Mosi K. Bennett

Evaluation of the Role of Endomyocardial Biopsy in 851 Patients With Unexplained Heart Failure From 2000–2009

Background—Endomyocardial biopsy (EMB) is often considered when the pathogenesis of heart failure cannot be determined by noninvasive testing. Uncertainty remains about the diagnostic and clinical use of EMB in various clinical scenarios. Methods and Results—We examined the characteristics of a cohort of patients with unexplained heart failure who underwent EMB at a tertiary care medical center. We categorized each patient into a clinical scenario as outlined by the 2007 AHA/ACC/ESC guidelines and determined the number of times EMB provided a diagnosis or altered the clinical course. A total of 851 patients underwent EMB from 2000–2009. Overall, 25.5% of EMBs provided a diagnosis and 22.7% of EMBs changed clinical course. Heart failure associated with unexplained restrictive cardiomyopathy was the most common clinical scenario, comprising 33.6% (286/851) of EMBs, and 84 (29.4%) of these EMBs were diagnostic. EMB for unexplained heart failure of <2 weeks duration had a diagnostic yield at 35% (39/109). There were 4 uncommon scenarios where EMB had a high diagnostic and clinical yield. There were 16 complications for an overall rate of 1.9%. Conclusions—We confirm that EMB is useful in acute onset unexplained cardiomyopathy. We demonstrate a role for EMB in suspected infiltrative disease and in the management of rare clinical scenarios, such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Our results suggest low use of EMB in chronic heart failure that responds to usual care.

Odor-evoked gene regulation and visualization in olfactory receptor neurons.

Odorant-evoked activity contributes to olfactory epithelium organization and axon targeting. We examined the consequences on gene expression of a genetic disruption of the channel responsible for olfactory transduction. Genes encoding calcium-binding EF-hand motifs, were among the most highly regulated transcripts consistent with the central role of Ca(2+) influx in neuronal depolarization. Several genes encoding integral membrane proteins are also highly regulated. One gene, Lrrc3b, was regulated more than 10-fold by odorant activity. Changes in expression occur within thirty minutes and are maintained for several hours. In genetic disruptions of Lrrc3b, a Lrrc3b-promoter-driven reporter adopts the activity-regulated expression of the endogenous gene. Individual olfactory glomeruli have a wide spectrum of activity levels that can be modulated by altering odor exposure. The Lrrc3b reporter mouse permits direct assessment of activity in identified glomeruli. In stable odorant environments, activity-regulated proteins provide a characteristic signature that is correlated with the olfactory receptor they express.

Increased lipofuscin on endomyocardial biopsy predicts greater cardiac improvement in adolescents and young adults

BACKGROUND The presence of interstitial fibrosis and lipofuscin in endomyocardial biopsies may indicate the chronicity of heart failure. Fibrosis is known to increase in the failing heart. Lipofuscin increases with age, but its relationship to heart function is unknown. This study investigated whether lipofuscin or fibrosis had predictive utility in indicating function or adverse event (death, transplant, assist device placement) at 1 year postbiopsy in adolescents and young adults. METHODS A retrospective analysis was performed on nontransplant endomyocardial biopsies between 2000 and 2009 from individuals aged 10-40 years. Clinical and demographic information including ejection fraction (EF), EF at 1 year, and adverse events were obtained as available. Lipofuscin and fibrosis were scored retrospectively in a blinded fashion for 201 biopsies. Linear regression and Cox proportional hazard models were used for multivariable analysis. RESULTS Increasing lipofuscin strongly correlated with patient age (P<.0001). Higher lipofuscin levels were correlated with a better EF at 1 year (P=.02). This remained significant (P=.04) after adjusting for age. The degree of fibrosis did not associate with any clinical variable and had no predictive capabilities in this study. CONCLUSIONS This is the first study to incorporate lipofuscin in predicting future heart function. We found that more lipofuscin correlates with better EFs at 1 year, suggesting that lipofuscin is a marker for improved cardiac compensation. This information can help clinicians devise treatment plans for individuals in this age group.

S100A1 in Human Heart Failure Lack of Recovery Following Left Ventricular Assist Device Support

Background—We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results—We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as &bgr;-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. &bgr;-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, &bgr;-adrenergic receptor, and the inotropic response fully recovered. Conclusions—S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.Background— We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results— We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered. Conclusions— S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.

Outcomes and predictors of recovery in acute-onset cardiomyopathy: A single-center experience of patients undergoing endomyocardial biopsy for new heart failure

BACKGROUND About one-third of patients with unexplained acute-onset heart failure (HF) recover left ventricular (LV) function; however, characterization of these patients in the setting of contemporary HF therapies is limited. We aim to describe baseline characteristics and predictors of recovery in patients with acute-onset cardiomyopathy. METHODS We previously described 851 patients with unexplained HF undergoing endomyocardial biopsy. In this study, 235 patients with acute-onset HF were further retrospectively examined. RESULTS Follow-up LV ejection fraction (LVEF) was available for 138 patients. At 1 year, 48 of 138 (33%) had LVEF recovery (follow-up LVEF ≥50%), and 90 of 138 (65%) had incomplete or lack of recovery. Higher cardiac index (P=.019), smaller LV diastolic diameter (P=.002), and lack of an intraventricular conduction delay (IVCD) (P=.002) were associated with LVEF recovery. IVCD (P=.001) and myocarditis (P=.016) were independent predictors of the composite end point of death, LV assist device placement, and/or transplant at 1 year. Those with an IVCD had a significantly lower 1-year survival than those without (P=.007). CONCLUSIONS Patients with a smaller LV end-diastolic diameter, higher cardiac index, and lack of IVCD at presentation for acute-onset HF were more likely to have LVEF recovery. IVCD was a poor prognostic marker in all patients presenting with acute cardiomyopathy.

S100A1 in Human Heart FailureCLINICAL PERSPECTIVE

Background—We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results—We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as &bgr;-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. &bgr;-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, &bgr;-adrenergic receptor, and the inotropic response fully recovered. Conclusions—S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.Background— We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results— We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered. Conclusions— S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.

EFFECT OF PULMONARY PRESSURE MONITORING (CARDIOMEMS HEART FAILURE SYSTEM, ST. JUDE MEDICAL) ON HOSPITAL ADMISSIONS AND EMERGENCY DEPARTMENT VISITS: A MULTICENTER REAL WORLD EXPERIENCE

Background: The CHAMPION trial showed a decrease in hospitalizations using the CardioMEMS HF System in patients with heart failure (HF). To our knowledge, there is no published multicenter data on the use of this device outside of a clinical trial setting. Methods: We retrospectively collected data

S100A1 in Human Heart FailureCLINICAL PERSPECTIVE: Lack of Recovery Following Left Ventricular Assist Device Support

Background—We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results—We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as &bgr;-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. &bgr;-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, &bgr;-adrenergic receptor, and the inotropic response fully recovered. Conclusions—S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.Background— We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results— We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered. Conclusions— S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.

S100A1 in Human Heart Failure: Lack of Recovery Following LVAD Support

Background—We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results—We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as &bgr;-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. &bgr;-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, &bgr;-adrenergic receptor, and the inotropic response fully recovered. Conclusions—S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.Background— We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling. Methods and Results— We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device–supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device–supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered. Conclusions— S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed.