Covid-19 positive donor utilization for heart transplantation: The new frontier for donor pool expansion.

BACKGROUND: Hearts from COVID-19 positive donors (CPD) are being utilized for heart transplantation by some centers; however, this is in the setting of the lack of guidelines or robust evidence. The paucity of evidence is reflected in the recent Organ Procurement and Transplantation Network (OPTN) communication describing CPD utilization as an "unknown risk." METHODS AND RESULTS: We analyzed the UNOS database for adult heart transplants performed between January 2021 to December 2022, and CPD comprised of a significant percentage of donors, being used in >10% of recipients in some UNOS regions. Between July 2022 and December 2022, 7.9% of heart transplants were with CPD, and in the same period Hepatitis C positive donors accounted for 7.1% and donation after circulatory death (DCD) accounted for 10.3%. CONCLUSION: If the transplant community comes up with a standardized approach and guidance in using CPD hearts, this could provide an effective donor pool expansion strategy.

A stepwise external cardioversion protocol for atrial fibrillation to maximize acute success rate.

AIMS: Cardioversion is a very commonly performed procedure for persistent atrial fibrillation (AF). However, there is no well-defined protocol to address failed external electrical direct current cardioversion. The aim of the study is to test the efficacy of a pre-defined stepwise cardioversion protocol for patients with persistent AF of ≤12 months. Success was the achievement of sinus rhythm. METHODS AND RESULTS: The study population included patients with persistent AF of ≤12 months duration requiring rhythm management. Patients were offered cardioversion using a pre-defined stepwise protocol using different electrode placement locations, applying compression at end of expiration, and higher energy delivered simultaneously through two defibrillators. : A total of 414 patients were included in the study, of which 362 (87.4%) required a single successful cardioversion. The remaining 52 (12.5%) patients required additional cardioversion attempts using the stepwise cardioversion protocol with an overall success rate of 99.3%. Two simultaneous defibrillators were required in 14 patients (3.4%). Patients with multiple cardioversions (13.5%) experienced more local skin irritation and pain compared with patients with single cardioversion (13.5% vs. 3.5%, P = 0.004). The predictor for the need for multiple cardioversion attempts is high body mass index, while high transthoracic impedance is associated with failed cardioversion. No major complications were observed during the study. CONCLUSION: The stepwise cardioversion protocol has a high success rate of >99% and can be safely performed in outpatient or inpatient settings.

Patterns and outcomes of COVID-19 donor utilization for heart transplant.

BACKGROUND: The outcomes following COVID-19 positive donor (CPD) utilization for heart transplant are unknown. METHODS: UNOS database was analyzed for heart transplants performed from the declaration of COVID-19 pandemic until September 30, 2022. RESULT: Since the onset of pandemic, there were 9876 heart transplants reported. COVID-19 antigen or NAT results were available in 7698 adult donors within 14 days of donation, of which 177 (2.3%) were positive. There was no difference in recipient demographics, including age (COVID positive donor vs. negative: 55 vs. 56 years, p = .2) and BMI. Listing status 1 and 2 were similar in both groups (7% vs. 10% and 48% vs. 49% respectively, p = .4). Durable and temporary mechanical support were similar in both groups pre-transplant (both groups 33%, p = .9). There was no difference in days on the waitlist (median 31 days, p = .9). Simultaneous renal transplant rates were similar (11% vs. 10%, p = .9). CPD utilization has increased since the onset of the pandemic, and the adoption is present across most UNOS regions. Post-transplant, there was no difference in length of stay (median 16 vs. 17 days, p = .9) and acute rejection episodes prior to discharge (3% vs. 8%, p = .1). In survival analysis of 90-day follow up, number of deaths reported were comparable (5% in both groups, p = .9) Follow-up LVEF was comparable (62% vs. 60%, p = .4). CONCLUSION: Active COVID-19 infection in donors did not affect survival or rejection rates in the short-term post-heart transplant.

Cardiac fibroblast sub-types in vitro reflect pathological cardiac remodeling in vivo.

Many heart diseases are associated with fibrosis, but it is unclear whether different types of heart disease correlate with different subtypes of activated fibroblasts and to which extent such diversity is modeled during in vitro activation of primary cardiac fibroblasts. Analyzing the expression of 82 fibrosis related genes in 65 heart failure (HF) patients, we identified a panel of 12 genes clearly distinguishing HF patients better from healthy controls than measurement of the collagen-related hydroxyproline content. A subcluster enriched in ischemic HF was recognized, but not for diabetes, high BMI, or gender. Single-cell transcriptomic analysis of in vitro activated mouse cardiac fibroblasts distinguished 6 subpopulations, including a contractile Acta2high precursor population, which was predicted by time trajectory analysis to develop into Acta2low subpopulations with high production of extracellular matrix molecules. The 12 gene profile identified in HF patients showed highest similarity to the fibroblast subset with the strongest expression of extracellular matrix molecules. Population markers identified were furthermore able to clearly cluster different disease stages in a murine model for myocardial infarct. These data suggest that major features of cardiac fibroblast activation in heart failure patients, in murine heart disease models, and in cell culture of primary murine cardiac fibroblast are shared.

Co-occurrence and phase relationship between alternans of the R wave amplitude (RWAA) and of the T wave (TWA) in ECGs.

Alternans of the T wave in ECG (TWA) has high negative but poor positive predictive value in the prediction of ventricular arrhythmia. Alternans of repolarization duration, i.e. of action potential duration (APD), causes TWA. Prior studies from our group showed that alternans of the maximum rate of depolarization also occurs when APD alternans occurs and the relationship between these two has the potential to affect formation of spatial discord, which may be more arrhythmogenic. Therefore, exploration of the co-occurrence of the alternans of depolarization and repolarization has the potential to improve the prediction. In the present study, we used a mathematical model to show that depolarization alternans appears as alternating amplitude of the R wave in the ECG. We also investigated the link between changes in R wave amplitude and TWA. Results from clinical grade ECGs available in the PhysioNet database show that amplitude of the R wave can change as predicted by our experimental results and the mathematical model. Using TWA as the marker of repolarization alternans and R wave amplitude alternans (RWAA) as the marker of depolarization alternans, we investigated the phase relation between them and observed that, similar to previous results from animals, the phase relation between the two can spontaneously change. That is, alternans of depolarization does co-occur with TWA and the phase relationship between the two is not invariant. These results support further investigation of the use of RWAA as a complementary method to TWA to improve positive predictive value for prediction of ventricular arrhythmia.

Phase Relation between Depolarization and Repolarization Alternans in ECG.

T-Wave Alternans (TWA) in the electro cardiogram (ECG) has been widely investigated as a potential predictor of ventricular arrhythmia. However, large clinical trials show that TWA has a high negative predictive value (NPV) but poor positive predictive value (PPV). Therefore, there is need for exploration of approaches to improve PPV of TWA. More recent studies suggest that whether alternans is spatially concordant or discordant affects arrhythmic potential. Results of our previous animal and simulation studies show that the phase relation between depolarization and repolarization alternans has an effect on the transition of concordant to discordant alternans. Towards the eventual goal of developing indexes that complement TWA and improve prediction of arrhythmia, the objectives in this study were to verify the existence of R wave amplitude alternans (RWAA, a surrogate of depolarization alternans) and investigate the phase relationship between RWAA and TWA in clinical grade ECGs. Results show that RWAA does occur in ECGs and that the phase relationship between RWAA and TWA can be labile. These results support further investigation of the co-occurrence of these alternans for prediction of arrhythmic events.

Coronary artery calcification in CKD-5D patients is tied to adverse cardiac function and increased mortality
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BACKGROUND: Coronary artery calcification (CAC) is common in patients with chronic kidney disease on hemodialysis (CKD-5D) and is an important predictor of mortality. However, cardiac functional links between CAC and mortality have not been well established. This study tested the hypothesis that CAC increases mortality by adversely affecting cardiac function. METHODS: Patients were recruited from 37 regional dialysis centers. 2-D and Doppler echocardiographic analyses were performed, and CAC was measured using 64-slice computed tomography. Relationships between CAC and echocardiographic measures of left ventricular (LV) function were analyzed. Survival was assessed with median follow-up of 37 months. RESULTS: There were 157 patients: 59% male, 46% Caucasian, 48% diabetic. Median age was 55 years, and median duration of CKD-5D was 45 months. Agatston CAC scores 100 were found in 69% of patients, with 51% having a score  400. CAC was associated with measures of LV systolic and diastolic function (global longitudinal strain (GLS; rho = 0.270, p = 0.004)), peak LV systolic velocity (rho = -0.259, p = 0.004), and estimate of LV filling pressure (E:E'; rho = 0.286, p = 0.001). Multivariate regression confirmed these relationships after adjustment for age, gender, LV ejection fraction, and coronary artery disease. Valvular calcification varied linearly with CAC (p < 0.05). Both LV diastolic and systolic functional measures were significant predictors of mortality, the strongest of which was LV diastolic dysfunction. CONCLUSIONS: These findings show a link between CAC, cardiac function, and mortality in CKD-5D. LV diastolic function (E:E'), peak LV systolic velocity, and GLS are independent predictors of mortality. Valvular calcification may be an important marker of CAC in CKD-5D. These effects on cardiac function likely explain the high mortality with CKD-5D and describe a potentially-valuable role for echocardiography in the routine management of these patients.
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Sildenafil in heart failure with reactive pulmonary hypertension (Sildenafil HF) clinical trial (rationale and design).

In this article, we present the rationale and design of the Sildenafil HF trial (ClinicalTrials.gov identifier: NCT02304705). We will randomize patients with heart failure and reactive pulmonary hypertension (pulmonary capillary wedge pressure > 15 mmHg, pulmonary vascular resistance > 3 Wood units) into two groups: the treatment group receiving sildenafil 20 mg 3 times a day and a matching placebo group. The duration of intervention will be 3 months. The primary outcome is 6-minute walk distance. Key features of this trial include (1) that reactive pulmonary hypertension is an inclusion criterion, (2) that patients will be enrolled regardless of left ventricular ejection fraction, and (3) that clinical stability in the 3 months preceding enrollment is not required.

Dose Related Patterns of Ventricular Arrhythmia due to Carvedilol Withdrawal in Patients with Systolic Heart Failure.

OBJECTIVES: This study evaluates the impact of carvedilol dose changes on the ventricular arrhythmia event rates for patients > 18 years of age with systolic heart failure and examines dose dependent effects of carvedilol withdrawal in dose reduction and discontinuation subgroups. METHODS: This retrospective cohort study included patients with systolic heart failure (EF < 40%) receiving carvedilol. The primary outcome was incidence of ventricular arrhythmia. Ventricular arrhythmia event rates were compared among carvedilol dose continuation, reduction and discontinuation groups. To assess dose dependent effects of beta-blocker withdrawal, dose reduction and discontinuation groups were divided into subgroups. RESULTS: Dose discontinuation (n=64) or reduction group (n=83) had significantly higher ventricular arrhythmia rates compared with dose continuation group (n=262) (65.6 vs. 33.7 vs. 15.3%, p < 0.001 for both comparisons). Dose discontinuation group also had a significantly higher ventricular arrhythmia event rate compared with dose reduction group (p<0.001). There were no significant differences in ventricular arrhythmia event rates among dose discontinuation or reduction subgroups. CONCLUSION: Continuation of carvedilol therapy was associated with a substantially lower ventricular arrhythmia event rate compared with reduction or discontinuation of carvedilol therapy. Dose dependent effects of beta-blocker withdrawal in subgroup analyses were not found.

QRS duration predicts death and hospitalization among patients with atrial fibrillation irrespective of heart failure: evidence from the AFFIRM study.

AIMS: The association of QRS duration (QRSd) with morbidity and mortality is understudied in patients with atrial fibrillation (AF). We sought to assess any association of prolonged QRS with increased risk of death or hospitalization among patients with AF. METHODS AND RESULTS: QRS duration was retrieved from the baseline electrocardiograms of patients enroled in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study and divided into three categories: <90, 90-119, ≥120 ms. Cox models were applied relating the hazards of mortality and hospitalizations to QRSd. Among 3804 patients with AF, 593 died and 2305 were hospitalized. Compared with those with QRS < 90 ms, patients with QRS ≥ 120 ms, had an increased mortality [hazard ratio (HR) 1.61, 95% confidence interval (CI): 1.29-2.03, P < 0.001] and hospitalizations (HR 1.14, 95% CI: 1.07-1.34, P = 0.043) over an average follow-up of 3.5 years. Importantly, for patients with QRS 90-119 ms, mortality and hospitalization were also increased (HR 1.31, P = 0.005 and 1.11, P = 0.026, respectively). In subgroup analysis based on heart failure (HF) status (previously documented or ejection fraction <40%), mortality was increased for QRS ≥ 120 ms patients with (HR 1.87, P < 0.001) and without HF (HR 1.63, P = 0.02). In the QRS 90-119 ms group, mortality was increased (HR 1.38, P = 0.03) for those with HF, but not significantly among those without HF (HR 1.23, P = 0.14). CONCLUSION: Among patients with AF, QRSd ≥ 120 ms was associated with a substantially increased risk for mortality (all-cause, cardiovascular, and arrhythmic) and hospitalization. Interestingly, an increased mortality was also observed among those with QRS 90-119 ms and concomitant HF.

The evolving role of cardiac troponin in the evaluation of cardiac disorders.

Due to their tissue specificity and ease of detection, the cardiac troponins (cTn) have emerged as the most important and most utilized biomarkers for the diagnosis of acute myocardial infarction (AMI). The recent achievement of greater sensitivity by cTn assay systems, however, has resulted in the detection of cTn in a wide array of medical conditions, highlighting myocardial cellular necrosis as a feature in several, seemingly unrelated medical conditions, yet complicating the interpretation of a positive test. Since elevated cTn levels are associated with worse clinical outcomes and, thereby, influence medical decisions, careful consideration should be given to the method by which these biomarkers are measured, the patient population on which the test is being applied, and applicable thresholds based on particular clinical conditions. The objective of this review is to trace the clinical evolution of the cTn biomarker from a test for AMI to a general marker of myocardial cellular necrosis with clinically important prognostic information.

Increased mortality among patients taking digoxin--analysis from the AFFIRM study.

AIMS: Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS: The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION: Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

Enhanced proliferation and migration of vascular smooth muscle cells in response to vascular injury under hyperglycemic conditions is controlled by beta3 integrin signaling.

Atheroma formation and restenosis following percutaneous vascular intervention involve the growth and migration of vascular smooth muscle cells (SMCs) into neointimal lesions, in part due to changes in the extracellular matrix. While some clinical studies have suggested that, in comparison to non-diabetics, beta3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of beta3 integrin inhibition on SMC responses in this context. To understand the molecular mechanisms underlying integrin-mediated regulation of SMC function in diabetes, we examined SMC responses in diabetic mice deficient in integrin beta3 and observed that the integrin was required for enhanced proliferation, migration and extracellular regulated kinase (ERK) activation. Hyperglycemia-enhanced membrane recruitment and catalytic activity of PKCbeta in an integrin beta3-dependent manner. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required alphaVbeta3, PKCbeta, and ERK activity. Furthermore, the integrin-kinase association was regulated by the alphaVbeta3 integrin ligand thrombospondin and the integrin modulator Rap1 under conditions of hyperglycemia. These results suggest that there are differences in SMC responses to vascular injury depending on the presence or absence of hyperglycemia and that SMC response under hyperglycemic conditions is largely mediated through beta3 integrin signaling.

Diagnosis of subclinical coronary atherosclerosis: challenges and insight.

BACKGROUND: In the last 30 years, significant progress has been made in our ability to stratify individuals on the basis of cardiovascular (CV) risk, allowing those at the highest risk of CV disease to be more aggressively treated. In the US, this has resulted in a gradual decline in CV mortality. Whether medical interventions in individuals at low-to-intermediate risk for CV disease translate into improved outcomes remains an open question, and depends largely on our ability to diagnose atherosclerosis at an earlier stage than is possible at present. OBJECTIVE: The objective of this paper is to review current literature on the diagnosis of subclinical atherosclerosis. METHODS: Medline searches for peer-reviewed publications using search terms relevant to the diagnosis of subclinical atherosclerosis were performed. RESULTS: Data from these references are discussed and grouped into three broad categories, including biomarkers, imaging and genomics. CONCLUSION: The recent identification of new biomarkers and genes associated with atherosclerosis combined with recent advances in cardiovascular imaging has enhanced our understanding of atherosclerosis. These techniques show promise in their ability to detect subclinical atherosclerosis indepenedent of conventional clinical CV risk factors. Further research is needed better to define roles for these technologies in the diagnosis of atherosclerosis among asymptomatic individuals.

Application of contrast echocardiography in the evaluation of a right-sided vegetative lesion.

Transesophageal echocardiography has significantly improved the detection of vegetative lesions, including those associated with indwelling central venous lines. However, in certain cases, the increased mobility of these lesions as well as the presence of indwelling catheters obscure the precise delineation of their origin and the detection of attachment to adjacent structures. We report a case of right-sided endocarditis in which the use of contrast was instrumental to the comprehensive evaluation of the lesion and to subsequent patient management.