Effect of beta blocker use and type on hypoglycemia risk among hospitalized insulin requiring patients.

BACKGROUND: Although beta blockers could increase the risk of hypoglycemia, the difference between subtypes on hypoglycemia and mortality have not been studied. This study sought to determine the relationship between type of beta blocker and incidence of hypoglycemia and mortality in hospitalized patients. METHODS: We retrospectively identified non-critically ill hospitalized insulin requiring patients who were undergoing bedside glucose monitoring and received either carvedilol or a selective beta blocker (metoprolol or atenolol). Patients receiving other beta blockers were excluded. Hypoglycemia was defined as any glucose < 3.9 mmol/L within 24 h of admission (Hypo1day) or throughout hospitalization (HypoT) and any glucose < 2.2 mmol/L throughout hospitalization (Hyposevere). RESULTS: There were 1020 patients on carvedilol, 886 on selective beta blockers, and 10,216 on no beta blocker at admission. After controlling for other variables, the odds of Hypo1day, HypoT and Hyposevere were higher for carvedilol and selective beta blocker recipients than non-recipients, but only in basal insulin nonusers. The odds of Hypo1day (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.28, 3.09, p = 0.0002) and HypoT (OR 1.38, 95% CI 1.02, 1.86, p = 0.03) but not Hyposevere (OR 1.90, 95% CI 0.90, 4.02, p = 0.09) were greater for selective beta blocker vs. carvedilol recipients in basal insulin nonusers. Hypo1day, HypoT, and Hyposevere were all associated with increased mortality in adjusted models among non-beta blocker and selective beta blocker recipients, but not among carvedilol recipients. CONCLUSIONS: Beta blocker use is associated with increased odds of hypoglycemia among hospitalized patients not requiring basal insulin, and odds are greater for selective beta blockers than for carvedilol. The odds of hypoglycemia-associated mortality are increased with selective beta blocker use or nonusers but not in carvedilol users, warranting further study.

Organizational Strategies to Create a Burnout-resistant Environment.

Burnout afflicts a significant number of academic faculty and clinicians. There are many efforts the individual can undertake to prevent or lessen burnout. However, it not likely these will be successful without the institutional environment that promotes and atmosphere that assures self-efficacy, a sense of value and meaning and clear communication between leaders and members of the organization. This review discusses the factors that organizations and their leaders can leverage to create such an environment. Such measures are critically important not only for the health of the individual but to the organization as well.

Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium.

BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the ß-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

Regulatory Variants Modulate Protein Kinase C α (PRKCA) Gene Expression in Human Heart.

PURPOSE: Protein kinase C α (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting PRKCA expression in human heart, and evaluate attributable risk of heart disease. METHODS: mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify cis-acting regulatory variants. Potential regulatory regions were tested with luciferase reporter gene assays and further evaluated in GTEx and genome-wide association studies. RESULTS: Located in a region with robust enhancer activity in luciferase reporter assays, rs9909004 (T > C, minor allele frequency =0.47) resides in a haplotype displaying strong eQTLs for PRKCA in heart (p = 1.2 × 10-23). The minor C allele is associated with both decreased PRKCA mRNA expression and decreased risk of phenotypes characteristic of heart failure in GWAS analyses (QT interval p = 3.0 × 10-14). While rs9909004 is the likely regulatory variant, other variants in high linkage disequilibrium cannot be excluded. Distinct regulatory variants appear to affect expression in other tissues. CONCLUSIONS: The haplotype carrying rs9909004 influences PRKCA expression in the heart and is associated with traits linked to heart failure, potentially affecting therapy of heart failure.

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

PURPOSE: This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS: Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = 33). RESULTS: CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p = 0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p = 0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day). CONCLUSION: Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

Dysfunction in the ßII spectrin-dependent cytoskeleton underlies human arrhythmia.

BACKGROUND: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. METHODS AND RESULTS: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that ßII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. ßII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/ßII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac ßII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, ßII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in ßII spectrin-deficient mice. CONCLUSIONS: Our findings identify ßII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

Dysfunction of the ß2-spectrin-based pathway in human heart failure.

ß2-Spectrin is critical for integrating membrane and cytoskeletal domains in excitable and nonexcitable cells. The role of ß2-spectrin for vertebrate function is illustrated by dysfunction of ß2-spectrin-based pathways in disease. Recently, defects in ß2-spectrin association with protein partner ankyrin-B were identified in congenital forms of human arrhythmia. However, the role of ß2-spectrin in common forms of acquired heart failure and arrhythmia is unknown. We report that ß2-spectrin protein levels are significantly altered in human cardiovascular disease as well as in large and small animal cardiovascular disease models. Specifically, ß2-spectrin levels were decreased in atrial samples of patients with atrial fibrillation compared with tissue from patients in sinus rhythm. Furthermore, compared with left ventricular samples from nonfailing hearts, ß2-spectrin levels were significantly decreased in left ventricle of ischemic- and nonischemic heart failure patients. Left ventricle samples of canine and murine heart failure models confirm reduced ß2-spectrin protein levels. Mechanistically, we identify that ß2-spectrin levels are tightly regulated by posttranslational mechanisms, namely Ca(2+)- and calpain-dependent proteases. Furthermore, consistent with this data, we observed Ca(2+)- and calpain-dependent loss of ß2-spectrin downstream effector proteins, including ankyrin-B in heart. In summary, our findings illustrate that ß2-spectrin and downstream molecules are regulated in multiple forms of cardiovascular disease via Ca(2+)- and calpain-dependent proteolysis.

The Frank-Starling mechanism involves deceleration of cross-bridge kinetics and is preserved in failing human right ventricular myocardium.

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and ß-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients.

A comparison of continuous intravenous insulin and subcutaneous insulin among patients with type 2 diabetes and congestive heart failure exacerbation.

BACKGROUND: The study aims to determine whether the route of insulin administration influences glycaemic variability and inflammatory or neurohormonal markers in patients with type 2 diabetes and congestive heart failure (CHF) exacerbation. METHODS: Patients (n = 65) were randomized to intravenous (IV) insulin (duration 48 h) or subcutaneous (SQ) insulin. Inflammatory cytokines and markers of lipid oxidation, high-frequency heart rate variability (n = 27) and cardiac impedance (pre-ejection period, n = 28) were used to estimate parasympathetic and sympathetic tone in patients with valid cardiac data. Glycaemic variability was measured using a continuous glucose monitor. RESULTS: Mean glucose was lower (7.7 ± 1.2 vs 9.4 ± 2.7 mmol/L, p = 0.004), coefficient of variation was higher (p = 0.03) and glycaemic lability index was similar on day 1 in the IV group compared with the SQ group, but groups were similar by day 2. The IV group had more confirmed hypoglycaemia (p = 0.005). There were no differences in hospital readmission or hospital length of stay between groups. There were no differences in CHF biomarkers, heart rate variability or pre-ejection period between groups. Increasing log glycaemic lability index was associated with lower on-treatment pre-ejection period (p = 0.03) while increasing coefficient of variation was associated with increasing brain natriuretic peptide (p = 0.004) and paroxonase-1 (p = 0.02). Other univariable analyses were not significant. CONCLUSIONS: There were modest, transient differences in glucose control between IV and SQ insulin in hospitalized CHF patients. However, the analyses do not support a link between insulin route and inflammatory markers or autonomic tone. Further study is needed to assess outcomes in hospitalized CHF patients.

Individual and Combined Associations of Genetic Variants in CYP3A4, CYP3A5, and SLCO1B1 With Simvastatin and Simvastatin Acid Plasma Concentrations.

Our objective was to evaluate the associations of genetic variants affecting simvastatin (SV) and simvastatin acid (SVA) metabolism [the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)*22 and the gene encoding cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5)*3] and transport [the gene encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) T521C] with 12-hour plasma SV and SVA concentrations. The variants were genotyped, and the concentrations were quantified by high performance liquid chromatography-tandem mass spectrometry in 646 participants of the Cholesterol and Pharmacogenetics clinical trial of 40 mg/d SV for 6 weeks. The genetic variants were tested for association with 12-hour plasma SV, SVA, or the SVA/SV ratio using general linear models. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentration. CYP3A4*1/*22 participants had 58% higher 12-hour plasma SV concentration compared with CYP3A4*1/*1 participants (P = 0.006). SLCO1B1 521T/C and 521C/C participants had 71% (P < 0.001) and 248% (P < 0.001) higher 12-hour plasma SVA compared with SLCO1B1 521T/T participants, respectively. CYP3A4 and SLCO1B1 genotypes combined categorized participants into low (<1), intermediate (≈1), and high (>1) SVA/SV ratio groups (P = 0.001). In conclusion, CYP3A4*22 and SLCO1B1 521C were significantly associated with increased 12-hour plasma SV and SVA concentrations, respectively. CYP3A5*3 was not significantly associated with 12-hour plasma SV or SVA concentrations. The combination of CYP3A4*22 and SLCO1B1 521C was significantly associated with SVA/SV ratio, which may translate into different clinical SV risk/benefit profiles.

Molecular mechanisms underlying cardiac protein phosphatase 2A regulation in heart.

Kinase/phosphatase balance governs cardiac excitability in health and disease. Although detailed mechanisms for cardiac kinase regulation are established, far less is known regarding cardiac protein phosphatase 2A (PP2A) regulation. This is largely due to the complexity of the PP2A holoenzyme structure (combinatorial assembly of three subunit enzyme from >17 subunit genes) and the inability to segregate "global" PP2A function from the activities of multiple "local" holoenzyme populations. Here we report that PP2A catalytic, regulatory, and scaffolding subunits are tightly regulated at transcriptional, translational, and post-translational levels to tune myocyte function at base line and in disease. We show that past global read-outs of cellular PP2A activity more appropriately represent the collective activity of numerous individual PP2A holoenzymes, each displaying a specific subcellular localization (dictated by select PP2A regulatory subunits) as well as local specific post-translational catalytic subunit methylation and phosphorylation events that regulate local and rapid holoenzyme assembly/disassembly (via leucine carboxymethyltransferase 1/phosphatase methylesterase 1 (LCMT-1/PME-1). We report that PP2A subunits are selectively regulated between human and animal models, across cardiac chambers, and even within specific cardiac cell types. Moreover, this regulation can be rapidly tuned in response to cellular activation. Finally, we report that global PP2A is altered in human and experimental models of heart disease, yet each pathology displays its own distinct molecular signature though specific PP2A subunit modulatory events. These new data provide an initial view into the signaling pathways that govern PP2A function in heart but also establish the first step in defining specific PP2A regulatory targets in health and disease.

Myocardial viability and survival in ischemic left ventricular dysfunction.

BACKGROUND: The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain. METHODS: In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of prespecified thresholds. RESULTS: Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P=0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P=0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P=0.53). CONCLUSIONS: The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH ClinicalTrials.gov number, NCT00023595.).

The impact of insurance and socioeconomic status on outcomes for patients with left ventricular assist devices.

BACKGROUND: There has been a steady increase of patients living in the community with Left Ventricular Assist Devices (LVADs). There is a significant gap in our fund of knowledge with respect to the impact that insurance and socioeconomic status has on outcomes for LVAD patients. We thus hypothesize that low neighborhood socioeconomic status and receipt of Medicaid, respectively, lead to earlier readmissions, earlier death, as well as longer time to transplantation among LVAD patients. METHODS: This was a retrospective review of 101 patients using existing data in the medical information warehouse database at The Ohio State University Medical Center. Primary outcomes measured included time to first event (first readmission or death), death, and time to rehospitalization. Our secondary outcome of interest included time from LVAD implantation to cardiac transplantation. RESULTS: Recipients of Medicaid did not have an increased risk of adverse events compared with patients without Medicaid coverage. Low Median Household Income (MHI) was associated with an increased risk of readmission (log-rank P = 0.0069) and time to first event (log-rank P = 0.0088). Bridge to transplantation was the only independent predictor of time to death (Hazard Ratio 2.1, [95% confidence interval = 1.03-4.37]). Low MHI and a history of atherosclerosis were both significant predictors for readmission and time to first event. Aldosterone antagonist use decreased the risk of readmission or time to first event by 46%. CONCLUSIONS: LVAD recipients with a low MHI were more likely to be readmitted to the hospital after LVAD implantation. Whether these patients are adequately monitored on an outpatient basis remains unclear.

Impact of Mental Health Treatment on Outcomes in Patients With Heart Failure and Ischemic Heart Disease.

BACKGROUND: There is conflicting evidence as to the impact of mental health treatment on outcomes in patients with heart disease. The aim of this study was to examine whether individuals who received mental health treatment for anxiety or depression after being hospitalized for ischemic disorders or heart failure had a reduced frequency of rehospitalizations, emergency department visits, or mortality compared with those who did not receive treatment. METHODS AND RESULTS: A population-based, retrospective, cohort design was used to examine the association between psychotherapy or antidepressant medication prescription and health service utilization and mortality in patients with coronary artery disease or heart failure and comorbid anxiety or depression. Those receiving versus not receiving mental health treatment were compared based on the frequency of rehospitalization, emergency department visits, and mortality. The study sample included 1563 patients who had a mean age of 50.1 years. Individuals who received both forms of mental health treatment for anxiety or depression were 75% less likely to be rehospitalized, 74% less likely to have an emergency department visit, and 66% less likely to die from any cause. CONCLUSIONS: Mental health treatment for anxiety or depression has a significant impact on outcomes in patients with cardiovascular disease consisting of reduced hospitalizations, emergency department visits, and in some conditions improved survival.

Ankyrin-B protein in heart failure: identification of a new component of metazoan cardioprotection.

Ankyrins (ankyrin-R, -B, and -G) are adapter proteins linked with defects in metazoan physiology. Ankyrin-B (encoded by ANK2) loss-of-function mutations are directly associated with human cardiovascular phenotypes including sinus node disease, atrial fibrillation, ventricular tachycardia, and sudden cardiac death. Despite the link between ankyrin-B dysfunction and monogenic disease, there are no data linking ankyrin-B regulation with common forms of human heart failure. Here, we report that ankyrin-B levels are altered in both ischemic and non-ischemic human heart failure. Mechanistically, we demonstrate that cardiac ankyrin-B levels are tightly regulated downstream of reactive oxygen species, intracellular calcium, and the calcium-dependent protease calpain, all hallmarks of human myocardial injury and heart failure. Surprisingly, ß(II)-spectrin, previously thought to mediate ankyrin-dependent modulation in the nervous system and heart, is not coordinately regulated with ankyrin-B or its downstream partners. Finally, our data implicate ankyrin-B expression as required for vertebrate myocardial protection as hearts deficient in ankyrin-B show increased cardiac damage and impaired function relative to wild-type mouse hearts following ischemia reperfusion. In summary, our findings provide the data of ankyrin-B regulation in human heart failure, provide insight into candidate pathways for ankyrin-B regulation in acquired human cardiovascular disease, and surprisingly, implicate ankyrin-B as a molecular component for cardioprotection following ischemia.

Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.

BACKGROUND: Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated. METHODS AND RESULTS: We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium. CONCLUSIONS: We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.

Differential regulation of EHD3 in human and mammalian heart failure.

Electrical and structural remodeling during the progression of cardiovascular disease is associated with adverse outcomes subjecting affected patients to overt heart failure (HF) and/or sudden death. Dysfunction in integral membrane protein trafficking has long been linked with maladaptive electrical remodeling. However, little is known regarding the molecular identity or function of these intracellular targeting pathways in the heart. Eps15 homology domain-containing (EHD) gene products (EHD1-4) are polypeptides linked with endosomal trafficking, membrane protein recycling, and lipid homeostasis in a wide variety of cell types. EHD3 was recently established as a critical mediator of membrane protein trafficking in the heart. Here, we investigate the potential link between EHD3 function and heart disease. Using four different HF models including ischemic rat heart, pressure overloaded mouse heart, chronic pacing-induced canine heart, and non-ischemic failing human myocardium we provide the first evidence that EHD3 levels are consistently increased in HF. Notably, the expression of the Na/Ca exchanger (NCX1), targeted by EHD3 in heart is similarly elevated in HF. Finally, we identify a molecular pathway for EHD3 regulation in heart failure downstream of reactive oxygen species and angiotensin II signaling. Together, our new data identify EHD3 as a previously unrecognized component of the cardiac remodeling pathway.

Personality Predicts the Efficacy of a Physician Leadership Development Program.

It is imperative for health care organizations to foster leadership skills in their workforce. Leadership development programs offer a potential mechanism to achieve this goal. These development programs are likely not equally effective for all participants. This study evaluates the efficacy of one such program and determines personality predictors of its efficacy. Before and after a 12-month leadership development program, 28 physicians from various disciplines completed self-reported measures of leadership knowledge across 3 domains. At baseline, participants also provided personality data across the Big-5 factors of personality as well as 2 narrow facets (learning-goal orientation and preference for collaboration). Results suggest that leadership development programs can increase knowledge across leadership domains. Extraversion and conscientiousness predict changes in knowledge. Learning-goal-orientation and preference for collaboration personality facets provide incremental predictive power. Leadership development programs can improve self-rated knowledge across a range of leadership domains and is differentially effective for people based on their personalities.

Impairment in quantitative microvascular function in non-ischemic cardiomyopathy as demonstrated using cardiovascular magnetic resonance.

BACKGROUND: Microvascular dysfunction (MVD) is present in various cardiovascular diseases and portends worse outcomes. We assessed the prevalence of MVD in patients with non-ischemic cardiomyopathy (NICM) as compared to subjects with preserved ejection fraction (EF) using stress cardiovascular magnetic resonance (CMR). METHODS: We retrospectively studied consecutive patients with NICM and 58 subjects with preserved left ventricular (LV) EF who underwent stress CMR between 2011-2016. MVD was defined visually as presence of a subendocardial perfusion defect and semiquantitatively by myocardial perfusion reserve index (MPRI<1.51). MPRI was compared between groups using univariate analysis and multivariable linear regression. RESULTS: In total, 41 patients with NICM (mean age 51 ± 14, 59% male) and 58 subjects with preserved LVEF (mean age 51 ± 13, 31% male) were identified. In the NICM group, MVD was present in 23 (56%) and 11 (27%) by semiquantitative and visual evaluation respectively. Compared to those with preserved LVEF, NICM patients had lower rest slope (3.9 vs 4.9, p = 0.05) and stress perfusion slope (8.8 vs 11.7, p<0.001), and MPRI (1.41 vs 1.74, p = 0.02). MPRI remained associated with NICM after controlling for age, gender, hypertension, ethnicity, diabetes, and late gadolinium enhancement (log MPR, ß coefficient = -0.19, p = 0.007). CONCLUSIONS: MVD-as assessed using CMR-is highly prevalent in NICM as compared to subjects with preserved LVEF even after controlling for covariates. Semiquantitative is able to detect a greater number of incidences of MVD compared to visual methods alone. Further studies are needed to determine whether treatment of MVD is beneficial in NICM.