serum amyloid A for long-term mortality among patients with subclinical carotid atherosclerosis.

BACKGROUND AND PURPOSE: Despite extensive research in the last decade, the role of serum amyloid A (SAA) in atherogenesis remains highly controversial. The aim of this study was therefore to assess whether SAA is associated with long-term mortality in patients with subclinical carotid artery disease. METHODS: One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. RESULTS: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Patients who died within the follow-up period had significantly higher baseline SAA serum levels compared to those who survived (12.9 vs 9.5 mg/dL; P < 0.001). In univariable Cox regression analysis, the risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of SAA (crude hazard ratio for cardiovascular mortality per increase of 1 SD of SAA levels was 1.14, 95% CI 1.08-1.22], P < 0.0001). However, SAA lost its significance after adjusting for high-sensitivity C-reactive protein (hsCRP), suggesting that SAA might not be directly associated with atherogenesis, but rather be a mere reflection of the individual patient's inflammatory status. CONCLUSIONS: Serum amyloid A is not independently associated with (cardiovascular) mortality in patients with subclinical carotid atherosclerosis.

Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue.

Interleukin (IL)-33 is a member of the IL-1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL-33 by 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL-33 mRNA and intracellular IL-33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL-33 was also up-regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y-27632, and by latrunculin B, but statin-induced IL-33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U-46619. The IL-33 promoter was 2.3-fold more accessible in statin-treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin-treated patients IL-33 protein was up-regulated as compared with the hearts of non-statin-treated patients (P = 0.048). As IL-33 was previously shown to exert cardioprotective effects, one could speculate that such up-regulation of IL-33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.

Predictive value of low interleukin-33 in critically ill patients.

Patients admitted to a medical intensive care unit (ICU) are characterized by an activated immune system and exhibit a high mortality rate irrespective of the underlying cause of admission. Interleukin (IL)-33 has been shown to be protective in experimental sepsis models and it has been demonstrated that circulating levels of its "decoy" receptor soluble ST2 (sST2) are associated with outcome in critically ill patients. The aim of the present study was to investigate whether circulating IL-33 is associated with 30-day mortality in patients admitted to a medical ICU. In this prospective, observational study, both IL-33 and sST2 levels were assessed in 223 consecutive patients at ICU admission using specific enzyme-linked immunosorbent assays (ELISAs). During the 30-day follow-up, 58 patients (26%) died. Circulating IL-33 was detectable in 166 patients and in 57 patients, serum IL-33 was below the detection limit. Both detectable IL-33 and sST2 below the median were strong predictors of survival in critically ill patients independent of acute physiology and chronic health evaluation II (APACHE II) score. IL-33 and sST2 predicted risk independent from each other. Patients with both, non-detectable levels of IL-33 and sST2 levels above the median, showed a dramatically increased mortality risk (HR 6.9 95% CI 3.0-16.2; p<0.001). Low levels of IL-33 and increased levels of sST2 predict mortality risk in critically ill patients independent from each other and APACHE II score. Both together showed additive predictive value suggesting a pathogenic role of the IL-33/ST2 system in critically ill patients.

Urokinase plasminogen activator protects cardiac myocytes from oxidative damage and apoptosis via hOGG1 induction.

The role of uPA in tissue remodeling and cell migration is already well established. In addition, uPA was reported to stabilize p53, a key cell cycle control, DNA repair and apoptosis initiation protein. We aimed to determine the role of uPA-uPAR signaling towards cell survival or apoptosis in human adult cardiac myocytes (HACM). HACM were stimulated with uPA and DNA damage was inflicted by incubating cells with 200 µM H2O2. To analyze for apoptotic cells we applied TUNEL staining. Oxidative damage foci were analyzed by staining for 8-oxoguanine base pairs. In vivo qPCR analysis from RNA extracted from failing human hearts demonstrated a close relation of uPA with apoptosis and the p53 pathway. Furthermore, we observed a close correlation of uPA and p53 protein in homogenized tissue lysates. In vitro studies revealed that uPA preincubation protected HACM from oxidative damage induced cell death and reduced oxidative damage foci. uPA protection is independent of its catalytic activity, as the amino terminal fragment of uPA showed similar protection. A key enzyme for repairing oxidative DNA damage is the p53 target hOGG1. We found a significant increase of hOGG1 after pretreatment of HACM with uPA. Knockdown of hOGG1 completely abrogated the protective effect of uPA. We conclude that uPA might have a tissue protective role in human hearts besides its role in tissue remodeling. Tissue protection is mediated by the DNA repair protein hOGG1. This might be beneficial during tissue remodeling and thus could be a target for therapeutic approaches in the diseased heart.

Red cell distribution width and mortality in carotid atherosclerosis.

BACKGROUND: Red cell distribution width (RDW) is associated with morbidity and mortality in chronic cardiac disease. The aim of the present study was to investigate the role of RDW as a predictor of adverse outcome in patients with carotid atherosclerosis. MATERIALS AND METHODS: We prospectively studied 1065 of 1286 consecutive patients with neurological asymptomatic carotid artery stenosis as assessed by duplex Doppler sonography. The study end points were all-cause mortality and cardiovascular mortality respectively. RESULTS: During a median follow-up time of 6·2 years (interquartile range 5·9-6·6), corresponding to 5551 overall person-years, 275 patients (25·8%) died. Of them, 182 patients (66·2%) died due to cardiovascular causes. RDW was significantly associated with adverse outcome. In a continuous multivariate Cox regression analysis, the adjusted hazard ratio for each per cent increase in RDW was 1·39 (95% CI 1·27-1·53; P < 0·001) for all-cause and 1·43 (95% CI 1·28-1·60; P < 0·001) for cardiovascular mortality respectively. Kaplan-Meier estimates showed a gradual relationship between increasing quartiles of RDW and death (log rank P < 0·001). Adjusted hazard ratios for all-cause death ranged from 0·89 to 1·94 for the highest vs. the lowest quartile (P < 0·001 for trend) and for cardiovascular death from 1·08 to 2·34 for the highest vs. the lowest quartile (P < 0·001 for trend) respectively. CONCLUSIONS: Red cell distribution width was significantly and independently associated with all-cause and cardiovascular death in patients with asymptomatic carotid atherosclerosis.

Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients.

OBJECTIVES: Despite underlying pathologies leading to ICU admittance are heterogeneous, many patients develop a systemic inflammatory response syndrome often in the absence of microbial pathogens. Mitochondrial DNA that shows similarities to bacterial DNA may be released after tissue damage and activates the innate immune system by binding to toll-like receptor-9 on immune cells. The aim of this study was to analyze whether levels of mitochondrial DNA are associated with 30-day survival and whether this predictive value is modified by the expression of its receptor toll-like receptor-9. DESIGN: Single-center, prospective, observational study. SETTING: A tertiary ICU in a university hospital. PATIENTS: Two hundred twenty-eight consecutive patients admitted to a medical ICU between August 2012 and August 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood was taken within 24 hours after ICU admission, and the levels of circulating mitochondrial DNA were quantified by real-time polymerase chain reaction. Toll-like receptor-9 expression in monocytes was measured by flow cytometry. Median acute physiology and chronic health evaluation II score was 20, and 30-day mortality was 25%. Median mitochondrial DNA levels at admission were significantly higher in nonsurvivors when compared with survivors (26.9, interquartile range = 11.2-60.6 ng/mL vs 19.7, interquartile range = 9.5-34.8 ng/mL; p < 0.05). Patients with plasma levels of mitochondrial DNA in the highest quartile (mitochondrial DNA > 38.2 ng/mL) had a 2.6-fold higher risk (p < 0.001) of dying, independently of age, gender, diagnosis, and acute physiology and chronic health evaluation II score. Mitochondrial DNA improved the c-statistic of acute physiology and chronic health evaluation II score (p < 0.05) and showed enhancement in individual risk prediction indicated by a net reclassification improvement of 32.3% (p < 0.05). Stratification of patients according to toll-like receptor-9 expression above/below median demonstrated that only patients with high expression of toll-like receptor-9 showed an increased risk associated with increased mitochondrial DNA levels (odds ratio, 2.7; p < 0.01), whereas circulating mitochondrial DNA was not associated with mortality in patients with low toll-like receptor-9 expression (odds ratio, 1.1; p = 0.98). CONCLUSIONS: Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.

Repeated occurrence of severe hypotension associated with azithromycin infusion in a patient with fulminant myocarditis: a case report.

Background: Intravenous administration of azithromycin has been linked to severe hypotension in some case reports in the past. We report a further case of profound shock requiring excessive use of vasopressors and extracorporeal membrane oxygenation (ECMO). Case summary: An 18-year-old Caucasian male was admitted due to fulminant myocarditis and signs of cardiogenic shock. He had to be put on venoarterial ECMO only hours after admission. Due to the occurrence of disseminated intravascular coagulation and heparin-induced thrombocytopenia, haemodynamic support was discontinued on Day 8. On Day 11 of his stay, the patient started to exhibit signs of severe infection and a single 1500 mg dose of azithromycin was prescribed. Immediately after starting the infusion, the patient developed profound hypotension and signs of cardiogenic shock. Consecutively, venoarterial ECMO had to be re-established, and the azithromycin infusion was stopped in the process. It took the restart of the compound to recognize the connection between the administration of the therapy and the occurrence of cardiogenic shock. After discontinuing azithromycin, no further sudden hypotensive episodes were recorded, and the patient received left ventricular assist device implantation as a bridge to recovery or transplant. Discussion: Rapid-onset hypotension appears to be a very rare but important adverse drug reaction associated with intravenous administration of azithromycin. Factors such as preceding infection and reduced biventricular function may facilitate the described occurrence.