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.

Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives.

BACKGROUND: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). OBJECTIVES: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. METHODS: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. RESULTS: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. CONCLUSIONS: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

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.

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.

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.

Long-Term Outcomes of Implantable Cardioverter-Defibrillator Therapy in the SCD-HeFT.

BACKGROUND: The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) randomized 2,521 patients with moderate heart failure (HF) to amiodarone, placebo drug, or implantable cardioverter-defibrillator (ICD) therapy. Original trial follow-up ended October 31, 2003. Over a median 45.5-month follow-up, amiodarone, compared with placebo, did not affect survival, whereas randomization to an ICD significantly decreased all-cause mortality by 23%. OBJECTIVES: This study sought to describe the extended treatment group survival of the SCD-HeFT cohort. METHODS: Mortality outcomes for the 1,855 patients alive at the end of the SCD-HeFT trial were collected between 2010 and 2011. These data were combined with the 666 deaths from the original study to compare long-term outcomes overall and for key pre-specified subgroups. RESULTS: Median (25th to 75th percentiles) follow-up was 11.0 (10.0 to 12.2) years. On the basis of intention-to-treat analysis, the ICD group had overall survival benefit versus placebo drug (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.028). When treatment benefit was examined as a function of time from randomization, attenuation of the ICD benefit was observed after 6 years (p value for the interaction = 0.0015). Subgroup analysis revealed long-term ICD benefit varied according to HF etiology and New York Heart Association (NYHA) functional class: ischemic HF HR: 0.81; 95% CI: 0.69 to 0.95; p = 0.009; nonischemic HF HR: 0.97; 95% CI: 0.79 to 1.20; p = 0.802; NYHA functional class II HR: 0.76; 95% CI: 0.65 to 0.90; p = 0.001; NYHA functional class III HR: 1.06; 95% CI: 0.86 to 1.31; p = 0.575. CONCLUSIONS: Follow-up of SCD-HeFT patients to 11 years demonstrated heterogenous treatment-related patterns of long-term survival with ICD benefit most evident at 11 years for ischemic HF patients and for those with NYHA functional class II symptoms at trial enrollment. (SCD-HeFT 10 Year Follow-up [SCD-HeFT10 Yr]; NCT01058837).

Impact of valganciclovir prophylaxis duration on cytomegalovirus disease in high-risk donor seropositive/recipient seronegative heart transplant recipients.

BACKGROUND: Few data support use of 6 over 3 months of antiviral prophylaxis for cytomegalovirus (CMV) disease prevention in donor seropositive/recipient seronegative (D+R-) heart transplant recipients (HTR). METHODS: We retrospectively assessed CMV disease and outcomes in 310 adult HTR between July 5, 2005, and December 30, 2016, at our center. Valganciclovir (VGCV) prophylaxis was given for 3-6 months in the D+R- group. Multivariable models evaluated risk factors for CMV disease in patients who received 3 vs 6 months (±1 month) of prophylaxis, with investigation of inverse probability weighting to correct for confounding variables. RESULTS: The incidence of CMV disease among all patients and the D+R- group was 8.7% (27/310) and 26.5% (22/83), respectively, and included syndrome in 22.2% (6/27) and end-organ involvement in 77.8% (21/27). In a multivariable model, 6 vs 3 months of antiviral prophylaxis was not associated with reduced risk for CMV disease (OR 2.28 [95% CI 0.66, 7.91], P = .19). CMV disease in D+R- HTR was associated with higher rates of hospitalization (87.5% [14/16] vs 6.3% [1/16], P < .001) and for a longer duration than in matched D+R- controls without disease. CONCLUSIONS: Cytomegalovirus disease remains a major cause of morbidity in D+R- HTR. In contrast to documented benefit in D+R- lung and kidney recipients, VGCV duration of 6 months was not associated with a lower incidence of CMV disease in D+R- HTR compared to 3-month duration and should be reconsidered in this patient population.

Improving the Use of Primary Prevention Implantable Cardioverter-Defibrillators Therapy With Validated Patient-Centric Risk Estimates.

OBJECTIVES: The authors previously developed the Seattle Proportional Risk Model (SPRM) in systolic heart failure patients without implantable cardioverter-defibrillators (ICDs)to predict the proportion of deaths that were sudden. They subsequently validated the SPRM in 2 observational ICD data sets. The objectives in the present study were to determine whether this validated model could improve identification of clinically important variations in the expected magnitude of ICD survival benefit by using a pivotal randomized trial of primary prevention ICD therapy. BACKGROUND: Recent data show that <50% of nominally eligible subjects receive guideline- recommended primary prevention ICDs. METHODS: In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), a placebo-controlled ICD trial in 2,521 patients with an ejection fraction ≤35% and symptomatic heart failure, we tested the use of patient-level SPRM-predicted probability of sudden death (relative to that of non-sudden death) as a summary measurement of the potential for ICD benefit. A Cox proportional hazards model was used to estimate variations in the relationship between patient-level SPRM predictions and ICD benefit. RESULTS: Relative to use of mortality predictions with the Seattle Heart Failure Model, the SPRM was much better at partitioning treatment benefit from ICD therapy (effect size was 2- to 3.6-fold larger for the ICD×SPRM interaction). ICD benefit varied significantly across SPRM-predicted risk quartiles: for all-cause mortality, a +10% increase with ICD therapy in the first quartile (highest risk of death, lowest proportion of sudden death) to a decrease of 66% in the fourth quartile (lowest risk of death, highest proportion of sudden death; p = 0.0013); for sudden death mortality, a 19% reduction in SPRM quartile 1 to 95% reduction in SPRM quartile 4 (p < 0.0001). CONCLUSIONS: In symptomatic systolic heart failure patients with a Class I recommendation for primary prevention ICD therapy, the SPRM offers a useful patient-centric tool for guiding shared decision making.

Systematic donor selection review process improves cardiac transplant volumes and outcomes.

BACKGROUND: Heart transplant remains the definitive therapy for advanced heart failure patients but is limited by organ availability. We identified a large number of donor hearts from our organ procurement organization (OPO) being exported to other regions. METHODS: We engaged a multidisciplinary team including transplant surgeons, cardiologists, and our OPO colleagues to identify opportunities to improve our center-specific organ utilization rate. We performed a retrospective analysis of donor offers before and after institution of a novel review process. RESULTS: Each donor offer made to our program was reviewed on a monthly basis from July 2013 to June 2014 and compared with the previous year. This review process resulted in a transplant utilization rate of 28% for period 1 versus 49% for period 2 (P = .007). Limiting the analysis to offers from our local OPO changed our utilization rate from 46% to 75% (P = .02). Transplant volume increased from 22 to 35 between the 2 study periods. Thirty-day and 1-year mortality were unchanged over the 2 periods. A total of 58 hearts were refused by our center and transplanted at other centers. During period 1, the 30-day and 1-year survival rates for recipients of those organs were 98% and 90%, respectively, comparable with our historical survival data. CONCLUSIONS: The simple process of systematically reviewing donor turndown events as a group tended to reduce variability, increase confidence in expanded criteria for donors, and resulted in improved donor organ utilization and transplant volumes.

Right ventricular sarcoidosis: is it time for updated diagnostic criteria?

A 55-year-old woman with a history of complete heart block, atrial flutter, and progressive right ventricular failure was referred to our tertiary care center to be evaluated for cardiac transplantation. The patient's clinical course included worsening right ventricular dysfunction for 3 years before the current evaluation. Our clinical findings raised concerns about arrhythmogenic right ventricular cardiomyopathy. Noninvasive imaging, including a positron emission tomographic scan, did not reveal obvious myocardial pathologic conditions. Given the end-stage nature of the patient's right ventricular failure and her dependence on inotropic agents, she underwent urgent listing and subsequent heart transplantation. Pathologic examination of the explanted heart revealed isolated right ventricular sarcoidosis with replacement fibrosis. Biopsy samples of the cardiac allograft 6 months after transplantation showed no recurrence of sarcoidosis. This atypical presentation of isolated cardiac sarcoidosis posed a considerable diagnostic challenge. In addition to discussing the patient's case, we review the relevant medical literature and discuss the need for updated differential diagnostic criteria for end-stage right ventricular failure that mimics arrhythmogenic right ventricular cardiomyopathy.

Use of the 6-min walk distance to identify variations in treatment benefits from implantable cardioverter-defibrillator and amiodarone: results from the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial).

OBJECTIVES: The purpose of this study was to determine if 6-min walk test data assists in treatment decisions for patients with heart failure. BACKGROUND: In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), a pre-specified subgroup analysis showed that patients with New York Heart Association functional class III symptoms did not benefit from implantable cardioverter-defibrillator (ICD) therapy and appeared to be harmed by amiodarone, whereas New York Heart Association functional class II patients obtained significant survival benefit from ICD. We postulated that a more objective measure of functional capacity, such as 6-min walk (6MW) distance, might provide a better tool for selecting these preventive therapies. METHODS: A 6MW test was performed before randomization in 2,397 patients. Median follow-up was 45.5 months. All-cause mortality was the primary endpoint, with cause-specific mortality (heart failure, arrhythmic) examined in secondary analyses. RESULTS: The hazard ratios (HRs) for ICD therapy compared to placebo were estimated within tertiles of baseline 6MW distance: HR: 0.42 (95% confidence interval [CI]: 0.26 to 0.66) for 6MW distance >386 m (top tertile); HR: 0.57 (95% CI: 0.39 to 0.83) for 6MW distance 288 to 386 m (middle tertile); and HR: 1.02 (95% CI: 0.75 to 1.39) for 6MW distance <288 m (bottom tertile). The corresponding HRs for amiodarone compared to placebo were 0.68 (95% CI: 0.46 to 1.02) for the top, 0.86 (95% CI: 0.61 to 1.21) for the middle, and 1.56 (95% CI: 1.17 to 2.09) for the bottom tertile. The 6MW distance was inversely related to heart failure-related mortality but not to arrhythmic mortality. ICD therapy reduced arrhythmic mortality in the top 2 tertiles of 6MW, but had no effect on heart failure mortality. CONCLUSIONS: A baseline 6MW distance <288 m identified a subgroup of SCD-HeFT patients who were harmed by amiodarone therapy and did not benefit from ICD. (Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]; NCT00000609).

Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used in advanced heart failure patients. Despite proven efficacy, optimal timing of LVAD implantation is not well defined. METHODS: Patients receiving an LVAD were prospectively recorded. Laboratory and clinical data were extracted and used to calculate the predicted survival with medical therapy using the Seattle Heart Failure Model (SHFM). This was compared with observed survival, hospital length of stay and timeliness of discharge. RESULTS: We identified 104 patients. Survival with an LVAD vs SHFM predicted survival was 69% vs 11% at 1 year, corresponding to a hazard ratio of 0.17 (p < 0.0001). SHFM-estimated 1-year survival with medical therapy increased from 4% in 1997 to 2004 to 25% in 2007-2008 (p < 0.0001). Subgroup analysis of higher vs lower risk LVAD patients showed observed 1-year survival of 83% vs 57% (p = 0.04). The lower risk group had a shorter length of stay (46 vs 75 days, p = 0.03), along with higher rates of discharge prior to transplant (88% vs 61%, p = 0.01) and discharge within 60 days of LVAD placement (77% vs 52%, p = 0.03). CONCLUSIONS: The SHFM allows prediction of important features of a patient's hospital course post-operatively, including length of stay and 1-year survival. Given evidence of improved survival and shorter hospital stay in lower risk patients, earlier LVAD placement based on a prediction model like the SHFM should be considered in advanced heart failure patients. The SHFM may have utility as a virtual control arm for single-arm LVAD trials.

Maximizing survival benefit with primary prevention implantable cardioverter-defibrillator therapy in a heart failure population.

BACKGROUND: Although implantable cardioverter-defibrillator (ICD) therapy reduces mortality in moderately symptomatic heart failure patients with an ejection fraction 20%), no benefit of ICD treatment was seen. Projected over each patient's predicted lifespan, ICD treatment added 6.3, 4.1, 3.0, 1.9, and 0.2 additional years of life in the lowest- to highest-risk groups, respectively. CONCLUSIONS: A clinical risk prediction model identified subsets of moderately symptomatic heart failure patients in SCD-HeFT in whom single-lead ICD therapy was of no benefit and other subsets in which benefit was substantial.

Prognostic importance of defibrillator shocks in patients with heart failure.

BACKGROUND: Patients with heart failure who receive an implantable cardioverter-defibrillator (ICD) for primary prevention (i.e., prevention of a first life-threatening arrhythmic event) may later receive therapeutic shocks from the ICD. Information about long-term prognosis after ICD therapy in such patients is limited. METHODS: Of 829 patients with heart failure who were randomly assigned to ICD therapy, we implanted the ICD in 811. ICD shocks that followed the onset of ventricular tachycardia or ventricular fibrillation were considered to be appropriate. All other ICD shocks were considered to be inappropriate. RESULTS: Over a median follow-up period of 45.5 months, 269 patients (33.2%) received at least one ICD shock, with 128 patients receiving only appropriate shocks, 87 receiving only inappropriate shocks, and 54 receiving both types of shock. In a Cox proportional-hazards model adjusted for baseline prognostic factors, an appropriate ICD shock, as compared with no appropriate shock, was associated with a significant increase in the subsequent risk of death from all causes (hazard ratio, 5.68; 95% confidence interval [CI], 3.97 to 8.12; P<0.001). An inappropriate ICD shock, as compared with no inappropriate shock, was also associated with a significant increase in the risk of death (hazard ratio, 1.98; 95% CI, 1.29 to 3.05; P=0.002). For patients who survived longer than 24 hours after an appropriate ICD shock, the risk of death remained elevated (hazard ratio, 2.99; 95% CI, 2.04 to 4.37; P<0.001). The most common cause of death among patients who received any ICD shock was progressive heart failure. CONCLUSIONS: Among patients with heart failure in whom an ICD is implanted for primary prevention, those who receive shocks for any arrhythmia have a substantially higher risk of death than similar patients who do not receive such shocks.

Incidence and clinical features of ganciclovir-resistant cytomegalovirus disease in heart transplant recipients.

BACKGROUND: The incidence and clinical and virologic aspects of ganciclovir-resistant cytomegalovirus (CMV) disease have not been well-characterized in heart transplant recipients. METHODS: We retrospectively analyzed all patients who underwent their first heart transplantation during the period from 1 January 1995 through 30 June 2005 at a single health care center. Cox proportional hazard regression was used to assess the relationship between clinical variables and CMV disease. Portions of the UL97 gene were sequenced in patients with slow clinical and/or virologic response to ganciclovir therapy. RESULTS: Cytomegalovirus disease developed in 32 (11.7%) of 274 patients at a median of 4.2 months after transplantation (range, 1.8-11.6 months after transplantation) and was independently associated with donor-seropositive/recipient-seronegative (D+/R-) serostatus (adjusted hazard ratio, 6.93; P<.001). The incidence of ganciclovir-resistant CMV disease was 1.5% overall (4 of 274 patients), 5% among D+/R- serostatus recipients (4 of 80 patients), and 12.5% among patients who developed CMV disease (4 of 32 patients). Ganciclovir-resistant CMV disease was significantly associated with D+/R- serostatus (4 [5%] of 80 vs. 0 [0%] of 153 patients; P=.02), greater prior exposure to ganciclovir (median duration of exposure, 150 vs. 69 days; P=.003), and substantial morbidity, including prolonged CMV-associated hospitalization (median duration of hospitalization, 66 vs. 0 days; P<.01). CONCLUSIONS: CMV disease, including ganciclovir-resistant disease, is an important clinical problem in D+/R- heart transplant recipients who receive antiviral prophylaxis. Strategies specifically designed to reduce the incidence and impact of CMV disease in this population are warranted.

Is pre-transplant vascular disease a risk factor for mortality and morbidity after heart transplantation?

BACKGROUND: Severe vascular disease is a relative contraindication to heart transplantation (HTx). We addressed the effect of vascular disease on HTx outcomes. METHODS: This is a nonconcurrent cohort study of 402 patients who received HTx at our institution between 1985 and 2004. Pre-transplant vascular evaluation included carotid, lower extremity, and renal artery duplex studies, and CT angiogram when indicated. Patients with severe and nontreatable vascular disease were excluded. Patients were divided into Group 1: those with pre-transplant vasculopathy, and Group 2: those without pre-transplant vasculopathy. Group 1 had 24 patients with 25 vascular lesions: 1 aortic dissection, 2 abdominal aortic aneurysm (AAA)'s, 5 carotid artery stenoses, 1 renal artery stenosis, and 16 peripheral vascular lesions. Interventions were performed to 15 lesions prior to HTx and to 2 lesions after HTx. RESULTS: Median follow-up was 5.5 years. Group 1 had higher incidence of ischemic cardiomyopathy (p<0.001), hypertension (p=0.028), chronic obstructive pulmonary disease (COPD) (p=0.004), and smoking history (p<0.001). There were no differences in sex, hyperlipidemia, diabetes, stroke, or renal dysfunction. Multivariate analysis revealed odds of post-transplant death in Group 1 was 1.4 (95% CI: 0.48-4.1, p=0.54) times greater than that in Group 2. Cox proportional hazards model for survival showed a 50% increase in the hazard of death in patients with pre-transplant vasculopathy, but without statistical significance. Group 1 had higher incidence of post-transplant stroke (p=0.001) but no difference in allograft coronary atherosclerosis. CONCLUSIONS: Pre-transplant vascular disease seems to have negative effect on outcomes after HTx. Larger scale study is needed for further evaluation.

Open-chest management after heart transplantation.

Postcardiotomy open-chest management has been widely used in cardiac surgery. Although this strategy can be applied to heart transplantation, the use of immunosuppressants in transplant recipients raises particular concerns about sternal wound infection and impaired healing. We performed a retrospective review of 403 patients who had undergone 410 heart transplantations at our institution from 1985 through 2004. Among them, 9 patients (2.2%) had open-chest management postoperatively. There were 8 men and 1 woman, with a mean age of 58 +/- 7 years. The graft ischemic time ranged from 130 to 374 minutes (mean, 218 +/- 99 min), and the cardiopulmonary bypass time ranged from 98 to 360 minutes (mean, 210 +/- 69 min). In all cases, the reason for open-chest management was hemodynamic lability that precluded chest closure after transplantation. One patient also experienced postoperative bleeding. All patients underwent delayed sternal closure between postoperative days 1 and 11 (median, 4 days). Delayed sternal closure did not cause any significant hemodynamic changes. One patient died of stroke on postoperative day 22. No patient had sternal wound infection or impaired wound healing during the follow-up period. We conclude that, when required, open-chest management is an effective and safe measure for hemodynamically unstable heart transplant patients.

Utility of impedance cardiography for the identification of short-term risk of clinical decompensation in stable patients with chronic heart failure.

OBJECTIVES: This study sought to assess the potential utility of impedance cardiography (ICG) in predicting clinical deterioration in ambulatory patients with heart failure (HF). BACKGROUND: Impedance cardiography uses changes in thoracic electrical impedance to estimate hemodynamic variables, but its ability to predict clinical events has not been evaluated. METHODS: We prospectively evaluated 212 stable patients with HF and a recent episode of clinical decompensation who underwent serial clinical evaluation and blinded ICG testing every 2 weeks for 26 weeks and were followed up for the occurrence of death or worsening HF requiring hospitalization or emergent care. RESULTS: During the study, 59 patients experienced 104 episodes of decompensated HF (16 deaths, 78 hospitalizations, and 10 emergency visits). Multivariate analysis identified 6 clinical and ICG variables that independently predicted an event within 14 days of assessment. These included three clinical variables (visual analog score, New York Heart Association functional class, and systolic blood pressure) and three ICG parameters (velocity index, thoracic fluid content index, and left ventricular ejection time). The three ICG parameters combined into a composite score was a powerful predictor of an event during the next 14 days (p = 0.0002). Visits with a high-risk composite score had 2.5 times greater likelihood and those with a low-risk score had a 70% lower likelihood of a near-term event compared with visits at intermediate risk. CONCLUSIONS: These results suggest that when performed at regular intervals in stable patients with HF with a recent episode of clinical decompensation, ICG can identify patients at increased near-term risk of recurrent decompensation.

Expectant management is safe for cholelithiasis after heart transplant.

BACKGROUND: The optimal management of cholelithiasis after heart transplant remains unclear. We use expectant management based on symptoms, without screening studies or prophylactic treatment. We hypothesized that expectant management for cholelithiasis after heart transplant does not result in significant mortality or morbidity from gallstone-associated disease. METHODS: Between November 1985 and August 2004, 409 heart transplants were performed in 402 recipients at the University of Washington. This is a non-concurrent cohort study of these recipients. RESULTS: Among recipients, 24 underwent cholecystectomy before heart transplant. After transplant, in the remaining 378 patients, 34 were found to have gallstones during the observation period. There was no mortality from gallstone-associated disease. Thirty patients developed morbidity from gallstones, including 25 cases of biliary colic, 3 of acute cholecystitis and 2 of pancreatitis, and there was 1 abnormal liver function test. Acute cholecystitis and pancreatitis were treated with conservative management followed by cholecystectomy. Cholecystectomy was performed in 32 patients after transplant. Indications included symptomatic cholelithiasis in 31, and prophylactic cholecystectomy prior to kidney transplant in 1. The laparoscopic approach was performed in 25 of these 32 patients. There was no mortality from cholecystectomy, but there were 4 complications: surgical site infections (n = 2); wound dehiscence (n = 1); and bile duct injury (n = 1). Median hospital stay was 1 day. CONCLUSIONS: Our expectant management for cholelithiasis after heart transplant resulted in no mortality or significant morbidity related to delay in treatment. Symptomatic cholelithiasis was successfully treated with cholecystectomy, mostly with the laparoscopic approach. We believe expectant management is safe for patients after heart transplant.