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.

Mechanical Circulatory Support Systems in Fulminant Myocarditis: Recent Advances and Outlook.

Background: Fulminant myocarditis (FM) constitutes a severe and life-threatening form of acute cardiac injury associated with cardiogenic shock. The condition is characterised by rapidly progressing myocardial inflammation, leading to significant impairment of cardiac function. Due to the acute and severe nature of the disease, affected patients require urgent medical attention to mitigate adverse outcomes. Besides symptom-oriented treatment in specialised intensive care units (ICUs), the necessity for temporary mechanical cardiac support (MCS) may arise. Numerous patients depend on these treatment methods as a bridge to recovery or heart transplantation, while, in certain situations, permanent MCS systems can also be utilised as a long-term treatment option. Methods: This review consolidates the existing evidence concerning the currently available MCS options. Notably, data on venoarterial extracorporeal membrane oxygenation (VA-ECMO), microaxial flow pump, and ventricular assist device (VAD) implantation are highlighted within the landscape of FM. Results: Indications for the use of MCS, strategies for ventricular unloading, and suggested weaning approaches are assessed and systematically reviewed. Conclusions: Besides general recommendations, emphasis is put on the differences in underlying pathomechanisms in FM. Focusing on specific aetiologies, such as lymphocytic-, giant cell-, eosinophilic-, and COVID-19-associated myocarditis, this review delineates the indications and efficacy of MCS strategies in this context.

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.

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.

Association of Periprocedural Inflammatory Activation With Increased Risk for Early Coronary Stent Thrombosis.

BACKGROUND: Stent thrombosis is a rare but deleterious event. Routine coronary angiography with percutaneous coronary intervention (PCI) is often deferred in the presence of laboratory markers of acute inflammation to prevent complications. The aim of this study was to investigate whether an acute inflammatory state is associated with an increased risk of early stent thrombosis. METHODS AND RESULTS: Within a prospective single-center registry, the association between preprocedural acute inflammatory activation, defined as C-reactive protein plasma levels >50 mg/L or a leukocyte count >12 g/L, and occurrence of early (≤30 days) stent thrombosis was evaluated. In total, 11 327 patients underwent PCI and of those, 6880 patients had laboratory results available. 49.6% of the study population received PCI for an acute coronary syndrome and 50.4% for stable ischemic heart disease. In patients with signs of acute inflammatory activation (24.9%), PCI was associated with a significantly increased risk for stent thrombosis (hazard ratio, 2.89; P<0.00001), independent of age, sex, kidney function, number and type of stents, presence of multivessel disease, choice of P2Y12 inhibitor, and clinical presentation. Elevated laboratory markers of acute inflammation were associated with the occurrence of stent thrombosis in both patients with acute coronary syndrome (hazard ratio, 2.63; P<0.001) and in patients with stable ischemic heart disease (hazard ratio, 3.57; P<0.001). CONCLUSIONS: An acute inflammatory state at the time of PCI was associated with a significantly increased risk of early stent thrombosis. Evidence of acute inflammation should result in deferred PCI in elective patients, while future studies are needed for patients with acute coronary syndrome.

Decreased percentages of plasmacytoid dendritic cells predict survival in critically ill patients.

Critically ill patients admitted to intensive care units (ICUs) experience a broad variety of life-threatening conditions. Irrespective of the initial cause of hospitalization, many experience systemic immune dysregulation. Dendritic cells (DCs) are the most potent antigen-presenting cells and play a pivotal role in regulating the immune response by linking the innate to the adaptive immune system. The aim of this study was to analyze whether DCs or their respective subsets are associated with 30-d mortality in an unselected patient cohort admitted to a medical ICU with a cardiovascular focus. A total of 231 patients were included in this single-center prospective observational study. Blood was drawn at admission and after 72 h. Subsequently, flow cytometry was utilized for the analysis of DCs and their respective subsets. In the total cohort, low percentages of DCs were significantly associated with sepsis, respiratory failure, and septic shock. In particular, a significantly lower percentage of circulating plasmacytoid DCs (pDCs) was found to be a strong and independent predictor of 30-d mortality after adjustment for demographic and clinical variables with an hazard ratio of 4.2 (95% confidence interval: 1.3-13.3, P = 0.015). Additionally, low percentages of pDCs were correlated with additional markers of inflammation and organ dysfunction. In conclusion, we observed low percentages of DCs in patients admitted to an ICU experiencing sepsis, respiratory failure, and cardiogenic shock, suggesting their depletion as a contributing mechanism for the development of immune paralysis. In our cohort, pDCs were identified as the most robust subset to predict 30-d mortality.

Effects of albiglutide on myocardial infarction and ischemic heart disease outcomes in patients with type 2 diabetes and cardiovascular disease in the Harmony Outcomes trial.

AIMS: Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide. METHODS AND RESULTS: Harmony Outcomes was an event-driven, multicenter, double-blind, placebo-controlled trial involving 9 463 patients > 40years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction or stroke. Within this post-hoc analysis, the effects of albiglutide on myocardial infarction subtypes and other ischemic endpoints were analyzed.During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one myocardial infarction, with 72 patients having more than one event. Treatment with albiglutide reduced both first events (hazard ratio (HR)0.75 (0.62-0.91)) and overall events (HR0.75 (0.61-0.91)) as well as first type 1 (HR0.73 (0.57-0.92)) and type 2 myocardial infarctions (HR0.65 (0.46-0.92)). The effect of albiglutide treatment was consistent for ST-segment elevation (HR0.69 (0.38-1.26)) and non-ST elevation (HR0.86 (0.66-1.2) myocardial infarction. CONCLUSIONS: Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in myocardial infarction that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischemic events in patients with type 2 diabetes.

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.

Research Priorities in Critical Care Cardiology: JACC Expert Panel.

Over the last several decades, the cardiac intensive care unit (CICU) has seen a substantial evolution in the patient population, comorbidities, and diagnoses. However, the generation of high-quality evidence to manage these complex and critically ill patients has been slow. Given the scarcity of clinical trials focused on critical care cardiology (CCC), CICU clinicians are often left to extrapolate from studies that either exclude or poorly represent the patient population admitted to CICUs. The lack of high-quality evidence and limited guidance from society guidelines has led to significant variation in practice patterns for many of the most common CICU diagnoses. Several barriers, both common to critical care research and unique to CCC, have impeded progress. In this multinational perspective, we describe key areas of priority for CCC research, current challenges for investigation in the CICU, and essential elements of a path forward for the field.

Public Out-of-Hospital Cardiac Arrest in Residential Neighborhoods.

BACKGROUND: Although one-half of all public out-of-hospital cardiac arrests (OHCAs) occur outside private homes in residential neighborhoods, their characteristics and outcomes remain unexplored. OBJECTIVES: The authors assessed interventions before ambulance arrival and survival for public OHCA patients in residential neighborhoods. METHODS: Public OHCAs from Vienna (2018-2021) and Copenhagen (2016-2020) were designated residential neighborhoods or nonresidential areas. Interventions (cardiopulmonary resuscitation [CPR], automated external defibrillator [AED] attached, and defibrillation) and 30-day survival were compared using a generalized estimation equation model adjusted for age and time of day and presented as ORs. RESULTS: We included 1,052 and 654 public OHCAs from Vienna and Copenhagen, respectively, and 68% and 55% occurred in residential neighborhoods, respectively. The likelihood of CPR, defibrillation, and survival in residential neighborhoods vs nonresidential areas (reference) were as follows: CPR Vienna, 73% vs 78%, OR: 0.78 (95% CI: 0.57-1.06), CPR Copenhagen, 83% vs 90%, OR: 0.54 (95% CI: 0.34-0.88), and CPR combined, 76% vs 84%, OR: 0.70 (95% CI: 0.53-0.90); AED attached Vienna, 36% vs 44%, OR: 0.69 (95% CI: 0.53-0.90), AED attached Copenhagen, 21% vs 43%, OR: 0.33 (95% CI: 0.24-0.48), and AED attached combined, 31% vs 44%, OR: 0.53 (95% CI: 0.42-0.65); defibrillation Vienna, 14% vs 20%, OR: 0.61 (95% CI: 0.43-0.87), defibrillation Copenhagen, 16% vs 36%, OR: 0.35 (95% CI: 0.24-0.51), and defibrillation combined, 15% vs 27%, OR: 0.46 (95% CI: 0.36-0.61); and 30-day survival rate Vienna, 21% vs 26%, OR: 0.84 (95% CI: 0.58-1.20), 30-day survival rate Copenhagen, 33% vs 44%, OR: 0.65 (95% CI: 0.47-0.90), and 30-day survival rate combined, 25% vs 36%, OR: 0.73 (95% CI: 0.58-0.93). CONCLUSIONS: Two-thirds of public OHCAs occurred in residential neighborhoods with fewer resuscitative efforts before ambulance arrival and lower survival than in nonresidential areas. Targeted efforts to improve early CPR and defibrillation for public OHCA patients in residential neighborhoods are needed.

Transcatheter interventions for left-sided valvular heart disease complicated by cardiogenic shock: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) in collaboration with the Association for Acute Cardiovascular Care (ACVC) and the ESC Working Group on Cardiovascular Surgery.

Valvular heart disease (VHD) is one of the most frequent causes of heart failure (HF) and is associated with poor prognosis, particularly among patients with conservative management. The development and improvement of catheter-based VHD interventions have broadened the indications for transcatheter valve interventions from inoperable/high-risk patients to younger/lower-risk patients. Cardiogenic shock (CS) associated with severe VHD is a clinical condition with a very high risk of mortality for which surgical treatment is often deemed a prohibitive risk. Transcatheter valve interventions might be a promising alternative in this setting given that they are less invasive. However, supportive scientific evidence is scarce and often limited to small case series. Current guidelines on VHD do not contain specific recommendations on how to manage patients with both VHD and CS. The purpose of this clinical consensus statement, developed by a group of international experts invited by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) Scientific Documents and Initiatives Committee, is to perform a review of the available scientific evidence on the management of CS associated with left-sided VHD and to provide a rationale and practical approach for the application of transcatheter valve interventions in this specific clinical setting.

Short-term toll-like receptor 9 inhibition leads to left ventricular wall thinning after myocardial infarction.

AIMS: Ischaemia-reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long-term consequence. The extent of neutrophil infiltration and neutrophil-mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll-like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor. METHODS AND RESULTS: Forty-nine male adult Sprague-Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30 min. Oligonucleotide (ODN) 2088, a toll-like receptor 9 (TLR9) antagonist, control-ODN, or DNase, were administered at the time of reperfusion and over 24 h via a mini-osmotic pump. The hearts were harvested 24 h or 4 weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4 weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P = 0.003) in association with drastically enhanced neutrophil infiltration (P = 0.005) and increased markers of tissue damage. Additionally, an up-regulation of the chemotactic receptor CXCR2 (P = 0.046) was found after TLR9 inhibition. No such effects were observed in control-ODN or DNase-treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury. CONCLUSIONS: Our data indicate a TLR9-dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down-regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR-/- mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24 h following IRI.

Data processing pipeline for cardiogenic shock prediction using machine learning.

Introduction: Recent advances in machine learning provide new possibilities to process and analyse observational patient data to predict patient outcomes. In this paper, we introduce a data processing pipeline for cardiogenic shock (CS) prediction from the MIMIC III database of intensive cardiac care unit patients with acute coronary syndrome. The ability to identify high-risk patients could possibly allow taking pre-emptive measures and thus prevent the development of CS. Methods: We mainly focus on techniques for the imputation of missing data by generating a pipeline for imputation and comparing the performance of various multivariate imputation algorithms, including k-nearest neighbours, two singular value decomposition (SVD)-based methods, and Multiple Imputation by Chained Equations. After imputation, we select the final subjects and variables from the imputed dataset and showcase the performance of the gradient-boosted framework that uses a tree-based classifier for cardiogenic shock prediction. Results: We achieved good classification performance thanks to data cleaning and imputation (cross-validated mean area under the curve 0.805) without hyperparameter optimization. Conclusion: We believe our pre-processing pipeline would prove helpful also for other classification and regression experiments.

Targeted Temperature Management After Out-of-Hospital Cardiac Arrest: Integrating Evidence Into Real World Practice.

Targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) has been a focus of debate in an attempt to improve post-arrest outcomes. Contemporary trials examining the role of TTM after cardiac arrest suggest that targeting normothermia should be the standard of care for initially comatose survivors of cardiac arrest. Differences in patient populations have been demonstrated across trials, and important subgroups may be under-represented in clinical trials compared with real-world registries. In this review, we aimed to describe the populations represented in international OHCA registries and to propose a pathway to integrate clinical trial evidence into practice. The patient case mix among registries including survivors to hospital admission was similar to the pivotal trials (shockable rhythm, witnessed arrest), suggesting reasonable external validity. Therefore, for the majority of OHCA, targeted normothermia should be the strategy of choice. There remains conflicting evidence for patients with a nonshockable rhythm, with no clear evidence-based justification for mild hypothermia over targeted normothermia.

Acute LDL-C reduction post ACS: strike early and strike strong: from evidence to clinical practice. A clinical consensus statement of the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Association of Preventive Cardiology (EAPC) and the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

After experiencing an acute coronary syndrome (ACS), patients are at a high risk of suffering from recurrent ischaemic cardiovascular events, especially in the very early phase. Low density lipoprotein-cholesterol (LDL-C) is causally involved in atherosclerosis and a clear, monotonic relationship between pharmacologic LDL-C lowering and a reduction in cardiovascular events post-ACS has been shown, a concept termed 'the lower, the better'. Current ESC guidelines suggest an LDL-C guided, step-wise initiation and escalation of lipid-lowering therapy (LLT). Observational studies consistently show low rates of guideline-recommended LLT adaptions and concomitant low rates of LDL-C target goal achievement, leaving patients at residual risk, especially in the vulnerable post-ACS phase. In addition to the well-established 'the lower, the better' approach, a 'strike early and strike strong' approach in the early post-ACS phase with upfront initiation of a combined lipid-lowering approach using high-intensity statins and ezetimibe seems reasonable. We discuss the rationale, clinical trial evidence and experience for such an approach and highlight existing knowledge gaps. In addition, the concept of acute initiation of PCSK9 inhibition in the early phase is reviewed. Ultimately, we focus on hurdles and solutions to provide high-quality, evidence-based follow-up care in post-ACS patients.

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.

RNA-targeted therapeutics in cardiovascular disease: the time is now.

Ribonucleic acid (RNA)-targeted therapeutics, including antisense oligonucleotide technologies as well as small interfering RNAs (siRNAs), represent a new class of medications that may overcome several of the disadvantages of small molecule drugs or monoclonal antibodies. Specifically, upstream targeting at the messenger RNA (mRNA) level renders any disease-related protein a potential target, even those pathways previously deemed 'undruggable'. Additional advantages include the comparably simple and cost-effective way of manufacturing and the long dosing intervals. A few agents are already approved and a wide array of cardiovascular drugs is in development, aimed at hypercholesterolaemia, hypertension, myocardial storage diseases, and the coagulation system. Here, we provide an update on the current status of RNA-targeted therapeutics in the cardiovascular arena.