Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study.

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial.

BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90). CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

HFSA Expert Consensus Statement on the Medical Management of Patients on Durable Mechanical Circulatory Support.

The medical management of patients supported with durable continuous flow left ventricular assist device (LVAD) support encompasses pharmacological therapies administered in the preoperative, intraoperative, postoperative, and chronic LVAD support stages. As patients live longer on LVAD support, the risks of LVAD-related complications and progression of cardiovascular and other diseases increase. Using existing data from cohort studies, registries, randomized trials, and expert opinion, this Heart Failure Society of America Consensus Document on the Medical Management of Patients on Durable Mechanical Circulatory Support offers best practices on the management of patients on durable mechanical circulatory support, focusing on pharmacological therapies administered to patients on continuous flow LVADs. Although quality data in the LVAD population are few, the use of guideline-directed heart failure medical therapies and the importance of blood pressure management, right ventricular preload and afterload optimization, and antiplatelet and anticoagulation regimens are discussed. Recommended pharmacological regimens used to mitigate or treat common complications encountered during LVAD support, including arrhythmias, vasoplegia, mucocutaneous bleeding, and infectious complications, are addressed. Finally, this document touches on important potential pharmacological interactions from antidepressants and herbal and nutritional supplements of relevance to providers of patients on LVAD support.

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

TTR variants in patients with dilated cardiomyopathy: An investigation of the DCM Precision Medicine Study.

PURPOSE: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported. METHODS: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes. RESULTS: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99). CONCLUSION: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.

State-of-the-art review on management of end-stage heart failure in amyloidosis: transplant and beyond.

Cardiac involvement occurs in light-chain (AL), transthyretin wild-type (wtATTR), and hereditary (hATTR) amyloidosis; other types of amyloidosis account for < 5% of all cardiac amyloidosis (CA). CA can present subclinically on screening, insidiously with symptoms such as exertional dyspnea, or abruptly as cardiogenic shock. Initially, CA patients were thought to be poor candidates for transplant due to short long-term survival; however, there is a marked improvement in heart and multi-organ transplant outcomes over the past 10 years with newer treatments and improvements in support with temporary and durable mechanical circulatory support while awaiting transplant. Patients with AL CA were reported to have worse post-OHT outcomes than patients with ATTR CA, but this gap is quickly closing with improved patient selection, novel chemotherapeutics, and perhaps with selected use of bone marrow transplantation. Waitlist mortality and transplantation rates have markedly improved for CA after the United Network for Organ Sharing (UNOS) policy change in October 2018. In this review, we will evaluate contemporary data from the last 5 years on advances in the field of transplantation and mechanical circulatory support in this patient population.

Targeted treatments of AL and ATTR amyloidosis.

The therapeutic landscape for cardiac amyloidosis is rapidly evolving. In the last decade, our focus has shifted from dealing with the inevitable complications of continued extracellular infiltration of amyloid fibrils to earlier identification of these patients with prompt initiation of targeted therapy to prevent further deposition. Although much of the focus on novel targeted therapies is within the realm of transthyretin amyloidosis, light chain amyloidosis has benefited due to an overlap particularly in the final common pathway of fibrillogenesis and extraction of amyloid fibrils from the heart. Here, we review the targeted therapeutics for transthyretin and light chain amyloidosis. For transthyretin amyloidosis, the list of current and future therapeutics continues to evolve; and therefore, it is crucial to become familiar with the underlying mechanistic pathways of the disease. Although targeted therapeutic choices in AL amyloidosis are largely driven by the hematology team, the cardiac adverse effect profiles of these therapies, particularly in those with advanced amyloidosis, provide an opportunity for early recognition to prevent decompensation and can help inform recommendations regarding therapy changes when required.

Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation.

RATIONALE: Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. OBJECTIVE: Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. METHODS AND RESULTS: Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of -15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P=9.95122×10-6). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice. CONCLUSIONS: We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.

Intravenous immunoglobulin in heart transplant recipients with mild to moderate hypogammaglobulinemia and infection.

BACKGROUND: Hypogammaglobulinemia (HGG) is a complication of solid organ transplantation leading to increased risk of infections. Intravenous immunoglobulin G (IVIG) replacement in patients with HGG may be able to reduce risk and morbidity associated with infection; however, there is scarce data about IVIG in mild to moderate HGG (IgG 400-700 mg/dl) and heart transplant recipients. METHODS: A single center, retrospective study was performed in heart transplant recipients with mild (IgG 500-700 mg/dl) to moderate (IgG 400-499 mg/dl) HGG in the presence of an infection. RESULTS: Forty-two patients were included in this study; 19 patients (45.2%) received IVIG and 23 (54.8%) patients did not. Patients in the IVIG group received on average one dose of IVIG at 0.5 g/kg. No differences in incidence of new infection at 3 months (26.3% vs. 17.4%; P = .71) and 6 months (42.1% vs. 34.8%; P = .63) were observed between the IVIG and non-IVIG groups. Infections based on mild or moderate HGG also had no differences at 3 and 6 months. CONCLUSION: Our findings suggest that a single infusion of IVIG in mild to moderate HGG may have little to no benefit in reducing incidence of new infections. Larger prospective studies are needed to confirm these findings.

Cardiovascular Risks with Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors and Monoclonal Antibody Therapy.

PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) have changed the therapeutic landscape across a range of solid malignancies. However, there is little data regarding the cardiovascular (CV) impact of these agents. The purpose of this review is to discuss reported CV effects, pathophysiology, pre-treatment screening, diagnostic workup, and treatment recommendations in this patient population. RECENT FINDINGS: It is apparent that CV events are not class dependent, and while infrequently reported in clinical trials, unique CV toxicity may occur with EGFR inhibitors, including structural, electrical, and vascular events. There remains an unmet need to fully elucidate the spectrum of CV events associated with EGFR inhibitors. Early CV screening, close clinical monitoring, coupled with a multidisciplinary approach between medical and cardio-oncology is needed to minimize the potentially detrimental impact of cardiotoxicity in this patient population.

Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy.

Importance: Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death. Objective: To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups. Design, Setting, and Participants: A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively. Exposures: The presence of DCM in a proband. Main Outcomes and Measures: Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative. Results: The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]). Conclusions and Relevance: In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives. Trial Registration: ClinicalTrials.gov Identifier: NCT03037632.

Remote versus early corticosteroid wean outcomes in heart transplant recipients in the contemporary era.

PURPOSE: The risks and benefits of remote corticosteroid weaning in heart transplant recipients more than 2 years post-transplant are unknown. We compared outcomes in patients undergoing early and remote steroid weaning after heart transplantation. METHODS: We performed a retrospective study (range 09, 1991-04, 2017). Primary outcomes included short-term and long-term mortality, allograft dysfunction, and burden of rejection. Secondary outcomes included impact on hemoglobin A1c, lipid panel, bone scan T-score, and body mass index. RESULTS: 63 patients underwent corticosteroid weaning between 2012 and 2017. Outcomes of patients weaned early (n = 34; median time from transplant = 1.1 years) were compared with those weaned late (n = 29; median time from transplant = 4.4 years). 52 (82.5%) patients were successfully weaned off corticosteroids. No statistically significant difference in outcomes was found between the early and late weaning groups (p = .20). There were no differences in allograft function (p-value = .16), incidence of rejection (p = .46), or mortality (p = .15). Improvement in metabolic profile was seen in both groups but was not statistically significant. CONCLUSIONS: In heart transplant recipients, remote vs early weaning of corticosteroids is not associated with significant differences in graft function or the incidence of rejection after 1-year follow-up. Moreover, there were no significant differences in survival up to 3 years between the two groups.

Musculoskeletal pathology as an early warning sign of systemic amyloidosis: a systematic review of amyloid deposition and orthopedic surgery.

BACKGROUND: Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival. QUESTIONS/PURPOSES: The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis. METHODS: We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT. RESULTS: This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid. CONCLUSIONS: This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations. LEVEL OF EVIDENCE: Level IV.

A principal components analysis of factors associated with successful implementation of an LVAD decision support tool.

BACKGROUND: A central goal among researchers and policy makers seeking to implement clinical interventions is to identify key facilitators and barriers that contribute to implementation success. Despite calls from a number of scholars, empirical insights into the complex structural and cultural predictors of why decision aids (DAs) become routinely embedded in health care settings remains limited and highly variable across implementation contexts. METHODS: We examined associations between "reach", a widely used indicator (from the RE-AIM model) of implementation success, and multi-level site characteristics of nine LVAD clinics engaged over 18 months in implementation and dissemination of a decision aid for left ventricular assist device (LVAD) treatment. Based on data collected from nurse coordinators, we explored factors at the level of the organization (e.g. patient volume), patient population (e.g. health literacy; average sickness level), clinician characteristics (e.g. attitudes towards decision aid; readiness for change) and process (how the aid was administered). We generated descriptive statistics for each site and calculated zero-order correlations (Pearson's r) between all multi-level site variables including cumulative reach at 12 months and 18 months for all sites. We used principal components analysis (PCA) to examine any latent factors governing relationships between and among all site characteristics, including reach. RESULTS: We observed strongest inclines in reach of our decision aid across the first year, with uptake fluctuating over the second year. Average reach across sites was 63% (s.d. = 19.56) at 12 months and 66% (s.d. = 19.39) at 18 months. Our PCA revealed that site characteristics positively associated with reach on two distinct dimensions, including a first dimension reflecting greater organizational infrastructure and standardization (characteristic of larger, more established clinics) and a second dimension reflecting positive attitudinal orientations, specifically, openness and capacity to give and receive decision support among coordinators and patients. CONCLUSIONS: Successful implementation plans should incorporate specific efforts to promote supportive and mutually informative interactions between clinical staff members and to institute systematic and standardized protocols to enhance the availability, convenience and salience of intervention tool in routine practice. Further research is needed to understand whether "core predictors" of success vary across different intervention types.

A Novel Model Incorporating Pectoralis Muscle Measures to Predict Mortality After Ventricular Assist Device Implantation.

BACKGROUND: We have previously demonstrated that pectoralis muscle mass and tissue attenuation obtained on preoperative CT scans were powerful predictors of mortality after left ventricular assist device implantation. In this analysis, we confirm our findings in a separate left ventricular assist device implantation cohort, and we present a novel, user-friendly mortality-prediction model incorporating these measures. METHODS AND RESULTS: Patients with chest CTs performed ≤ 3 months prior to left ventricular assist device implantation at University of Minnesota (n = 143) and Houston Methodist Hospital (n = 133) were identified. Unilateral pectoralis muscle mass indexed to body surface area (PMI) and attenuation (approximated by mean Hounsfield units) (PHUm) were measured on preoperative chest CT scans. To develop a prediction model incorporating pectoralis muscle measures, we implemented a cross-validated model-selection approach using Cox proportional hazards regression models. The final model included PHUm, PMI, African American race, creatinine, total bilirubin, body mass index, bridge to transplant, and presence or absence of contrast. Receiver-operating characteristic curves for 30-, 90- and 365-day survival were generated. The area under the curve for the model at 30, 90 and 365 days was 0.78, 0.76 and 0.76, respectively. CONCLUSIONS: The Minnesota Pectoralis Risk Score had favorable discrimination in this multicenter dataset. These skeletal-muscle measures appear to add important information to preoperative risk assessment.

Delayed autologous stem cell transplantation following cardiac transplantation experience in patients with cardiac amyloidosis.

This study sought to retrospectively investigate the outcomes of patients with light-chain amyloidosis (AL) with advanced cardiac involvement who were treated with a strategy of heart transplantation (HT) followed by delayed autologous stem cell transplantation (ASCT) at 1-year posttransplant. Patients with AL amyloidosis with substantial cardiac involvement have traditionally had very poor survival (eg, several months). A few select centers have reported their outcomes for HT followed by a strategy of early ASCT (ie, 6 months) for CA. The outcomes of patients undergoing a delayed strategy have not been reported. All patients with AL amyloidosis at a single institution undergoing evaluation for HT from 2004-2018 were included. Retrospective analyses were performed. Sixteen patients underwent HT (including two combined heart-kidney transplant) for AL amyloidosis. ASCT was performed in a total of nine patients to date at a median 13.5 months (12.8-32.9 months) post-HT. Survival was 87.5% at 1 year and 76.6% at 5 years, comparable to institutional outcomes for nonamyloid HT recipients. In addition to these 16 patients, two patients underwent combined heart-lung transplantation. A strategy of delayed ASCT 1-year post-HT for patients with AL amyloidosis is feasible, safe, and associated with comparable outcomes to those undergoing an earlier ASCT strategy.

Inflammatory Cardiomyopathic Syndromes.

Inflammatory activation occurs in nearly all forms of myocardial injury. In contrast, inflammatory cardiomyopathies refer to a diverse group of disorders in which inflammation of the heart (or myocarditis) is the proximate cause of myocardial dysfunction, causing injury that can range from a fully recoverable syndrome to one that leads to chronic remodeling and dilated cardiomyopathy. The most common cause of inflammatory cardiomyopathies in developed countries is lymphocytic myocarditis most commonly caused by a viral pathogenesis. In Latin America, cardiomyopathy caused by Chagas disease is endemic. The true incidence of myocarditis is unknown to the limited utilization and the poor sensitivity of endomyocardial biopsies (especially for patchy diseases such as lymphocytic myocarditis and sarcoidosis) using the gold-standard Dallas criteria. Emerging immunohistochemistry criteria and molecular diagnostic techniques are being developed that will improve diagnostic yield, provide additional clues into the pathophysiology, and offer an application of precision medicine to these important syndromes. Immunosuppression is recommended for patients with cardiac sarcoidosis, giant cell myocarditis, and myocarditis associated with connective tissue disorders and may be beneficial in chronic viral myocarditis once virus is cleared. Further trials of immunosuppression, antiviral, and immunomodulating therapies are needed. Together, with new molecular-based diagnostics and therapies tailored to specific pathogeneses, the outcome of patients with these disorders may improve.

Development of anthracycline-induced dilated cardiomyopathy due to mutation on LMNA gene in a breast cancer patient: a case report.

BACKGROUND: Anthracyclines are highly effective anticancer medication prescribed for the treatment of breast cancer. Nevertheless, the use of anthracyclines as chemotherapeutic agents involves a risk for development of cardiac toxicity which may cause restrictive and dilated cardiomyopathy. Currently, genetic predisposition is not considered as a risk factor for cardiotoxicity associated to the use of anthracyclines. CASE PRESENTATION: We report the case of a 37-years old Panamanian female patient diagnosed with breast cancer who developed clinical signs of severe heart failure after treatment with doxorubicin. A diagnosis of anthracycline induced cardiomyopathy was made and treatment was initiated accordingly. A whole exome sequencing study performed to the patient showed the presence of a missense mutation in LMNA gene, which codifies for lamin A/C. Our results points to a correlation between the LMNA variant and the anthracycline cardiotoxicity developed by the woman. Improvement of the clinical symptoms and the left ventricle ejection fraction was observed after proper treatment. CONCLUSIONS: This case report suggests for the first time a potential genetic predisposition for anthracyclines induced cardiomyopathy in patients with mutations in LMNA gene. Perhaps chemotherapies accelerate or deliver the "second-hit" in the development of DCM in patients with genetic mutations. More data is needed to understand the contribution of LMNA variants that predispose to DCM in patients receiving cardiotoxic therapies.

Recent advances in heart failure.

PURPOSE OF REVIEW: Acute heart failure continues to be a challenge as there is limited benefit of numerous agents that have been tested. Cardiac resynchronization therapy remains standard of care, yet timing and need for implantable cardiac defibrillator has been brought into question with the recent randomized trials. Several recent advances have been made towards management of heart failure both in drug and device therapy. The purpose of this review is to provide an update on the most important recent studies on heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). RECENT FINDINGS: Two new drugs have been added to the armamentarium for HFrEF; ivabradine and angiotensin receptor-neprilysin inhibitors (ARNIs). Initial data from a new left ventricular assist device (LVAD) pump, the HeartMate 3 (HM III), have demonstrated no reports of pump thrombosis at 6 months, but stroke and right ventricle failure continue to be a challenge with comparable rates compared with the HeartMate II. Several large studies in HFpEF failed to show improvement in outcomes and management continues to be geared towards lifestyle modification and symptom relief. SUMMARY: Newer therapies and devices have met with great success, yet there are several therapies that provide no benefit and even harm. A careful review of the recent literature remains instrumental to the effective management of patients with heart failure.