Howard D. Weinberger

Management of Cardiac Sarcoidosis in the United States: A Delphi Study

BACKGROUND No formal guidelines exist to guide physicians caring for patients with sarcoidosis in their screening for management of patients with cardiac sarcoidosis. We conducted a modified Delphi study to investigate if a consensus could be reached on the best approaches for screening for and management of cardiac sarcoidosis. METHODS A modified Delphi study design with two rounds of questionnaires was used to investigate if a consensus existed among sarcoid experts in the United States on the best management approaches for cardiac sarcoidosis. Experts were identified based on their national reputation as sarcoid experts and by being actively involved in sarcoidosis clinics at their institutions. RESULTS Overall agreement was low to moderate. Agreement was reached on the role of history, physical examination, and 12-lead ECG in screening, echocardiogram, Holter monitor, myocardial fluorodeoxyglucose PET scan, and cardiac MRI in workup, and steroids in treatment. Agreement was not reached on the role of signal-averaged ECG in screening, optimum dose of prednisone, use of steroid-sparing agents, and duration of treatment. Several comments underscore the diverse approaches and uncertainty that exist in managing cardiac sarcoidosis. CONCLUSIONS Our study highlights the dilemma that sarcoid experts face in their approach to cardiac sarcoidosis. It also highlights the lack of agreement among sarcoid experts on key aspects of diagnosis and management and stresses the importance of collaborative efforts to investigate the best strategies for screening for and management of cardiac sarcoidosis.

Pathophysiology of Sodium and Water Retention in Heart Failure

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.

Microtubules modulate cardiomyocyte β-adrenergic response in cardiac hypertrophy

The role of microtubules in modulating cardiomyocyte beta-adrenergic response was investigated in rats with cardiac hypertrophy. Male Sprague-Dawley rats underwent stenosis of the abdominal aorta (hypertensive, HT) or sham operation (normotensive, NT). Echocardiography and isolated left ventricular cardiomyocyte dimensions demonstrated cardiac hypertrophy in the HT rats after 30 wk. Cardiomyocyte microtubule fraction was assayed by high-speed centrifugation and Western blot. In contrast to previous reports of increased microtubules after acute pressure overload, microtubule fraction for HT was significantly lower than that for NT. Cardiomyocytes were exposed to either 1 microM colchicine, 10 microM taxol, or equivalent volume of vehicle. Colchicine decreased microtubules, and taxol increased microtubules in both groups. Cardiomyocyte cytosolic calcium ([Ca2+]c) and shortening/relaxation dynamics were assessed during exposure to increasing isoproterenol concentrations. The beta-adrenergic response for these variables in the HT group was blunted compared with NT. However, increased microtubule assembly by taxol partially recovered the normal beta-adrenergic response for time to peak [Ca2+]c, time to peak shortening, and mechanical relaxation variables. Microtubule assembly may play a significant role in determining cardiomyocyte beta-adrenergic response in chronic cardiac hypertrophy.

Cardiac myosin heavy chains lacking the light chain binding domain cause hypertrophic cardiomyopathy in mice

Myosin is a chemomechanical motor that converts chemical energy into the mechanical work of muscle contraction. More than 40 missense mutations in the cardiac myosin heavy chain (MHC) gene and several mutations in the two myosin light chains cause a dominantly inherited heart disease called familial hypertrophic cardiomyopathy. Very little is known about the biochemical defects in these alleles and how the mutations lead to disease. Because removal of the light chain binding domain in the lever arm of MHC should alter myosins force transmission but not its catalytic function, we tested the hypothesis that such a mutant MHC would act as a dominant mutation in cardiac muscle. Hearts from transgenic mice expressing this mutant myosin are asymmetrically hypertrophied, with increases in mass primarily restricted to the cardiac anterior wall. Histological examination demonstrates marked cellular hypertrophy, myocyte disorganization, small vessel coronary disease, and severe valvular pathology that included thickening and plaque formation. Skinned myocytes and multicellular preparations from transgenic hearts exhibited decreased Ca2+ sensitivity of tension and decreased relaxation rates after flash photolysis of diazo 2. These experiments demonstrate that alterations in myosin force transmission are sufficient to trigger the development of hypertrophic cardiomyopathy.Myosin is a chemomechanical motor that converts chemical energy into the mechanical work of muscle contraction. More than 40 missense mutations in the cardiac myosin heavy chain (MHC) gene and several mutations in the two myosin light chains cause a dominantly inherited heart disease called familial hypertrophic cardiomyopathy. Very little is known about the biochemical defects in these alleles and how the mutations lead to disease. Because removal of the light chain binding domain in the lever arm of MHC should alter myosins force transmission but not its catalytic function, we tested the hypothesis that such a mutant MHC would act as a dominant mutation in cardiac muscle. Hearts from transgenic mice expressing this mutant myosin are asymmetrically hypertrophied, with increases in mass primarily restricted to the cardiac anterior wall. Histological examination demonstrates marked cellular hypertrophy, myocyte disorganization, small vessel coronary disease, and severe valvular pathology that included thickening and plaque formation. Skinned myocytes and multicellular preparations from transgenic hearts exhibited decreased Ca2+ sensitivity of tension and decreased relaxation rates after flash photolysis of diazo 2. These experiments demonstrate that alterations in myosin force transmission are sufficient to trigger the development of hypertrophic cardiomyopathy.

Comparison of Amlodipine and Long-Acting Diltiazem in the Treatment of Mild or Moderate Hypertension*

The comparative effects of the once a day calcium channel antagonists amlodipine and long-acting diltiazem were assessed in a parallel design, investigator-blinded, multicenter trial in 123 patients with diastolic blood pressures ranging from 95 to 114 mm Hg before treatment. Patients were randomized to one of the two drugs and titrated at 2-week intervals to 5 or 10 mg of amlodipine or 180, 240, or 360 mg of long-acting diltiazem during a 10-week treatment period. Both drugs significantly reduced resting, sitting, standing, and 24-h ambulatory systolic and diastolic pressures. Amlodipine caused significantly greater reductions in sitting and standing systolic pressures, standing diastolic pressures, and 24-h ambulatory systolic and diastolic pressures versus diltiazem. Sitting systolic pressures were reduced from 151.9 +/- 2.0 (SE) at baseline to 137.9 +/- 1.8 mm Hg with amlodipine treatment and from 149.0 +/- 2.1 to 145.1 +/- 2.5 mm Hg with diltiazem. Sitting diastolic pressures were reduced from 100.2 +/- 0.6 to 87.8 +/- 1.0 mm Hg with amlodipine and from 101.1 +/- 1.0 to 91.9 +/- 1.1 mm Hg with diltiazem. Reductions in standing systolic pressures after treatment were -12.1 +/- 1.5 mm Hg amlodipine v -4.6 +/- 1.5 mm Hg diltiazem (P < .01), and reductions in standing diastolic pressures were -11.8 +/- 0.9 mm Hg amlodipine v -8.6 +/- 0.9 mm Hg diltiazem (P < .02). Heart rates did not change significantly with either drug during the study. Two subjects in each group dropped out because of adverse experiences. Although both agents were well tolerated and reduced blood pressures consistently over the 10-week test period, amlodipine was more effective than diltiazem in reducing systolic and diastolic blood pressures to the target pressures of < 140 mm Hg systolic and < 90 mm Hg diastolic over a range of doses widely used in clinical practice.

Effects of Angiotensin Receptor Blockade on Haemodynamics and Gene Expression after Myocardial Infarction

AbstractIntroduction: Despite the fact that congestive heart failure (CHF) remains the most common disease in the developed world and has been extensively studied, there is little known about the molecular and cellular mechanisms of cardiac dysfunction. Angiotensin has been implicated as a mediator of cardiac injury; however, the mechanisms of its action have not been delineated. The objective of this study was to examine the relationship between the haemodynamic and molecular events during cardiac dysfunction and the role of the angiotensin system. Study design: We examined the effects of the angiotensin receptor blocker, valsartan, on changes in the haemodynamic and gene expression patterns in a postmyocardial infarction model in the rat. Methods: Myocardial infarction (MI) was induced in rats by coronary artery ligation. Cardiac haemodynamicswere monitored using echocardiography. Gene expression profiles after myocardial infarction were identified using Affymetrix Genechip® oligonucleotide arrays. Results: Myocardial contractility, as assessed by cardiac output and left ventricle (LV) fraction of shortening, was reduced in untreated animals by week 3 after MI (p < 0.05 versus baseline), and preserved with valsartan treatment as observed by the nonsignificant changes versus baseline. LV dilatation, as demonstrated by increases in LVsystolic and diastolic diameters, developed by week 3 in untreated animals (p < 0.05 versus baseline) while valsartan-treated animals were protected and showed no significant increases in diameter size compared with baseline. LV hypertrophy, as shown by LV posterior wall thickness, was more profound in untreated animals (p < 0.05 versus baseline) than in those treated with valsartan at weeks 3 and 4. Changes in gene expression at 4 weeks after MI included those encoding muscle-specific genes, fibrous tissue proliferation, immune response and various others. Treatment with valsartan reversed these changes in 67% of overexpressed genes and 83% of underexpressed genes. Conclusion: Angiotensin receptor blockade with valsartan was found to protect cardiac function, and this beneficial effect was accompanied by a reversal of changes in gene expression induced by MI.

Prevention of acute renal failure

Abstract Acute renal failure is a common occurrence in the contemporary practice of medicine, and current mortality rates range from 10% to 80%. Practical measures to prevent acute renal failure in hospitalized patients include aggressive resuscitation of traumatized patients, careful vigilance to maintain adequate circulating blood volume and renal perfusion, avoidance of nephrotoxins, and selective use of volume expansion and forced diuresis.

Congenital Duplication of the Tricuspid Valve Presenting as a Circumscribed Obstructive Mass in the Right Ventricular Outflow Tract

Congenital duplication of the tricuspid valve is a rare condition. We present a case of a 32-year-old man with an increase in intensity of a long-standing heart murmur and intermittent palpitations. The murmur was evaluated by transthoracic and transesophageal echocardiography that identified a mass in the right ventricle and right ventricular outflow tract resulting in partial obstruction of the right ventricular outflow tract. This mass was determined to be congenital duplication of the tricuspid valve by histologic examination after surgical excision.

Subjective cognitive complaints and neuropsychological performance in former smokers with and without chronic obstructive pulmonary disease

ABSTRACT Objective: This study examined the association of perceived cognitive difficulties with objective cognitive performance in former smokers. We hypothesized that greater perceived cognitive difficulties would be associated with poorer performance on objective executive and memory tasks. Method: Participants were 95 former smokers recruited from the COPDGene study. They completed questionnaires (including the Cognitive Difficulties Scale [CDS] and the Hospital Anxiety and Depression Scale [HADS]), neuropsychological assessment, and pulmonary function testing. Pearson correlations and t-tests were conducted to examine the bivariate association of the CDS (total score and subscales for attention/concentration, praxis, delayed recall, orientation for persons, temporal orientation, and prospective memory) with each domain of objective cognitive functioning (memory recall, executive functioning/processing speed, visuospatial processing, and language). Simultaneous multiple linear regression was used to further examine all statistically significant bivariate associations. The following covariates were included in all regression models: age, sex, pack-years, premorbid functioning (WRAT-IV Reading), HADS total score, and chronic obstructive pulmonary disease (COPD) status (yes/no based on GOLD criteria). Results: In regression models, greater perceived cognitive difficulties overall (using CDS total score) were associated with poorer performance on executive functioning/processing speed tasks (b = −0.07, SE = 0.03, p = .037). Greater perceived cognitive difficulties on the CDS praxis subscale were associated with poorer performance on executive functioning/processing speed tasks (b = −3.65, SE = 1.25, p = .005), memory recall tasks (b = −4.60, SE = 1.75, p = .010), and language tasks (b = −3.89, SE = 1.39, p = .006). Conclusions: Clinicians should be aware that cognitive complaints may be indicative of problems with the executive functioning/processing speed and memory of former smokers with and without COPD.