Highlights From the Circulation Family of Journals.

Temporary mechanical circulatory support (MCS) devices provide hemodynamic assistance for shock refractory to pharmacological treatment. Most registries have focused on single devices or specific etiologies of shock, limiting data regarding overall practice patterns with temporary MCS in cardiac intensive care units. The CCCTN (Critical Care Cardiology Trials Network) is a multicenter network of tertiary CICUs in North America. Between September 2017 and September 2018, each center (n=16) contributed a 2-month snapshot of consecutive medical CICU admissions. Of the 270 admissions using temporary MCS, 33% had acute myocardial infarction-related cardiogenic shock (CS), 31% had CS not related to acute myocardial infarction, 11% had mixed shock, and 22% had an indication other than shock. Among all 585 admissions with CS or mixed shock, 34% used temporary MCS during the CICU stay with substantial variation between centers (range: 17%-50%). The most common temporary MCS devices were intraaortic balloon pumps (72%), Impella (17%), and veno-arterial extracorporeal membrane oxygenation (11%), although intraaortic balloon pump use also varied between centers (range: 40%-100%). Patients managed with intraaortic balloon pump versus other forms of MCS (advanced MCS) had lower Sequential Organ Failure Assessment scores and less severe metabolic derangements. Illness severity was similar at high- versus low-MCS utilizing centers and at centers with more advanced MCS use. There is wide variation in the use of temporary MCS among patients with shock in tertiary CICUs. While hospital-level variation in temporary MCS device selection is not explained by differences in illness severity, patient-level variation appears to be related, at least in part, to illness severity.

Cardiogenic shock (CS) is a complex clinical entity that continues to carry a high risk of mortality. The landscape of CS management has changed with the advent of several temporary mechanical circulatory support (MCS) devices designed to provide hemodynamic support. It remains challenging to understand the role of different temporary MCS devices in patients with CS, as many of these patients are critically ill, requiring complex care with multiple MCS device options. Each temporary MCS device can provide different types and levels of hemodynamic support. It is important to understand the risk/benefit profile of each one of them for appropriate device selection in patients with CS. MCS may be beneficial in CS patients through augmentation of cardiac output with subsequent improvement of systemic perfusion. Selecting the optimal MCS device depends on several variables including the underlying etiology of CS, clinical strategy of MCS use (bridge to recovery, bridge to transplant or durable MCS, or abridge to decision), amount of hemodynamic support needed, associated respiratory failure, and institutional preference. Furthermore, it is even more challenging to determine the appropriate time to escalate from one MCS device to another or combine different MCS devices. In this review, we discuss the current available data published in the literature on the management of CS and propose a standardized approach for escalation of MCS devices in patients with CS. Shock teams can play an important role to help in hemodynamic-guided management and algorithm-based step-by-step approach in early initiation and escalation of temporary MCS devices at different stages of CS. It is important to define the etiology of CS, and stage of shock and recognize univentricular vs biventricular shock for appropriate device selection and escalation of therapy.

Obesity and diets high in saturated fat increase the risk of arrhythmias and sudden cardiac death. However, the molecular mechanisms are not well understood. We hypothesized that an increase in dietary saturated fat could lead to abnormalities of calcium homeostasis and heart rhythm by a NOX2 (NADPH oxidase 2)-dependent mechanism. We investigated this hypothesis by feeding mice high-fat diets. In vivo heart rhythm telemetry, optical mapping, and isolated cardiac myocyte imaging were used to quantify arrhythmias, repolarization, calcium transients, and intracellular calcium sparks. We found that saturated fat activates NOX (NADPH oxidase), whereas polyunsaturated fat does not. The high saturated fat diet increased repolarization heterogeneity and ventricular tachycardia inducibility in perfused hearts. Pharmacological inhibition or genetic deletion of NOX2 prevented arrhythmogenic abnormalities in vivo during high statured fat diet and resulted in less inducible ventricular tachycardia. High saturated fat diet activates CaMK (Ca2+/calmodulin-dependent protein kinase) in the heart, which contributes to abnormal calcium handling, promoting arrhythmia. We conclude that NOX2 deletion or pharmacological inhibition prevents the arrhythmogenic effects of a high saturated fat diet, in part mediated by activation of CaMK. This work reveals a molecular mechanism linking cardiac metabolism to arrhythmia and suggests that NOX2 inhibitors could be a novel therapy for heart rhythm abnormalities caused by cardiac lipid overload.

Utilization and Outcomes of Temporary Mechanical Circulatory Support Devices in Cardiogenic Shock

AHA/ACCF Scientific Statement on the Evaluation of Syncope

ObjectiveTo highlight recent developments in the utilization of mechanical circulatory support (MCS) devices as bridge-to-transplant strategies and to discuss trends in MCS use following the changes to the United Network for Organ Sharing (UNOS) heart allocation system.BackgroundMCS devices have played an increasingly important role in the treatment of heart failure patients. Over the past several years, technological advancements have led to new developments in MCS devices and expanding indications for MCS use. In October of 2018, the UNOS heart allocation policy was revised to prioritize higher-urgency patients, including those supported with temporary MCS devices. Since then, changes in trends of MCS utilization have been observed.MethodsArticles from the PubMed database regarding the use of MCS devices as bridge-to-transplant strategies were reviewed.ConclusionsOver the past decade, utilization of temporary MCS devices, which include the intra-aortic balloon pump (IABP), percutaneous ventricular assist devices (pVADs), and extracorporeal membrane oxygenation (ECMO), has become increasingly common. Recent advancements in MCS include the development of pVADs that can fully unload the left ventricle (LV) as well as devices designed to provide right-sided support. Technological advancements in durable left ventricular assist devices (LVADs) have also led to improved outcomes both on the device and following heart transplantation. Following the 2018 UNOS heart allocation policy revision, the utilization of temporary MCS in advanced heart failure patients has further increased and the proportion of patients bridged directly from a temporary MCS device has exponentially risen. However, following the start of the COVID-19 pandemic, the trends have reversed, with a decrease in the percentage of patients bridged from a temporary MCS device. As long-term data following the allocation policy revision becomes available, future studies should investigate how trends in MCS use for patients with advanced heart failure continue to evolve.

Originally intended for life-saving salvage therapy, the use of temporary mechanical circulatory support (MCS) devices has become increasingly widespread in a variety of clinical settings in the contemporary era. Their use as a short-term, prophylactic support vehicle has expanded to include procedures in the catheterization laboratory, electrophysiology suite, operating room and intensive care unit. Accordingly, MCS device design and technology continue to develop at a rapid pace. In this Review, we describe the functionality, indications, management and complications associated with temporary MCS, together with scenario-specific utilization, goal-directed development and bioengineering of future devices. We address various considerations for the use of temporary MCS devices in both prophylactic and rescue scenarios, with input from stakeholders from various cardiovascular specialties, including interventional and heart failure cardiology, electrophysiology, cardiothoracic anaesthesiology, critical care and cardiac surgery.

To determine in arrhythmogenic right ventricular cardiomyopathy the value of QT interval dispersion for identifying the induction of sustained ventricular tachycardia in the electrophysiological study or the risk of sudden cardiac death. We assessed QT interval dispersion in the 12-lead electrocardiogram of 26 patients with arrhythmogenic right ventricular cardiomyopathy. We analyzed its association with sustained ventricular tachycardia and sudden cardiac death, and in 16 controls similar in age and sex. (mean +/- SD). QT interval dispersion: patients = 53.8+/-14.1 ms; control group = 35.0+/-10.6 ms, p = 0.001. Patients with induction of ventricular tachycardia: 52.5+/-13.8 ms; without induction of ventricular tachycardia: 57.5+/-12.8 ms, p =0.420. In a mean follow-up period of 41+/-11 months, five sudden cardiac deaths occurred. QT interval dispersion in this group was 62.0+/-17.8, and in the others it was 51.9+/-12.8 ms, p = 0.852. Using a cutoff > or =60 ms to define an increase in the degree of the QT interval dispersion, we were able to identify patients at risk of sudden cardiac death with a sensitivity of 60%, a specificity of 57%, and positive and negative predictive values of 25% and 85%, respectively. Patients with arrhythmogenic right ventricular cardiomyopathy have a significant increase in the degree of QT interval dispersion when compared with the healthy population. However it, did not identify patients with induction of ventricular tachycardia in the electrophysiological study, showing a very low predictive value for defining the risk of sudden cardiac death in the population studied.

Background: Cardiogenic shock (CS) affects up to 10% of hospitalized patients with acute myocardial infarction (AMI), leading to over 30% mortality despite treatment. In patients with AMI-CS refractory to vasopressors and inotropes, temporary mechanical circulatory support (MCS) devices have been used to provide hemodynamic support. Recently, Impella demonstrated significant mortality benefit in AMI-CS in the DanGer shock trial. However, it has not demonstrated such benefit over other devices, such as IABP and ECMO in other trials (ISAR-Shock, IMPRESS in Severe Shock, IMPELLA-STIC). Here we performed this network meta-analysis of all available studies including the DanGer shock trial comparing Impella with other MCS devices in AMI-CS patients. Method: We performed a Bayesian network meta-analysis to synthesize direct and indirect evidence from relevant studies published until April 2024 using PubMed, Embase, and Scopus databases comparing Impella with other strategies for treating AMI-CS patients. The primary outcome was a short-term mortality defined as in-hospital or 30-day mortality. This study is registered with PROSPERO, and data analysis was performed using the “BUGSnet” package in R. Result: Out of 7,211 studies, 17 were deemed eligible. These included five RCTs and 12 observational studies, encompassing 16,654 patients with AMI-CS assigned to 3 different MSC interventions: Impella, IABP, and ECMO in 9 different combinations or alone. Based on SUCRA value, IABP was the most effective strategy in regard to short-term mortality (73.46), long-term mortality (75.59), major bleeding (66.4), renal replacement therapy (73.02); Impella along with IABP for stroke (95.24), ischemic stroke (99.68), device-related bleeding (90.22), MI (94.38); ECMO for hemolysis (91.66); standard of care for peripheral ischemic complications (88.66), sepsis (78.71). In sub-analysis using the RCTs only, Impella was ranked best for short-term mortality (74.53). Conclusion: Based on the findings of this network meta-analysis, IABP could potentially provide both short-term and long-term mortality benefits, as well as reduce the risk of bleeding. Meanwhile, combining it with Impella could potentially reduce the risk of cerebral ischemia.

Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices.

Outcomes With Femoral IABP in Heart Failure and Acute Myocardial Infarction-Related Cardiogenic Shock.

case presentation: A 48-year-old woman presents with exertional dyspnea and recurrent syncope. One year earlier, a permanent pacemaker was placed after she complained of fatigue and was found to have high-grade atrioventricular block. Now, she has echocardiographic evidence of moderate to severe left ventricular (LV) systolic dysfunction with regional wall-motion abnormalities. Nuclear imaging is notable for heterogeneous myocardial uptake of technetium Tc99m sestamibi, and coronary angiography reveals widely patent epicardial vessels. Multiple episodes of nonsustained ventricular tachycardia (VT) are documented on continuous ECG monitoring. What are the diagnostic considerations for this patient, and what further evaluations are indicated? This patient presents with dilated cardiomyopathy (DCM) with electric instability (DCM+E), which we define as conduction disease and arrhythmia out of proportion to the severity of LV systolic dysfunction. Diverse causes can result in DCM+E and fall into general categories of inflammatory, infectious, hereditary, and infiltrative processes. Cardiac presentation associated with these conditions is distinct from more common causes of DCM such as ischemic heart disease, viral myocarditis, valvular dysfunction, pregnancy, or substance abuse. Clinical features that are suggestive of DCM+E include supraventricular arrhythmias or conduction disease that precedes cardiomyopathy, multiple VT morphologies, and features suggestive of ischemic heart disease (Q waves, regional wall-motion abnormalities, perfusion defects, ventricular aneurysm) in the absence of epicardial stenoses. In this Clinician Update, we focus on the diagnostic approach to patients with DCM+E. Emphasis is placed on diagnoses that are relatively common or for which the clinical management would be impacted significantly by recognition of the underlying cause. Ischemic heart disease may present with conduction disease and a high burden of arrhythmia, especially in the setting of acute myocardial ischemia/infarction. The exclusion of obstructive coronary artery disease is strongly recommended in patients with DCM+E because atherosclerosis is so prevalent, evidence-based treatment is readily available, and the …

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder in which cardiomyocytes lack structural integrity and signaling is compromised resulting in the disruption of normal rhythms and formation of fibrosis. Patients suffer from arrhythmia and are at increased risk of sudden cardiac death and heart failure. Previous work has demonstrated that heterozygous mutations in the desmosomal gene, plakophilin-2 ( PKP2 ), are the most common cause of ARVC. Our objective was to investigate the mechanisms of ARVC development and test a potential ARVC gene therapy strategy using a novel mouse model of Pkp2. Methods: A knock-in (KI) mouse model with a point mutation corresponding to human PKP2 ( PKP2 c.2146-1G>C or Pkp2 KI) was generated via CRISPR/Cas9 technology. High fat diet (HFD) was used to induce the ARVC phenotype in the Pkp2 KI heterozygous (het) mice. The Pkp2 KI het mice were crossed with a cardiac-specific Pkp2 cKO (αMHC-Cre ERT ) mouse to generate a tamoxifen inducible model (KIxKO). Cardiac function was assessed by echocardiography and arrhythmia burden by EKG. The KIxKO animals received AAV:PKP2 via retro-orbital injection. Results: Pkp2 KI het animals with normal chow had slow and mild ARVC development, and 50% decrease in PKP2 protein expression, with right ventricle (RV) dilation not occurring until animals were 9 months old. Induction with HFD from 8 weeks hastened and worsened the RV dilation. In contrast, the KIxKO mice exhibited >90% decrease in PKP2 protein expression and a correspondingly severe ARVC phenotype starting from 3 weeks after Tamoxifen induction. This included a high arrhythmia burden and both RV area dilation and decreased ejection fraction, indicating the mice eventually progressed to biventricular heart failure. This resulted in 100% mortality in KIxKO animals by 9 weeks post-tamoxifen induction. A single dose of AAV:PKP2 gene therapy (6E13 vg/kg) maintained ejection fraction, prevented ARVC development and improved survival in the KIxKO mice after 9 weeks of treatment. Conclusion: The current results demonstrated that AAV:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations resulting in haploinsufficiency.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosome genes. Secondary findings of pathogenic/likely pathogenic variants, primarily loss-of-function (LOF) variants, are recommended for clinical reporting; however, their prevalence and associated phenotype in a general clinical population are not fully characterized. From whole-exome sequencing of 61 019 individuals in the DiscovEHR cohort, we screened for putative loss-of-function variants in PKP2, DSC2, DSG2, and DSP. We evaluated measures from prior clinical ECG and echocardiograms, manually over-read to evaluate ARVC diagnostic criteria, and performed a PheWAS (phenome-wide association study). Finally, we estimated expected penetrance using Bayesian inference. One hundred forty individuals (0.23%; 59±18 years old at last encounter; 33% male) had an ARVC variant (G+). None had an existing diagnosis of ARVC in the electronic health record, nor significant differences in prior ECG or echocardiogram findings compared with matched controls without variants. Several G+ individuals satisfied major repolarization (n=4) and ventricular function (n=5) criteria, but this prevalence matched controls. PheWAS showed no significant associations of other heart disease diagnoses. Combining our best genetic and disease prevalence estimates yields an estimated penetrance of 6.0%. The prevalence of ARVC loss-of-function variants is ≈1:435 in a general clinical population of predominantly European descent, but with limited electronic health record-based evidence of phenotypic association in our population, consistent with a low penetrance estimate. Prospective deep phenotyping and longitudinal follow-up of a large sequenced cohort is needed to determine the true clinical relevance of an incidentally identified ARVC loss-of-function variant.

Sudden killer