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Biomedical subjects

Sheldon E Litwin

Publications and source records attributed to Sheldon E Litwin.

18 recordsLinked to original sources
PubMed2006

Left ventricular hypertrophy in severe obesity: interactions among blood pressure, nocturnal hypoxemia, and body mass.

Obese subjects have a high prevalence of left ventricular (LV) hypertrophy. It is unclear to what extent LV hypertrophy results directly from obesity or from associated conditions, such as hypertension, impaired glucose homeostasis, or obstructive sleep apnea. We tested the hypothesis that LV hypertrophy in severe obesity is associated with additive effects from each of the major comorbidities. Echocardiography and laboratory testing were performed in 455 severely obese subjects with body mass index 35 to 92 kg/m(2) and 59 nonobese reference subjects. LV hypertrophy, defined by allometrically corrected (LV mass/height(2.7)), gender-specific criteria, was present in 78% of the obese subjects. Multivariable regression analyses showed that average nocturnal oxygen saturation <85% was the strongest independent predictor of LV hypertrophy (P<0.001), followed by systolic blood pressure (P<0.015) and then body mass index (P<0.05). With regard to LV mass, there were synergistic effects between hypertension and body mass index (P interaction <0.001) and between hypertension and reduced nocturnal oxygen saturation. Severely obese subjects had normal LV endocardial fractional shortening (35+/-6% versus 35+/-6%) but mildly decreased midwall fractional shortening (15+/-2% versus 17+/-2%; P<0.001), indicating subtle myocardial dysfunction. In conclusion, more severe nocturnal hypoxemia, increasing systolic blood pressure, and body mass index are all independently associated with increased LV mass. The effects of increased blood pressure seem to amplify those of sleep apnea and more severe obesity.

Adult↗
PubMed2006

Integrin activation in the heart: a link between electrical and contractile dysfunction?

Integrins mechanically link the cytoskeleton to the extracellular matrix in cardiac myocytes and are thereby involved in mechanotransduction. Integrins appear to be necessary for cardiac myocyte hypertrophy. To determine the effect of increased integrin ligation and signaling on adult cardiac function, a heart-specific truncated alpha(5) integrin (gain of function) was conditionally expressed in mice. Four days later, we observed an 80% reduction in amplitude of the QRS complex, profound systolic dysfunction, decreased connexin43, loss of gap junctions, and abnormal intercalated discs. Surprisingly, isolated left ventricular myocytes contracted normally and exhibited normal Ca(2+) transients. This suggested that cell/cell electrical and/or mechanical coupling was disrupted. To distinguish electrical from mechanical coupling deficits, we compared the papillary muscle force generated by electrically stimulated versus rapid cooling contractions in which intracellular Ca(2+) is released without electrical depolarization. Both were decreased in the transgenic muscle. However, electrically stimulated contractions were more significantly reduced than rapid cooling contractures. This suggests a component of cell/cell electrical uncoupling. Optical mapping revealed a loss of the normal elliptical isochronal activation pattern implying a loss of preferential conduction through gap junctions. For the first time, we have shown that integrins can regulate both mechanical and electrical coupling in the adult heart, even in the absence of primary hemodynamic alterations. Furthermore, we demonstrated that unregulated integrin activation leads to both contractile dysfunction and arrhythmias.

Animals↗
PubMed2006

Quercetin-supplemented diets lower blood pressure and attenuate cardiac hypertrophy in rats with aortic constriction.

Quercetin (Q), a flavonoid found in berries and onions, can reduce blood pressure in hypertensive animals and inhibit signal transduction pathways in vitro that regulate cardiac hypertrophy. We hypothesized that quercetin could prevent cardiovascular complications in rats with abdominal aortic constriction (AAC). Rats consumed standard or Q-supplemented chow (1.5 g Q/kg chow) for 7 days before AAC or sham surgery (SHAM, n = 15; AAC, n = 15; SHAMQ, n = 15; AACQ, n = 14). Fourteen days after surgery, plasma and liver Q concentrations were elevated (P < 0.05) and hepatic lipid oxidation was reduced (P < 0.05) in Q-treated versus untreated rats. Carotid arterial blood pressure and cardiac hypertrophy were attenuated (P < 0.05), and cardiac protein kinase C betaII translocation was normalized (P < 0.05) in AACQ versus AAC. Expression of cardiac beta-myosin heavy-chain mRNA was also reduced in AACQ versus AAC (P < 0.05). However, extracellular regulated kinase 1/2 phosphorylation was similar in AAC versus AACQ. The level of aortic endothelial dysfunction (wire myography) was also similar between AAC and AACQ, in spite of reduced aortic thickening in AACQ. Importantly, Q-treated rats did not show any deleterious changes in myocardial function (echocardiography). Our data supports an antihypertensive and antihypertrophic effect of Q in vivo in the absence of changes concerning vascular and myocardial function.

Animals↗
PubMed2006

Serological diagnosis of Trypanosoma cruzi: evaluation of three enzyme immunoassays and an indirect immunofluorescent assay.

Chagas' disease is an important cause of heart failure in Latin America, but is rare in the United States. The immigration of persons from endemic countries increases the potential of encountering patients with the disease. Concerns have also been raised about the introduction of Trypanosoma cruzi, the parasite that causes the disease, into the blood supply and during organ transplantation. To compare Chagas' antibody tests that are available in the United States, we evaluated three IgG ELISAs, CeLLabs T. cruzi ELISA, Hemagen Chagas' kit and IVD Research Chagas' Serum Microwell ELISA, and MarDx indirect immunofluorescent assays. The CeLLabs and Hemagen IgG ELISAs had 100 % agreement, sensitivity and specificity. The IVD Research IgG ELISA had 94.6 % agreement, 100 % sensitivity and 93 % specificity.

Adult↗
PubMed2006

Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) has been implicated in important metabolic processes. A mouse lacking PGC-1beta (PGC1betaKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1betaKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1beta ablation was partially compensated by up-regulation of PGC-1alpha in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1betaKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1betaKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1betaKO mice have impaired mitochondrial function. Lack of PGC-1beta also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.

Adipose Tissue, Brown↗
PubMed2005

Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density.

Diabetics have worse outcomes than nondiabetics after a variety of cardiac insults. We tested the hypothesis that impaired insulin receptor signaling in myocytes worsens cardiac remodeling and function following injury, even in the absence of hyperglycemia. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wild type (WT) mice were treated with isoproterenol (ISO) for 2 or 5 days. Heart rates and cardiac mass increased comparably following ISO in WT and CIRKO mice. After 5 days, WT hearts were hyperdynamic by echocardiographic and left ventricular pressure measurements. However, CIRKO hearts had a blunted increase in contractility and relaxation following ISO. Interestingly, single myocytes isolated from both CIRKO ISO and WT ISO hearts had increased cellular shortening with prolonged time to peak shortening vs. respective shams. Thus, loss of myocytes or extramyocyte factors, rather than intrinsic dysfunction of surviving myocytes, caused the blunted inotropic response in ISO treated CIRKO hearts. Indeed, CIRKO ISO mice had increased troponin release after 2 days and greater interstitial and sub-endocardial fibrosis at 5 days than did ISO WT. Apoptosis assessed by TUNEL and caspase staining was increased in CIRKO ISO compared to WT ISO hearts; however, very few of the apoptotic nuclei were clearly in cardiac myocytes. After 5 days of ISO treatment, VEGF expression was increased in WT but not in CIRKO hearts. In keeping with this finding, capillary density was reduced in CIRKO ISO relative to WT ISO. Basal expression of hypoxia-inducible factor-1alpha was lower in CIRKO vs. WT hearts and may explain the blunted VEGF response. Thus, absence of insulin receptor signaling in the cardiac myocyte worsens catecholamine-mediated myocardial injury, at least in part, via mechanisms that tend to impair myocardial blood flow and increase ischemic injury.

Animals↗
PubMed2005

Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity.

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28-37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased beta-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-alpha regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-alpha regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

Animals↗
PubMed2005

PKC translocation and ERK1/2 activation in compensated right ventricular hypertrophy secondary to chronic emphysema.

BACKGROUND: Right ventricular hypertrophy (RVH) is an important complication of chronic lung disease. However, the signal transduction pathways involved as well as the physiological changes to the right ventricle have not been investigated. Emphysema was produced in male, Syrian Golden hamsters by intra-tracheal instillation of 250 IU/kg elastase (Emp, n = 17). Saline treated animals served as controls (Con, n = 15). RESULTS: Nine months later, Emp hamsters had 75% greater lung volume, and evidence of RVH at the gross and myocyte level (RV:tibia length Emp 6.84 +/- 1.18 vs. Con 5.14 +/- 1.11 mg/mm; myocyte cross sectional area Emp 3737 vs. Con 2695 microm2), but not left ventricular hypertrophy. Serial echocardiographic analysis from baseline to nine months after induction of emphysema revealed increasing right ventricular internal dimension and decreased pulmonary artery acceleration time only in Emp hamsters. There was an increase in translocation of PKC betaI and PKC epsilon from cytosolic to membranous cell fractions in RV of Emp hamsters. Phosphorylation of PKC epsilon was unchanged. Translocation of PKC alpha and betaII were unchanged. Emp animals had a 22% increase in phospho-ERK 1/2, but no change in levels of total ERK 1/2 compared to Con. CONCLUSION: These data suggest that PKC betaI, epsilon and ERK 1/2 may play a role in mediating compensated RVH secondary to emphysema and may have clinical relevance in the pathogenesis of RVH.

Animals↗
PubMed2005

Doppler-derived left ventricular filling pressures and the regulation of heart rate recovery after exercise in patients with suspected coronary artery disease.

Slowed heart rate (HR) recovery after exercise is strongly predictive of increased long-term mortality. The factors responsible for impaired HR regulation are not fully understood. We performed echocardiography with tissue Doppler imaging in 121 patients before maximal exercise testing. HR recovery was measured 1 minute after the end of exercise in the supine position. The best echocardiographic correlate of HR recovery was the ratio of early mitral flow velocity (E) to early diastolic mitral annular velocity (Ea; r = -0.781, p <0.001). This correlation was not affected by the use of negative chronotropic agents. Patients whose E/Ea was <10 had a faster 1-minute HR recovery and a greater chronotropic response during exercise than did those whose E/Ea was >/=10. Receiver-operator characteristic analysis showed that an E/Ea >/=10.3 predicted 1-minute HR recovery of </=18 beats/min, with 83% sensitivity and 100% specificity. Neither left ventricular ejection fraction nor the presence of a "slow relaxation" mitral inflow pattern (E/A <1.0) was predictive of impaired HR recovery. Thus, slowed HR recovery is strongly associated with increased E/Ea, a marker of increased left ventricular filling pressures. E/Ea at rest may become a simple, reliable, and sensitive predictor of increased long-term mortality, even in the absence of overt heart failure.

Adult↗
PubMed2005

Close coupling of systolic and diastolic function: combined assessment provides superior prediction of exercise capacity.

BACKGROUND: Isolated diastolic dysfunction is thought to account for approximately 50% of cases of heart failure. We tested the hypotheses that (1) the use of different methods for assessing systolic and diastolic function may contribute to the apparent frequency with which they are dissociated and (2) that combined assessment of systolic and diastolic function is superior to either one alone. METHODS AND RESULTS: A total of 110 patients underwent echocardiography with tissue Doppler imaging (TDI) of the mitral annulus before maximal exercise testing. The correlation between left ventricular (LV) ejection fraction (EF) and exercise capacity was weak (r = 0.199). Among patients with EF greater than 55%, those with normal exercise capacity (>7 METs) had a higher systolic velocity of the mitral annulus than those achieving less than 7 METs (9.6 +/- 0.3 versus 7.5 +/- 0.4 cm/s, P = .001). The mitral annular systolic (Sa) and early diastolic (Ea) velocities each correlated moderately with exercise tolerance (r = 0.40 and 0.49, respectively). Sa and Ea correlated highly with each other (r = 0.79, P < .001). The sum of isovolumic contraction and relaxation times measured from TDI correlated moderately with exercise duration (r = -0.59). A combined index of systolic and diastolic function that includes isovolumic contraction and relaxation times and ejection time had the best correlation with achieved METs (r = -0.73, P < .001). A TDI index of cardiac performance higher than 0.52 had excellent sensitivity (86%) and specificity (100%) for predicting reduced exercise tolerance lower than 7 METs. CONCLUSION: When assessed with the same technique, LV systolic and diastolic function are tightly linked. A TDI-derived combined index of myocardial performance is the best predictor of exercise capacity.

Adult↗
PubMed2005

Effect of fiber orientation on propagation: electrical mapping of genetically altered mouse hearts.

BACKGROUND: Epicardial potentials reveal the strong effects of fiber anisotropy, rotation, imbrication, and coupling on propagation in the intact heart. From the patterns of the surface potentials, we can obtain information about the local fiber orientation, anisotropy, the transmural fiber rotation, and which direction the wave front is traveling through the wall. In this study, lessons learned from epicardial potential mapping of large hearts were applied to studies conducted in genetically altered mouse hearts. METHODS: An inducible model of the overexpression of a gain-of-function alpha5 integrin (cytoplasmic domain truncation) was created in mouse. After 3 days of administration of doxycycline, the animals exhibited an altered electrical phenotype of markedly reduced amplitude of the QRS complex on the surface electrocardiogram. Epicardial potentials were recorded from Langendorff-perfused mouse hearts with alpha5 integrin gain-of-function mutations and from wild-type (WT) control hearts. A cylindrical electrode array consisting of 184 sites with 1-mm uniform interelectrode spacing was placed around the heart, and unipolar electrograms were recorded during atrial and ventricular stimulation at different basic cycle lengths. RESULTS: The total ventricular activation time for the transgenic animals was greater than that of the WT hearts for atrial and ventricular pacing locations. The isopotential maps from the mutated hearts showed a loss of anisotropy, as revealed by the more rounded and less elliptically shaped wave fronts seen immediately after epicardial point stimulation when compared with WT hearts. The weaker potential maxima in the mutated hearts did not exhibit the normal expansion and rotation associated with an advancing wave front in a normal heart, suggesting abnormalities in myocyte coupling in these hearts. Isopotential maps provided additional information about fiber architecture from the electric field that was not obtained from optical recordings alone. These findings provided a phenotypic characterization and specific insights into the mechanisms of the electrical abnormalities associated with altered integrin signaling in cardiac myocytes.

Action Potentials↗
PubMed2004

Mechanisms of exercise intolerance: insights from tissue Doppler imaging.

BACKGROUND: A decreased ratio of early to late diastolic mitral inflow velocities (E/A <1.0) reflects slowing of left ventricular (LV) relaxation. This finding is widely believed to indicate significant diastolic dysfunction. However, E/A <1.0 is common during normal aging and often is not associated with symptoms of heart failure. We asked (1) whether slowed LV relaxation is associated with exercise intolerance and (2) whether tissue Doppler imaging of the early diastolic mitral annular velocity (Ea) is helpful in understanding mechanisms of exercise intolerance. METHODS AND RESULTS: Patients (n=121) underwent echocardiography before maximal exercise testing. Fifty-nine subjects had E/A <1.0, and 36 subjects had E/Ea > or =10. Exercise capacity was similar in the population with a normal mitral inflow pattern and those with a slow relaxation pattern when E/Ea was <10. In contrast, the subjects with slow relaxation and E/Ea > or =10 had reduced exercise tolerance. Of all the echo and clinical parameters assessed, E/Ea had the best correlation with exercise capacity (r=-0.684, P<0.001) and was the strongest independent predictor of exercise capacity < or =7 METs by multivariate analysis (prevalence-corrected odds ratio=12.6, P<0.001). E/Ea continued to be strongly associated with exercise capacity in all age groups and in those with preserved or reduced systolic function. CONCLUSIONS: Of the subjects with slow LV relaxation, only those with E/Ea > or =10 have objective evidence of reduced exercise tolerance. These data suggest that elevated LV filling pressures rather than slow relaxation per se reduce exercise capacity.

Adult↗
PubMed2003

Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction.

BACKGROUND: We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model. METHODS: New Zealand white rabbits underwent circumflex coronary ligation after direct intramyocardial injection of either Terplex alone or Terplex + 50 microg pVEGF-165. Serial echocardiography and histologic studies were performed (n = 12/group). Mortality did not differ between groups. The data is reported as the mean +/- standard deviation. RESULTS: Over the 21 days following coronary ligation, pVEGF-165-treated animals demonstrated significant improvement in fractional shortening (20-25%, p = 0.02), long axis two-dimensional ejection fraction (42-51%, p=0.02) and short axis m-mode ejection fraction (46-54%, p = 0.02). No significant improvements were noted in the control group. VEGF-treated animals had a 50% increase in peri-infarct vessel density and a trend towards a smaller infarct size (20% vs. 29%, p = 0.10). In animals receiving pVEGF-165, the diastolic ventricular area increased from 1.87 +/- 0.24 cm2 prior to ligation to 2.19 +/- 0.23 cm2 at 21 days following ligation, compared to an increase from 1.84 +/- 0.38 to 2.54 +/- 0.55 cm2 over the same period in control animals (p = 0.03). Similarly, the systolic ventricular area in VEGF-165 animals increased from 1.06 +/- 0.26 cm2 prior to ligation to 1.50 +/- 0.29 cm2 at 21 days following ligation, compared to an increase from 1.16 +/- 0.30 to 1.86 +/- 0.43 cm2 over the same period in the control animals (p = 0.04). CONCLUSION: TerplexDNA mediated delivery of plasmid VEGF administered at the time of coronary occlusion improves left ventricular function and reduces left ventricular dilation following myocardial infarction.

Animals↗
PubMed2003

Minimally invasive aortic banding in mice: effects of altered cardiomyocyte insulin signaling during pressure overload.

We developed a minimally invasive method for producing left ventricular (LV) pressure overload in mice. With the use of this technique, we quickly and reproducibly banded the transverse aorta with low surgical morbidity and mortality. Minimally invasive transverse aortic banding (MTAB) acutely and chronically increased LV systolic pressure, increased heart weight-to-body weight ratio, and induced myocardial fibrosis. We used this technique to determine whether reduced insulin signaling in the heart altered the cardiac response to pressure overload. Mice with cardiac myocyte-restricted knockout of the insulin receptor (CIRKO) have smaller hearts than wild-type (WT) controls. Four weeks after MTAB, WT and CIRKO mice had comparably increased LV systolic pressure, increased cardiac mass, and induction of mRNA for beta-myosin heavy chain and atrial natriuretic factor. However, CIRKO hearts were more dilated, had depressed LV systolic function by echocardiography, and had greater interstitial fibrosis than WT mice. Expression of connective tissue growth factor was increased in banded CIRKO hearts compared with WT hearts. Thus lack of insulin signaling in the heart accelerates the transition to a more decompensated state during cardiac pressure overload. The use of the MTAB approach should facilitate the study of the pathophysiology and treatment of pressure-overload hypertrophy.

Animals↗
PubMed2002

Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression.

To investigate the role of insulin signaling on postnatal cardiac development, physiology, and cardiac metabolism, we generated mice with a cardiomyocyte-selective insulin receptor knockout (CIRKO) using cre/loxP recombination. Hearts of CIRKO mice were reduced in size by 20-30% due to reduced cardiomyocyte size and had persistent expression of the fetal beta-myosin heavy chain isoform. In CIRKO hearts, glucose transporter 1 (GLUT1) expression was reduced by about 50%, but there was a twofold increase in GLUT4 expression as well as increased rates of cardiac glucose uptake in vivo and increased glycolysis in isolated working hearts. Fatty acid oxidation rates were diminished as a result of reduced expression of enzymes that catalyze mitochondrial beta-oxidation. Although basal rates of glucose oxidation were reduced, insulin unexpectedly stimulated glucose oxidation and glycogenolysis in CIRKO hearts. Cardiac performance in vivo and in isolated hearts was mildly impaired. Thus, insulin signaling plays an important developmental role in regulating postnatal cardiac size, myosin isoform expression, and the switching of cardiac substrate utilization from glucose to fatty acids. Insulin may also modulate cardiac myocyte metabolism through paracrine mechanisms by activating insulin receptors in other cell types within the heart.

Animals↗
PubMed2002

Enhanced sodium-calcium exchange in the infarcted heart: effects on sarcoplasmic reticulum content and cellular contractility.

Arrhythmias and contractile dysfunction both contribute to the high morbidity and mortality in patients with congestive heart failure. Contractile dysfunction is generally believed to reflect a decrease in the amplitude of intracellular Ca(2+) transients, whereas tachyarrythmias are often initiated in the setting of cellular Ca(2+) overload. In a rabbit model of left ventricular dysfunction due to myocardial infarction, we found evidence that myocyte sarcoplasmic reticulum Ca(2+) content may be normal or even increased at slow stimulation rates. This may occur because prolonged action potential duration promotes Ca(2+) influx via the Na(+)/Ca(2+) exchanger. Despite preserved SR Ca(2+) content, intracellular Ca(2+) transients and contractions may be reduced in amplitude because of impaired synchronization of Ca(2+) release events throughout the myocyte.

Animals↗