Biomedical subjects
Publications and source records attributed to S Frantz.
As the number of implanted pacemakers and the incidence of malignant tumors increases, the probability of radiation-mediated pacemaker dysfunction increases. Radiation can substantially damage pacemaker electronics. We report here a case, with loss of communication after radiation therapy.
The baroreflex mechanism is a central part of the regulation of the cardiovascular system, particularly in the control of vagal and sympathetic outflow to the heart and the peripheral circulation. Failure of the baroreflex is a rare cause of secondary hypertension. It is characterized by drastic changes in sympathetic activation and blood pressure following complete denervation of the baroreflex. Here, we report a case of baroreflex failure following bilateral carotid artery surgery and radiation. Moreover, postoperative orthostatic hypotension with recurrent syncope suggests a rare subform, the selective baroreflex failure, where efferent parasympathetic activity is preserved. Both high blood pressure and orthostatically induced syncope improved substantially after treatment with clonidine.
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A region with a major effect on blood pressure (BP) is located on rat chromosome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in second filial generation rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we report the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 and SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains, the segments in WISA1 and SISA1 did not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombination in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared with that of their respective parental strain, which was of a magnitude similar to those seen in the original congenic strains. The findings strongly indicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgressed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-conferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies.
Growing evidence from patients with heart failure and from experimental animal models implicates effectors of innate immunity in the pathogenesis of this syndrome. The expression of the innate immunity signaling protein, Toll-like receptor 4 (TLR4), is increased in cardiac myocytes in situ and in failing myocardium, but the mechanism by which TLRs may be activated in the failing heart remains unclear. We report that TLR2, which is expressed in cardiac myocytes, participates in the response of these cells to oxidative stress, a major contributor to the pathogenesis of cardiac dysfunction. Hydrogen peroxide increased nuclear factor kappaB (NF-kappaB) activation in Chinese hamster ovary fibroblasts that overexpress TLR2 but not in normal or TLR4-overexpressing Chinese hamster ovary cells, an effect that was abrogated by an alpha-TLR2 antibody. In neonatal rat ventricular myocytes, the alpha-TLR2 antibody inhibited hydrogen peroxide-induced nuclear translocation of NF-kappaB and activator protein-1 (AP-1). Inhibition of TLR2 had no effect on tumor necrosis factor alpha-induced NF-kappaB or AP-1 activation, on the DNA binding of the basal transcription factor Oct-1, or on hydrogen peroxide-induced phosphorylation of p38 MAP kinase. Importantly, oxidative stress-induced cytotoxicity was enhanced by blocking TLR2. Given the importance of cytotoxicity and apoptosis to the pathology of the ischemic heart, an anti-apoptotic effect of TLR2 in cardiac myocytes exposed to elevated levels of ROS may limit further cardiac dysfunction.
Matrix metalloproteinase-9 (MMP-9) is prominently overexpressed after myocardial infarction (MI). We tested the hypothesis that mice with targeted deletion of MMP9 have less left ventricular (LV) dilation after experimental MI than do sibling wild-type (WT) mice. Animals that survived ligation of the left coronary artery underwent echocardiographic studies after MI; all analyses were performed without knowledge of mouse genotype. By day 8, MMP9 knockout (KO) mice had significantly smaller increases in end-diastolic and end-systolic ventricular dimensions at both midpapillary and apical levels, compared with infarcted WT mice; these differences persisted at 15 days after MI. MMP-9 KO mice had less collagen accumulation in the infarcted area than did WT mice, and they showed enhanced expression of MMP-2, MMP-13, and TIMP-1 and a reduced number of macrophages. We conclude that targeted deletion of the MMP9 gene attenuates LV dilation after experimental MI in mice. The decrease in collagen accumulation and the enhanced expression of other MMPs suggest that MMP-9 plays a prominent role in extracellular matrix remodeling after MI.
Expression of innate immune response proteins, including IL-1beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappaB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.
Little is known about the regulation of total creatine concentration in heart, skeletal muscle, brain, liver and kidney in response to increased dietary creatine intake. The phosphorylated fraction of intracellular creatine (phosphocreatine) remain relatively constant, and therefore, higher intracellular creatine levels may increase the energy reserve of the heart [phosphocreatine and phosphoryl transfer via creatine kinase (CK)] and of other organs. To test the effect of supplying exogenous creatine on the myocardial energy reserve and on creatine content of various organs, rats were given chow containing 0 (Untreated), 1, 3, 5, or 7% (of diet weight) creatine for ;40 days. Thereafter, hearts were perfused and left ventricular developed pressure and heart rate were recorded. High-energy phosphate concentrations were determined with 31P-NMR spectroscopy, CK reaction velocity by 31P-magnetization transfer. Total creatine was determined in heart, skeletal muscle, brain, liver, kidney and serum by high-performance liquid chromatography (HPLC). Creatine feeding increased serum creatine by 73% (1% creatine), 142% (3%), 166% (5%) and 202% (7%). In the heart, increased serum creatine levels did not affect mechanical function; ATP, phosphocreatine, inorganic phosphate, CK reaction velocity and total creatine were all unchanged. Total creatine also remained constant in brain and skeletal muscle, while creatine content increased 4.6-fold in the liver and 1.9-fold in the kidney. We conclude that myocardial energy reserve via CK cannot be increased by exogenous creatine treatment.
We tested whether angiotensin-converting enzyme (ACE) inhibitor therapy with quinapril prevents the deterioration of mechanical function and high-energy phosphate metabolism that occurs in chronically infarcted heart. Rats were subjected to ligation of the left anterior descending coronary artery (LAD) or sham operation. Four groups were studied: sham-operated rats (n = 10), rats with myocardial infarction (MI, n = 9), sham-operated quinapril-treated rats (n = 8), and infarcted quinapril-treated (n = 13) rats. Treated rats received 6 mg/kg/day of the ACE inhibitor quinapril orally, initiated 1 h after MI or sham operation. Eight weeks after LAD ligation or sham operation, hearts were isolated and buffer-perfused isovolumically. High-energy phosphate metabolism and intracellular pH were continuously recorded with 31P-nuclear magnetic resonance (NMR) spectroscopy. Hearts were subjected to 15-min control, 30-min hypoxia (95% N2/5% CO2, and 30-min reoxygenation. Left ventricular developed pressure (LVDP) was reduced in infarcted hearts (58 +/- 10 vs. 98 +/- 9 mm Hg in sham, p < 0.05), and this reduction was partially prevented by quinapril (78 +/- 8 mm Hg). ATP content of residual intact myocardium after sham operation or MI was unchanged. Creatine phosphate was reduced in infarcted hearts (107 +/- 10 vs. 138 +/- 5% of control ATP, p < 0.05), and quinapril prevented this decrease (131 +/- 8%). Therefore, quinapril preserved both function and high-energy phosphate metabolism in the chronically infarcted heart. However, when hearts were subjected to acute hypoxia, susceptibility to acute metabolic stress was substantially increased in both quinapril-treated groups: ATP content at end-hypoxia was reduced to 31 +/- 7 and 37 +/- 6% in sham and infarcted quinapril-treated groups, whereas ATP in untreated sham and infarcted hearts was 66 +/- 6 and 66 +/- 3% of baseline values (p < 0.05 untreated vs. quinapril treated). Likewise, recovery of LVDP during reoxygenation was impaired by quinapril treatment (15 +/- 7 and 15 +/- 4 mm Hg in quinapril-treated sham and MI vs. 73 +/- 9 and 46 +/- 9 mm Hg in untreated sham and MI groups, p < 0.05 untreated vs. quinapril treated). The most likely explanation for the unexpected finding of increased susceptibility to acute metabolic stress in the quinapril-treated groups is reduced wall thickness leading to increased wall stress. The preservation of high-energy phosphate content in residual intact hearts after MI may contribute to the beneficial effects of ACE inhibitors after MI.
Three commercial swine herds were selected for study, because pigs at slaughter consistently had lung lesions typical of bronchopneumonia and snout lesions consistent with atrophic rhinitis. Pigs were reared in the conventional system for each herd except that they were identified at birth and weighted at various intervals. At slaughter, individual pig lungs and snout were examined for lesions of pneumonia and atrophic rhinitis, respectively. Lesions were scored and correlated with growth indicators for each pig. Included in the growth indicators were: average daily gain (growing phase), average daily gain (finishing phase), average daily gain (total), and days to reach 104.5-kg body weight. Additionally, for each pig, scores for lung lesions were correlated to grades for snout lesions. Three correlation coefficients for measurements of pigs within herd B were significant and included days to 104.5-kg body weight and grades for snout lesions, -0.15 (P less than 0.02); average daily gain (finishing) and grades for snout lesions, 0.17 (P less than 0.01); and average daily gain (total) and grades for snout lesions, 0.16 (P less than 0.01). Contrary to findings in other investigations, pigs that attained market weight at the youngest age did not have the lowest score for lung lesions, the lowest grade for snout lesions, or the least extensive or severe lesions. Combining data from all 3 herds, the mean scores for lung lesions and mean grades for snout lesions decreased significantly (P less than 0.05) as the age of pigs at slaughter increased. All other statistical correlations were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclosporine (cyclosporin A, CsA) is a selective T-cell immunosuppressant that works primarily through inhibition of both antigen presentation and lymphokine production. It has dramatically improved the prognosis for solid organ transplantation. Significant nephrotoxicity has been associated with its systemic use. Topical CsA 2% was used in 11 high-risk corneal transplant patients (8 men; 3 women; average age, 44 years). Ten (91%) of 11 corneas remained clear at an average follow-up of 16 months (range, 6-24 months). All patients had transient epithelial keratitis. Systemic whole blood levels of CsA measured by high-performance liquid chromatography (HPLC) ranged from 14 to 64 ng/ml. All previous reports on the use of topical CsA in high-risk corneal transplant patients have not detected systemic CsA levels.
Short-term results of aggressive surgical management were compared with results of medical management in forty-three patients with preinfarction angina admitted to the coronary-care unit (CCU) over an 18 month period. These patients were selected from 1,609 consecutive admissions to the CCU because they met strict criteria for preinfarction angina: severe chest pain at rest, ST-segment elevation or depression during pain which subsided rapidly after cessation of pain, and normal serum enzymes (CPK, SGOT, and LDH). Twenty-three patients had coronary angiography, done with operating room and pump standby. One patient, who had total occlusion of the left main coronary artery, died during the study. Twenty-one of the remaining patients were considered surgical candidates, and were treated immediately after angiography with 1 to 3 vein bypass grafts. There was one late postoperative death and, of the 20 survivors, 2 had ECG evidence of acute myocardial infarction and one had mild angina at time of discharge. In contrast, of the 21 patients treated medically, 13 sustained acute MI, resulting in 8 instances of congestive heart failure and 4 cases of ventricular fibrillation. Four patients died in cardiogenic shock. With the use of rigid criteria, a small subgroup of patients with variant angina at high risk of developing AMI has been identified and categorized as having preinfarction angina. Our experience suggests that aggressive surgery immediately following coronary angiography offers a lower incidence of MI, morbidity, and death than does medical management.
BACKGROUND: Genetically altered mice will provide important insights into a wide variety of processes in cardiovascular physiology underlying myocardial infarction (MI). Comprehensive and accurate analyses of cardiac function in murine models require implementation of the most appropriate techniques and experimental protocols. OBJECTIVE: In this study we present in vivo, whole-animal techniques and experimental protocols for detailed electrophysiological characterization in a mouse model of myocardial ischemia and infarction. METHODS: FVB mice underwent open-chest surgery for ligation of the left anterior descending coronary artery or sham-operation. By means of echocardiographic imaging, electrocardiography, intracardiac electrophysiology study, and conscious telemetric ECG recording for heart rate variability (HRV) analysis, we evaluated ischemic and post-infarct cardiovascular morphology and function in mice. RESULTS: Coronary artery ligation resulted in antero-apical infarction of the left ventricular wall. MI mice showed decreased cardiac function by echocardiography, infarct-typical pattern on ECG, and increased arrhythmia vulnerability during electrophysiological study. Electrophysiological properties were determined comprehensively, but were not altered significantly as a consequence of MI. Autonomic nervous system function, measured by indices of HRV, did not appear altered in mice during ischemia or infarction. CONCLUSIONS: Cardiac conduction, refractoriness, and heart rate variability appear to remain preserved in a murine model of myocardial ischemia and infarction. Myocardial infarction may increase vulnerability to inducible ventricular tachycardia and atrial fibrillation, similarly to EPS findings in humans. These data may be of value as a reference for comparison with mutant murine models necessitating ischemia or scar to elicit an identifiable phenotype. The limitations of directly extrapolating murine cardiac electrophysiology data to conditions in humans need to be considered.