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Biomedical subjects

Brian D Hoit

Publications and source records attributed to Brian D Hoit.

At least 19 recordsLinked to original sources
PubMed2006

High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction.

Lipid accumulation in nonadipose tissue due to enhanced circulating fatty acids may play a role in the pathophysiology of heart failure, obesity, and diabetes. Accumulation of myocardial lipids and related intermediates, e.g., ceramide, is associated with decreased contractile function, mitochondrial oxidative phosphorylation, and electron transport chain (ETC) complex activities. We tested the hypothesis that the progression of heart failure would be exacerbated by elevated myocardial lipids and an associated ceramide-induced inhibition of mitochondrial oxidative phosphorylation and ETC complex activities. Heart failure (HF) was induced by coronary artery ligation. Rats were then randomly assigned to either a normal (10% kcal from fat; HF, n = 8) or high saturated fat diet (60% kcal from saturated fat; HF + Sat, n = 7). Sham-operated animals (sham; n = 8) were fed a normal diet. Eight weeks postligation, left ventricular (LV) function was assessed by echocardiography and catheterization. Subsarcolemmal and interfibrillar mitochondria were isolated from the LV. Heart failure resulted in impaired LV contractile function [decreased percent fractional shortening and peak rate of LV pressure rise and fall (+/-dP/dt)] and remodeling (increased end-diastolic and end-systolic dimensions) in HF compared with sham. No further progression of LV dysfunction was evident in HF + Sat. Mitochondrial state 3 respiration was increased in HF + Sat compared with HF despite elevated myocardial ceramide. Activities of ETC complexes II and IV were elevated in HF + Sat compared with HF and sham. High saturated fat feeding following coronary artery ligation was associated with increased oxidative phosphorylation and ETC complex activities and did not adversely affect LV contractile function or remodeling, despite elevations in myocardial ceramide.

Animals↗
PubMed2006

Low carbohydrate/high-fat diet attenuates cardiac hypertrophy, remodeling, and altered gene expression in hypertension.

The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hypertrophy, remodeling, contractile dysfunction, and induction of molecular markers of hypertrophy (ie, expression of mRNA for atrial natriuretic factor and myosin heavy chain beta). Dahl salt-sensitive rats were fed either a low-fat (10% of total energy from fat) or a high-fat (60% of total energy from fat) diet on either low-salt or high-salt (6% NaCl) chow for 12 weeks. Hearts were analyzed for mRNA markers of ventricular remodeling and activities of the mitochondrial enzymes citrate synthase and medium chain acyl-coenzyme A dehydrogenase. Similar levels of hypertension were achieved with high-salt feeding in both diet groups (systolic pressure of approximately 190 mm Hg). In hypertensive rats fed low-fat chow, left ventricular mass, myocyte cross-sectional area, and end-diastolic volume were increased, and ejection fraction was decreased; however, these effects were not observed with the high-fat diet. Hypertensive animals on low-fat chow had increased atrial natriuretic factor mRNA, myosin heavy chain isoform switching (alpha to beta), and decreased activity of citrate synthase and medium chain acyl-coenzyme A dehydrogenase, which were all attenuated by high-fat feeding. In conclusion, increased dietary lipid intake can reduce cardiac growth, left ventricular remodeling, contractile dysfunction, and alterations in gene expression in response to hypertension.

Animals↗
PubMed2006

Captopril prevents myosin light chain phosphatase isoform switching to preserve normal cGMP-mediated vasodilatation.

Congestive heart failure (CHF) is characterized by abnormal vasoconstriction and an impairment in nitric oxide (NO)-mediated vasodilatation. We have previously demonstrated that the decrease in sensitivity to NO lies at least partially at the level of the smooth muscle and is due to a reduction in the relative expression of the leucine zipper positive (LZ(+)) isoform of the myosin targeting subunit (MYPT1) of myosin light chain phosphatase. We hypothesized that since the attenuated vasodilatory response to NO in CHF has been shown to be secondary to an increased activity of the renin-angiotensin system, angiotensin converting enzyme (ACE) inhibition could affect MYPT1 isoform expression. To test this hypothesis, a rat myocardial infarction (MI) model of CHF was used; following left coronary artery ligation, rats were divided into control and captopril-treated groups. A third group of rats was given prazosin for 4 weeks. In the untreated control group, left ventricular function (LVF) was reduced at 2 weeks post-MI and remained at this level. Captopril treatment attenuated the fall in LVF. In the control aorta and iliac artery, the expression of the LZ(+) MYPT1 isoform fell 44-52% between 2 and 4 weeks post-MI, whereas in animals treated with captopril, MYPT1 isoform expression did not change. A decrease in the sensitivity to cGMP-mediated smooth muscle relaxation occurred coincident with the decrease in LZ(+) MYPT1 expression. The change in LZ(+) MYPT1 expression was not due to the decrease in afterload, as prazosin therapy produced an improvement in LVF but did not increase the relative expression of LZ(+) MYPT1 isoform. These data suggest that ACE inhibition, unique from pure afterload reduction, prevents MYPT1 isoform switching, which would preserve normal flow, or NO-mediated vasodilatation.

Animals↗
PubMed2006

Dissociation between gene and protein expression of metabolic enzymes in a rodent model of heart failure.

Studies in advanced heart failure show down-regulation of fatty acid oxidation genes, possibly due to decreased expression of the nuclear transcription factors peroxisome proliferator activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha). We assessed mRNA and protein expression of PPARalpha and RXRalpha, and for several PPAR/RXR regulated metabolic proteins at 8 and 20 weeks following myocardial infarction induced by coronary artery ligation. Infarction resulted in heart failure, as indicated by reduced LV fractional shortening and increased end diastolic area compared to sham. There was a progressive increase in LV end systolic area, myocardial ceramide content and atrial natriuretic peptide mRNA, and a deterioration in LV fractional area of shortening from 8 to 20 weeks. Protein and mRNA expression of PPARalpha and RXRalpha were not different among groups. The mRNA for PPAR/RXR regulated genes (e.g. medium chain acyl-CoA dehydrogenase (MCAD)) was down-regulated at 8 and 20 weeks post-infarction; however, neither the protein expression nor activity of MCAD was reduced compared to sham. In conclusion, reduced mRNA expression of PPAR/RXR regulated genes is not dependent on reduced PPAR/RXR protein expression.

Acyl-CoA Dehydrogenase↗
PubMed2006

Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin.

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.

Adipose Tissue↗
PubMed2006

Intrafamilial variability of noncompaction of the ventricular myocardium.

BACKGROUND: Noncompaction of the ventricular myocardium (NVM) is a relatively uncommon form of cardiomyopathy characterized by a highly trabeculated myocardium. This report describes the clinical and genetic evaluation of a 3-generation kindred. METHODS: Family members were initially evaluated by 2-dimensional echocardiography. Most family members with signs of NVM were further evaluated by magnetic resonance imaging. Genetic analyses included mutational screening of the taffazin (TAZ) and alpha-dystrobrevin (DTNA) genes. RESULTS: Eight family members had signs of NVM. Considerable interindividual variation was noted in terms of spatial distribution and severity of affected regions and ventricular dysfunction. Depending on which of 2 previously proposed quantitative diagnostic criteria were used and where ventricular myocardial measurements were taken, between 4 and 7 of these individuals had findings that were considered diagnostic. Magnetic resonance imaging served as a useful adjunct for confirming or establishing diagnoses in all 8 individuals. No mutation was found in TAZ or DTNA. CONCLUSIONS: This kindred demonstrates the remarkably wide phenotypic spectrum that can be seen in familial cases of NVM, ranging from prenatal/neonatal lethality to a complete lack of symptoms. The fact that all 8 affected individuals either have shown improvement in ventricular function or symptoms during childhood or have been asymptomatic indicates that NVM can have a relatively benign course. The degree and nature of cardiac involvement are also quite varied, and there is a weak correlation with ventricular function and symptoms. Evaluation of families with NVM requires careful assessment that uses a combination of imaging techniques and diagnostic criteria.

Adolescent↗
PubMed2006

Echocardiographic characterization of the cardiovascular phenotype in rodent models.

Echocardiographic techniques are commonly utilized to describe the rodent cardiovascular phenotype. These approaches are contrasted with other in vivo methods and are positioned in the assay selection process by a review of studies from our laboratory and others. Although not conventionally considered a biomarker, the technique has the potential to be exploited as a marker of intentional or unanticipated toxic biological effects in the preclinical development of drugs and chemicals.

Animals↗
PubMed2006

Chronic treatment with trimetazidine reduces the upregulation of atrial natriuretic peptide in heart failure.

Trimetazidine (TMZ) is effective for the treatment of ischemic cardiomyopathy; however, little is known about the effect of TMZ in established injury-induced heart failure. When rats with established infarct-induced heart failure were treated for 12 weeks with TMZ there was no effect on left ventricular function or dilation, or on mRNA expression of fatty acid oxidation enzymes. On the other hand, TMZ significantly reduced atrial natriuretic peptide mRNA levels compared with untreated rats.

Acyl-CoA Dehydrogenase↗
PubMed2006

Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure.

INTRODUCTION: Renin-angiotensin-aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This study's aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)-induced CHF. METHODS AND RESULTS: Dogs were assigned randomly to treatment with oral placebo or eplerenone (50 mg/day) and divided into four groups: two sham-operated (no RVP) and two RVP groups. After 5 weeks of no RVP or RVP at 230 beats/min along with concurrent placebo or eplerenone treatment, dogs underwent electrophysiologic and echocardiographic studies. Sustained atrial tachyarrhythmia inducibility (>10-minute duration), atrial effective refractory periods (ERPs), systolic and diastolic function, and left atrial and left ventricular (LV) chamber sizes were assessed. Placebo-treated RVP dogs developed CHF with LV systolic and diastolic dysfunction, left atrial and LV enlargement, increased atrial ERPs, and inducible sustained atrial tachyarrhythmias. Eplerenone treatment in RVP dogs significantly suppressed sustained atrial tachyarrhythmia inducibility, nonuniformly prolonged atrial ERPs and attenuated LV diastolic dysfunction without modifying left atrial or LV dilation or ejection fractions in CHF. Isoproterenol (2-4 microg/min) reversed eplerenone's atrial antiarrhythmic and ERP prolonging effects in CHF. Eplerenone did not alter atrial ERPs in sham (no RVP) dogs without CHF. CONCLUSIONS: Eplerenone suppresses inducibility of sustained atrial tachyarrhythmias, selectively prolongs atrial ERPs, and attenuates LV diastolic remodeling in RVP-induced CHF. Aldosterone blockade may be a promising new approach for atrial tachyarrhythmia prevention in CHF.

Administration, Oral↗
PubMed2006

The double jeopardy of blunt chest trauma: a case report and review.

Cardiac injury, specifically valvular rupture, must be considered after blunt chest trauma even in previously healthy patients. Isolated mitral regurgitation (MR) and tricuspid regurgitation (TR) due to blunt chest trauma are rare phenomena. More unique is simultaneous complete papillary muscle rupture of the mitral valve (MV) and tricuspid valve (TV) with only four patients being previously reported in the literature. This case describes a patient with complete transection of the posteromedial papillary muscle of the MV with severe MR and a concomitant flail TV with severe TR following a motor vehicular accident. The importance of transthoracic and transesophageal echocardiography in the early evaluation of patients following blunt chest trauma is also highlighted by this case.

Accidents, Traffic↗
PubMed2005

Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure.

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARalpha agonist fenofibrate (150 mg.kg(-1).day(-1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 +/- 6%) compared with sham operated (86 +/- 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.

Animals↗
PubMed2005

Nitric oxide and cardiopulmonary hemodynamics in Tibetan highlanders.

When O2 availability is reduced unavoidably, as it is at high altitude, a potential mechanism to improve O2 delivery to tissues is an increase in blood flow. Nitric oxide (NO) regulates blood vessel diameter and can influence blood flow. This field study of intrapopulation variation at high altitude tested the hypothesis that the level of exhaled NO (a summary measure of pulmonary synthesis, consumption, and transfer from cells in the airway) is directly proportional to pulmonary, and thus systemic, blood flow. Twenty Tibetan male and 37 female healthy, nonsmoking, native residents at 4,200 m (13,900 ft), with an average O2 saturation of hemoglobin of 85%, participated in the study. The geometric mean partial pressure of NO exhaled at a flow of 17 ml/s was 23.4 nmHg, significantly lower than that of a sea-level reference group. However, the rate of NO transfer out of the airway wall was seven times higher than at sea level, which implied the potential for vasodilation of the pulmonary blood vessels. Mean pulmonary blood flow (measured by cardiac index) was 2.7 +/- 0.1 (SE) l/min, and mean pulmonary artery systolic pressure was 31.4 +/- 0.9 (SE) mmHg. Higher exhaled NO was associated with higher pulmonary blood flow; yet there was no associated increase in pulmonary artery systolic pressure. The results suggest that NO in the lung may play a key beneficial role in allowing Tibetans at 4,200 m to compensate for ambient hypoxia with higher pulmonary blood flow and O2 delivery without the consequences of higher pulmonary arterial pressure.

Adaptation, Physiological↗
PubMed2005

Strain-dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice.

Recently, we showed that compared with the A/J inbred mouse strain, C57BL/6J (B6) mice have an athlete's cardiac phenotype. We postulated that strain differences would result in greater left ventricular (LV) hypertrophy in response to isoproterenol in B6 than A/J mice and tested the hypothesis that a differential response could be explained partly by differences in beta-adrenergic receptor (beta-AR) density and/or coupling. A/J and B6 mice were randomized to receive daily isoproterenol (100 mg/kg sc) or isovolumic vehicle for 5 days. Animals were studied using echocardiography, tail-cuff blood pressure, histopathology, beta-AR density and percent high-affinity binding, and basal and stimulated adenylyl cyclase activities. One hundred twenty-eight mice (66 A/J and 62 B6) were studied. Isoproterenol-treated A/J mice demonstrated greater percent increases in echocardiographic LV mass/body weight (97 +/- 11 vs. 20 +/- 10%, P = 0.001) and in gravimetric heart mass/body weight versus same-strain controls than B6 mice. Histopathology scores (a composite of myocyte hypertrophy, nuclear changes, fibrosis, and calcification) were greater in isoproterenol-treated A/J vs. B6 mice (2.8 +/- 0.2 vs.1.9 +/- 0.3, P < 0.05), as was quantitation of myocyte damage (22.3 +/- 11.5 vs. 4.3 +/- 3.5%). Interstrain differences in basal beta-AR density, high-affinity binding, and adenylyl cyclase activity were not significant. However, whereas isoproterenol-treated A/J mice showed nonsignificant increases in all beta-AR activity measures, isoproterenol-treated B6 mice had lower beta-AR density (57 +/- 6 vs. 83 +/- 8 fmol/mg, P < 0.05), percent high-affinity binding (15 +/- 2 vs. 26 +/- 3%, P < 0.005), and GTP + isoproterenol-stimulated adenylyl cyclase activity (10 +/- 1.1 vs. 5.8 +/- 1.5 pmol cAMP.mg(-1).min(-1)) compared with controls. High-dose, short-term isoproterenol produces greater macro- and microscopic cardiac hypertrophy and injury in A/J than B6 mice. A/J mice, unlike B6 mice, do not experience beta-AR downregulation or uncoupling in response to isoproterenol. Abnormalities in beta-adrenergic regulation may contribute to strain-related differences in the vulnerability to isoproterenol-induced cardiac changes.

Adenylyl Cyclases↗
PubMed2005

Prognostic value of elevated circulating heart-type fatty acid binding protein in patients with congestive heart failure.

BACKGROUND: Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured and is a novel marker for the diagnosis of acute myocardial infarction. The purpose of the present study was to examine the clinical significance of increased serum H-FABP levels in patients with congestive heart failure. METHODS AND RESULTS: Serum levels of H-FABP were measured in 179 patients admitted with congestive heart failure and 20 age-matched normal controls by using a sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a mean follow-up period of 20 months with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of H-FABP were higher in patients with congestive heart failure than in control subjects (5.7 +/- 4.8 ng/mL versus 2.7 +/- 0.8 ng/mL, P < .01) and increased with advancing NYHA class (P < .01). The cardiac event rate was markedly higher in patients with elevated H-FABP levels than in those with normal levels (43% versus 7%, P < .0001). Furthermore, the Cox multivariate proportional hazard analysis revealed that the elevated H-FABP level was the only independent predictor for cardiac events (chi2= 7.397, P < .01). CONCLUSIONS: Elevation of H-FABP indicates latent and ongoing cardiomyocyte damage and identifies patients at high risk for future cardiac events in congestive heart failure.

Aged↗
PubMed2005

High-fat diet prevents cardiac hypertrophy and improves contractile function in the hypertensive dahl salt-sensitive rat.

1. The role that dietary lipid and plasma fatty acid concentration play in the development of cardiac hypertrophy in response to hypertension is not clear. 2. In the present study, we treated Dahl salt-sensitive rats with either normal chow (NC), normal chow with salt added (NC + salt) or a diet high in long-chain saturated fatty acids with added salt (HFD + salt). Cardiac function was assessed by echocardiography and left ventricular (LV) catheterization. 3. The HFD + salt group had significantly higher plasma free fatty acid concentrations and myocardial triglyceride content compared with the NC + salt group, but did not upregulate the activity of the fatty acid oxidation enzyme medium chain acyl-coenzyme A dehydrogenase. Systolic blood pressure was elevated to a similar extent in the NC + salt and HFD + salt groups compared with the NC group. Although LV mass was increased in the NC + salt group compared with the NC group, LV mass in the HFD + salt group did not differ from that of the NC group and was significantly lower than that in the NC + salt group. 4. There was no evidence of cardiac dysfunction in the NC + salt group compared with the NC group; however, high fat feeding significantly increased LV contractile performance (e.g. increased cardiac output and peak dP/dt). 5. In conclusion, the HFD + salt diet prevented the hypertrophic response to hypertension and improved the contractile performance of the heart. It remains to be determined whether preventing cardiac hypertrophic adaptations would be deleterious to the heart if the hypertensive stress is maintained long term.

Animals↗