Changing Strategy Between Bridge to Transplant and Destination LVAD Therapy After the First 3 Months: Analysis of the STS-INTERMACS Database.

BACKGROUND: Left ventricular assist devices (LVADs) have been implanted as bridge to transplantation (BTT), bridge to candidacy (BTC) or destination therapy (DT) on the basis of relative and absolute contraindications to transplantation. Multiple factors may lead to changes in the strategy of support after LVAD implantation. METHODS: Based on INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) 2012-2020 data, 11,262 patients survived to 3 months on continuous-flow LVADs with intent of BTT or DT. Preimplant characteristics and early events post-LVAD were analyzed in relation to changes in BTT or DT strategy during the next 12 months. RESULTS: Among 3216 BTT patients at 3 months, later transplant delisting or death without transplant occurred in 536 (16.7%) and was more common with age, profiles 1-2, renal dysfunction, and independently for prior cardiac surgery (HR 1.25, 95% CI 1.04-1.51; P = 0.02). Post-LVAD events of infections, gastrointestinal bleeding, stroke, and right heart failure as defined by inotropic therapy, predicted delisting and death, as did in-hospital location at 3 months (HR 1.67, 95% CI 1.20-2.33; P = 0.0024). Of 8046 patients surviving to 3 months with the intent of destination therapy, 750 (9.3%) subsequently underwent listing or transplantation, often with initial histories of acute HF (HR 1.70, 95% CI 1.27-2.27; P = 0.0012) or malnutrition-cachexia (1.73, 95% CI 1.14-2.63; P = 0.0099). Multiple gastrointestinal bleeding events (≥ 4) with LVAD increased transition from BTT to DT (HR 4.22, 95% CI 1.46-12.275; P = 0.0078) but also from DT to BTT (HR 5.17, 95% CI 1.92-13.9; P = 0.0011). CONCLUSIONS: Implant strategies change over time in relation to preimplant characteristics and adverse events post implant. Preimplant recognition of factors predicting later change in implant strategy will refine initial triage, whereas further reduction of post-LVAD complications will expand options, including eventual consideration of heart transplantation.

A multicenter evaluation of external outflow graft obstruction with a fully magnetically levitated left ventricular assist device.

BACKGROUND: The HeartMate 3 (HM 3; Abbott) left ventricular assist device (LVAD) has improved hemocompatibility-related adverse outcomes. In sporadic cases, external compression of the outflow graft causing obstruction (eOGO) can result from substance accumulation between the outflow graft and its bend relief. We sought to evaluate the prevalence, course, and clinical implications of eOGO in an international study. METHODS: A multicenter retrospective analysis of HM 3 LVADs implanted between November 2014 and April 2021 (n = 2108) was conducted across 17 cardiac centers in 8 countries. We defined eOGO as obstruction >25% in the cross-sectional area in imaging (percutaneous angiography, computed tomography, or intravascular ultrasound). The prevalence and annual incidence were calculated. Serious adverse events and outcomes (death, transplantation, or device exchange) were analyzed for eOGO cases. RESULTS: Of 2108 patients, 62 were diagnosed with eOGO at a median LVAD support duration of 953 (interquartile range, 600-1267) days. The prevalence of eOGO was 3.0% and the incidence at 1, 2, 3, 4, and 5 years of support was 0.6%, 2.8%, 4.0%, 5.2%, and 9.1%, respectively. Of 62 patients, 9 were observed, 27 underwent surgical revision, 15 underwent percutaneous stent implantation, 8 received a heart transplant, and 2 died before intervention. One patient underwent surgical revision and later stent implantation. The mortality with therapeutic intervention was 9/53 (17.0%). CONCLUSIONS: Although uncommon, HM 3 LVAD-supported patients might develop eOGO with an increasing incidence after 1 year of support. Although engineering efforts to reduce this complication are under way, clinicians must maintain a focus on early detection and remain vigilant.

Early aspirin use, allograft rejection, and cardiac allograft vasculopathy in heart transplantation.

BACKGROUND: Early aspirin (ASA) use after orthotopic heart transplantation (OHT) has been associated with lower rates of cardiac allograft vasculopathy (CAV). We hypothesized that the inverse association between ASA use and CAV incidence may be most pronounced in patients with allograft rejection. METHODS: Patients receiving OHT at a single center 2004-2010 (n = 120) were categorized by early ASA use post-transplant (ASA use for > 6 months in the first year) and the presence of biopsy-defined acute cellular rejection (ACR) and/or antibody-mediated rejection (AMR) during 5-year follow-up. Propensity scores for ASA treatment were estimated using boosting models and applied by inverse probability of treatment weighting. The association between ASA use and time to moderate/severe CAV (ISHLT ≥ 2) was investigated. RESULTS: Among patients with ACR or AMR, ASA therapy was associated with significantly lower rates of CAV≥ 2 (3.3 vs. 30.1%; P = .001; HRadj .07; 95% CI .01-.52), whereas ASA therapy was not associated with lower rates of CAV in patients with no rejection (5.6 vs. 5.3%; P = .90; HRadj 1.26; 95% CI .08-20.30; pinteraction  = .09). CONCLUSIONS: Early ASA use after OHT was associated with lower rates of moderate to severe CAV only in those patients with episodes of allograft rejection.

Feasibility of somatostatin receptor-targeted imaging for detection of myocardial inflammation: A pilot study.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: Thirteen patients, with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG-PET (median time 37 days [IQR 25-55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n = 6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8-7.1] higher in the heart, but only 2.25 times [1.7-3.0; P = .019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggest that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor­associated myocarditis. Although the full spectrum of immune checkpoint inhibitor­associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor­associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

Diagnostic Accuracy of Advanced Imaging in Cardiac Sarcoidosis.

Background The diagnostic yield of cardiac sarcoidosis (CS) by endomyocardial biopsy is limited. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and cardiac magnetic resonance imaging (MRI) may facilitate noninvasive diagnosis, but the accuracy of this approach is not well defined. We aimed to correlate findings from FDG PET and cardiac MRI with histological findings from explanted hearts of patients who underwent cardiac transplantation. Methods We analyzed the explanted heart histology for all patients who underwent cardiac transplant at our center from April 2008 to July 2018 and had pretransplant FDG PET (n=18) or cardiac MRI (n=31). The likelihood of CS based on FDG PET or cardiac MRI was categorized in a blinded fashion using a previously published method. RESULTS: Using a CS probable cutoff for FDG PET resulted in a sensitivity of 100.0% (95% CI, 54.1%-100.0%) and a specificity of 33.3% (95% CI, 9.9%-65.1%). Three of the 9 CS probable by FDG PET cases were found to be arrhythmogenic cardiomyopathy. The test characteristics of cardiac MRI are more challenging to comment on using our data as there was only one confirmed case of CS on post-transplant histological assessment. Of the 8 CS highly probable or probable cases by cardiac MRI, 3 were found to be dilated cardiomyopathy, and 2 were found to be end-stage hypertrophic cardiomyopathy. Conclusions FDG PET and cardiac MRI can help facilitate the diagnosis of CS in patients with advanced heart failure with a high degree of sensitivity but lower specificity.

Ambulatory Advanced Heart Failure in Women: A Report From the REVIVAL Registry.

OBJECTIVES: This study sought to explore clinical characteristics and outcomes in women and men with ambulatory advanced heart failure (HF). BACKGROUND: Women have been underrepresented in studies of advanced HF and have an increased mortality on the transplant waiting list and early after mechanical circulatory support (MCS). An increased understanding of the differential burden of HF between women and men is required to inform the use of mechanical circulatory support in ambulatory advanced HF patients. METHODS: REVIVAL (Registry Evaluation for Vital Information on Ventricular Assist Devices in Ambulatory Life) is a prospective, observational study of 400 outpatients with chronic systolic HF, New York Heart Association functional class II to IV, and 1 additional high-risk feature. Clinical characteristics, quality of life, and functional capacity were compared between women and men, as was a primary composite endpoint of death, durable MCS, or urgent heart transplantation at 1 year. RESULTS: REVIVAL enrolled 99 women (25% of the cohort) who had similar age, ejection fraction, INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles, medication use, and willingness to consider MCS as the men enrolled; however, women reported significantly greater limitations in quality of life with respect to physical limitation, reduced 6-min walk distance, and more frequent symptoms of depression. Nevertheless, 1-year combined risk of death, durable MCS, or urgent transplantation did not differ between women and men (24% vs. 22%; p = 0.94). CONCLUSIONS: This study represents the largest report to date of women with ambulatory advanced HF receiving contemporary therapies. Systematic elicitation of patient-reported outcome measures uncovered an added burden of HF in women and may be an appropriate target of augmented support and intervention.

Early aspirin use and the development of cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of morbidity and mortality after orthotopic heart transplantation (OHT). Little is known about the influence of aspirin on clinical expression of CAV. METHODS: We followed 120 patients with OHT at a single center for a median of 7 years and categorized them by the presence or absence of early aspirin therapy post-transplant (aspirin treatment ≥6 months in the first year). The association between aspirin use and time to the primary end-point of angiographic moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) was investigated. Propensity scores for aspirin treatment were estimated using boosting models and applied by inverse probability of treatment weighting (IPTW). RESULTS: Despite a preponderance of risk factors for CAV among patients receiving aspirin (male sex, ischemic heart disease as the etiology of heart failure, and smoking), aspirin therapy was associated with a lower rate of moderate or severe CAV at 5 years. Event-free survival was 95.9% for patients exposed to aspirin compared with 79.6% for patients without aspirin exposure (log-rank p = 0.005). IPTW-weighted Cox regression revealed a powerful inverse association between aspirin use and moderate to severe CAV (adjusted hazard ratio 0.13; 95% confidence interval 0.03-0.59), which was directionally consistent for CAV of any severity (adjusted hazard ratio 0.50; 95% confidence interval 0.23-1.08). CONCLUSIONS: This propensity score-based comparative observational analysis suggests that early aspirin exposure may be associated with a reduced risk of development of moderate to severe CAV. These findings warrant prospective validation in controlled investigations.

Variable Contribution of Heart Failure to Quality of Life in Ambulatory Heart Failure With Reduced, Better, or Preserved Ejection Fraction.

OBJECTIVES: The relative contribution of heart failure (HF) compared with other medical and nonmedical factors on diminished quality of life (QOL) across subtypes with reduced, better, and preserved left ventricular ejection fraction (LVEF) in a large ambulatory HF population was evaluated. BACKGROUND: Dominant factors influencing limited QOL in patients with HF have not been investigated. METHODS: Before routine HF clinic visits, 726 patients with ambulatory HF (mean age 56 ± 15 years, 37% women) completed a 1-page questionnaire that assessed QOL and relative contributions of HF compared with other medical and nonmedical factors to their QOL limitations. Visual analogue scales were used to assess overall QOL, breathing, and energy level. Results were compared across reduced (57%), preserved (16%) and better (improvement in LVEF ≥50%) (19%) subtypes. RESULTS: Just under one-half of patients (48%) rated QOL as limited dominantly by HF, 19% rated HF and medical problems as equally limiting, 18% cited medical problems as dominant, and 15% cited nonmedical factors. Patients with HF with better LVEF had the highest overall QOL score and less dyspnea burden than those with HF with preserved EF. Independent correlates of HF-dominated diminished QOL were prior cardiac surgery, worse New York Heart Association functional class, renin-angiotensin-aldosterone antagonism, use of diuretic agents, lower body mass index, lower LVEF, and lack of arthritis or history of cancer. CONCLUSIONS: Fewer than one-half of patients with ambulatory HF rated HF as the greatest limitation to their QOL, suggesting that this important outcome will be difficult to affect by HF-targeted therapies alone, particularly in those with higher LVEFs and comorbidities. Patients with HF with better LVEF represent a distinct subtype with better overall QOL.

A history of devices as an alternative to heart transplantation.

The rapid evolution of mechanical circulatory support (MCS) has extended survival and improved quality of life for patients suffering from the most advanced heart failure (HF). Survival at one year after placement of a left ventricular assist device exceeds 80%. MCS and transplant have developed in counterpoint to each other. Patients with HF now have a meaningful option for lifelong support even if they are not candidates for heart transplant. As the profiles of MCS recipients change and the next generation of devices emerges, new challenges and opportunities await physicians caring for patients with cardiac failure.

Myocardial parvovirus B19 persistence: lack of association with clinicopathologic phenotype in adults with heart failure.

BACKGROUND: Multiple viruses have been isolated from the heart, but their significance remains controversial. We sought to determine the prevalence of cardiotropic viruses in endomyocardial biopsy (EMB) samples from adult patients with heart failure (HF) and to define the clinicopathologic profile of patients exhibiting viral positivity. METHODS AND RESULTS: EMB from 100 patients (median ejection fraction, 30%; interquartile range [IQR], 20% to 45%) presenting for cardiomyopathy evaluation (median symptom duration, 5 months; IQR, 1 to 13 months) were analyzed by polymerase chain reaction for adenovirus, cytomegalovirus, enteroviruses, Epstein-Barr virus, and parvovirus B19. Each isolate was sequenced, and viral load was determined. Parvovirus B19 was the only virus detected in EMB samples (12% of subjects). No patient had antiparvovirus IgM antibodies, but all had IgG antibodies, suggesting viral persistence. The clinical presentation of parvovirus-positive patients was markedly heterogeneous with both acute and chronic HF, variable ventricular function, and ischemic cardiomyopathy. No patient met Dallas histopathologic criteria for active or borderline myocarditis. Two patients with a positive cardiac MRI and presumed "parvomyocarditis" had similar viral loads to autopsy controls without heart disease. The oldest parvovirus-positive patients were positive for genotype 2, suggesting lifelong persistence in the myocardium. CONCLUSIONS: Parvovirus B19 was the only virus isolated from EMB samples in this series of adult patients with HF from the United States. Positivity was associated with a wide array of clinical presentations and HF phenotypes. Our studies do not support a causative role for parvovirus B19 persistence in HF and, therefore, advocate against the use of antiviral therapy for these patients.

Patient expectations from implantable defibrillators to prevent death in heart failure.

BACKGROUND: Indications for implantable cardioverter-defibrillators (ICDs) in heart failure (HF) are expanding and may include more than 1 million patients. This study examined patient expectations from ICDs for primary prevention of sudden death in HF. METHODS AND RESULTS: Study participants (n = 105) had an EF <35% and symptomatic HF, without history of ventricular tachycardia/fibrillation or syncope. Subjects completed a written survey about perceived ICD benefits, survival expectations, and circumstances under which they might deactivate defibrillation. Mean age was 58, LVEF 21%, 40% were New York Heart Association Class III-IV, and 65% already had a primary prevention ICD. Most patients anticipated more than10 years survival despite symptomatic HF. Nearly 54% expected an ICD to save >or=50 lives per 100 during 5 years. ICD recipients expressed more confidence that the device would save their own lives compared with those without an ICD (P < .001). Despite understanding the ease of deactivation, 70% of ICD recipients indicated they would keep the ICD on even if dying of cancer, 55% even if having daily shocks, and none would inactivate defibrillation even if suffering constant dyspnea at rest. CONCLUSIONS: HF patients anticipate long survival, overestimate survival benefits conferred by ICDs, and express reluctance to deactivate their devices even for end-stage disease.

Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart.

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.