AMPD1 gene mutation in congestive heart failure: new insights into the pathobiology of disease progression.
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AMP Deaminase↗
Biomedical subjects
A M Feldman
Publications and source records attributed to A M Feldman.
Enhanced external counterpulsation in the management of patients with cardiovascular disease.
Studies over the past several decades support the hypothesis that enhanced external counterpulsation (EECP) can provide long-term benefits in patients with angina secondary to chronic coronary disease. Numerous non-sham controlled trials have recently been substantiated by a multicenter, randomized trial. Although the mechanism by which this mechanical treatment effects an alteration in cellular processes within the myocardium remains unclear, recent scientific investigations suggest that shear stress induced by chronic exposure to EECP might result in the release of a variety of growth factors and the subsequent stimulation of angiogenesis in the coronary beds. Ongoing clinical trials in patients with significant left ventricular dysfunction, an international registry, and additional clinical trials may help to elucidate further the role of this novel and unique therapy in our clinical armamentarium.
Angina Pectoris↗
The human phospholamban gene: structure and expression.
Phospholamban, through modulation of sarcoplasmic reticulum calcium-ATPase activity, is a key regulator of cardiac diastolic function. Alterations in phospholamban expression may define parameters of muscle relaxation. In experimental animals, phospholamban is differentially expressed in various striated and smooth muscles, and within the four chambers of the heart. Decreased phospholamban expression within the heart during heart failure has also been observed. Furthermore, regulatory elements of mammalian phospholamban genes remain poorly defined. To extend these studies to humans, we (1) characterized phospholamban expression in various human organs, (2) isolated genomic clones encoding the human phospholamban gene, and (3) prepared human phospholamban promoter/luciferase reporter constructs and performed transient transfection assays to begin identification of regulatory elements. We observed that human ventricle and quadriceps displayed high levels of phospholamban transcripts and proteins, with markedly lower expression observed in smooth muscles, while the right atria also expressed low levels of phospholamban. The human phospholamban gene structure closely resembles that reported for chicken, rabbit, rat, and mouse. Comparison of the human to other mammalian phospholamban genes indicates a marked conservation of sequence for at least 217 bp upstream of the transcription start site, which contains conserved motifs for GATA, CP1/NFY, M-CAT-like, and E-box elements. Transient transfection assays with a series of plasmids containing deleted 5' flanking regions (between -2530 and -66 through +85) showed that sequences between -169 and the CP1-box at -93 were required for maximal promoter activity in neonatal rat cardiomyocytes. Activity of these reporters in HeLa cells was markedly lower than that observed in rat cardiomyocytes, suggesting at least a partial tissue selectivity of these reporter constructs.
Adenosine Triphosphatases↗
Characterization of proximal transcription regulatory elements in the rat phospholamban promoter.
Phospholamban is a major regulator of cardiac diastole, with alterations in expression associated with modified cardiac relaxation. To study transcriptional regulation of phospholamban expression, we made reporter constructs that expressed luciferase under control of putative promoter sequences from the rat phospholamban gene. When transfected into neonatal rat cardiomyocytes, constructs containing at least 159 nucleotides preceding the transcription start site were equally active, while truncation to -66/+64 removed all promoter activity. Constructs were more active in cardiomyocytes than in HeLa cells (which do not express phospholamban), but did not show absolute cell-type specificity of expression. Addition of sequences upstream to -4032, all of the intron (7.4 kb), or 3'UTR sequences (0. 8 kb) did not enhance cell-specific expression. To focus on the basal promoter region (-159/-66), a series of deletion constructs were made that identified a novel 35 bp region (-159/-125; Phospholamban Promoter Element 1, PPE1) required for promoter activity in cardiomyocytes. Site-specific mutations identified nucleotides -150/-133 as containing most of the promoter-enhancing activity. While the rat PPE1 is highly conserved (>70%) in four other mammalian phospholamban genes, it does not contain previously characterized regulatory elements. In cardiomyocytes the PPE1 sequence markedly enhanced activity of the SV40 early promoter. A conserved CCAAT element (-83/-79) was also required for promoter activity in both cardiomyocytes and HeLa cells. Exonuclease III footprinting identified protein/DNA interactions in both the extended CCAAT box and PPE1 domains. Gel shift studies identified the CCAAT elements as binding CBF/NF-Y.
3' Untranslated Regions↗
Proinflammatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells.
OBJECTIVE: Tissue inhibitors of metalloproteinases (TIMPs) are downregulated in the failing human heart. The objective of the present study was to test the hypothesis that cytokines might be involved in the regulation of TIMPs in cardiac cells. METHODS: Neonatal Sprague-Dawley rat ventricular cells were exposed to 100 units/ml tumor necrosis factor-alpha and/or 5 ng/ml interleukin-1 beta. The mRNA and protein expression of TIMPs-1-4 and disintegrin metalloproteinase was analyzed using Northern blot, ELISA and/or Western blot, respectively. Proteolytic activity and extracellular matrix degradation and turnover were determined using gelatin zymography and pulse-chase experiments. RESULTS: The TIMP-1 mRNA was upregulated in cardiac cells, while TIMP-1 protein levels were unchanged in myocytes but downregulated in non-myocytes. The TIMP-2 expression did not change with the cytokine treatment. TIMP-3 was downregulated at both the mRNA and protein levels in cardiac cells. TIMP-4 protein was transiently increased and then returned to control level. In contrast, disintegrin metalloproteinase mRNA and protein were significantly upregulated in those cells. The gelatinolytic activity and extracellular matrix protein degradation were significantly increased. CONCLUSIONS: Tumor necrosis factor-alpha and interleukin-1 beta regulate the expression of TIMPs and disintegrin metalloproteinase, which may in turn contribute to the increased matrix degradation in cardiac cells. Since heart failure in humans is characterized by both re-expression of myocardial cytokines and remodeling of the extracellular matrix, those in vitro results suggest a potential role for those cytokines in the regulation of extracellular matrix remodeling and therefore in the transition to the end-stage heart failure phenotype.
Animals↗
Intravenous immune globulin in the therapy of peripartum cardiomyopathy.
OBJECTIVES: We sought to evaluate the effect of therapy with intravenous immune globulin on recovery of left ventricular function in women presenting with peripartum cardiomyopathy. BACKGROUND: Peripartum cardiomyopathy is a rare complication of pregnancy that results in significant morbidity and mortality in women of childbearing age. Intravenous immune globulin has been reported to improve left ventricular systolic function in patients with acute dilated cardiomyopathy and myocarditis, but its effectiveness in peripartum cardiomyopathy is unknown. METHODS: In this retrospective study, we compared the clinical outcomes of six women with peripartum cardiomyopathy treated with intravenous immune globulin (2 g/kg) with those of 11 recent historical control subjects. All women in the study were referred between 1991 and 1998 with class II to IV heart failure and a left ventricular ejection fraction of <0.40. Left ventricular ejection was reassessed during early follow-up (6.1+/-2.9 months). RESULTS: The two groups did not differ in terms of baseline left ventricular ejection fraction, left ventricular end-diastolic diameter, months to presentation, age or multiparity. The improvement in left ventricular ejection fraction in patients treated with immune globulin was significantly greater than in the conventionally treated group (increase of 26+/-8 ejection fraction units vs. 13+/-13, p = 0.042). CONCLUSIONS: In this small retrospective study of women with peripartum cardiomyopathy, patients treated with immune globulin had a greater improvement in ejection fraction during early follow-up than patients treated conventionally. Given the poor prognosis of women with peripartum cardiomyopathy who do not improve, this therapy merits further study.
Adolescent↗
Effect of inotrope withdrawal on morbidity and mortality in patients with chronic heart failure: results of the vesnarinone trial withdrawal substudy. Vest Withdrawal Substudy Group.
BACKGROUND: The use of inotropic agents in the therapy of patients with congestive heart failure (CHF) is controversial. One concern regarding inotropic therapy has been that drug withdrawal could be associated with a worsening of symptoms. METHODS AND RESULTS: We took advantage of the discontinuation of the recent trial of vesnarinone in the therapy of CHF to assess the effects of withdrawal of the inotropic agent, vesnarinone, in patients with chronic CHF who had been randomized to receive either placebo or 30 or 60 mg of vesnarinone. Contrary to our initial hypothesis, withdrawal of vesnarinone did not impact on either morbidity or mortality over a period of 6 months. CONCLUSION: Although these results suggest vesnarinone withdrawal is safe, the applicability of these results to other inotropic agents remains unclear.
Cardiotonic Agents↗
Differential regulation of cardiac expression of IL-6 and TNF-alpha by A2- and A3-adenosine receptors.
The proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 have been implicated in the development of congestive heart failure. Adenosine inhibits the expression of TNF-alpha and IL-6 in macrophages. We determined the effect of adenosine on cytokine expression in rat cardiomyocytes and trabecular muscles obtained from patients with cardiomyopathy. In myocytes, adenosine suppressed TNF-alpha mRNA by 40% (P < 0.05) and induced a 4.7-fold increase in IL-6 mRNA (P < 0.05) with a twofold increase in IL-6 protein release (P < 0.001). The effect on TNF-alpha could be replicated by A2 agonist. The effect on IL-6 could be replicated by A3 agonist, but not by A1 and A2 agonists, and was completely suppressed by A3 antagonist. In human trabecular muscles, A2 agonist suppressed TNF-alpha mRNA by 60% (P < 0.05), but adenosine had no effect on IL-6. In the failing heart, IL-6 was immunolocalized to inflammatory cells. Thus A2 and A3 receptors differentially regulate cardiac expression of TNF-alpha and IL-6. Rat cardiomyocytes and the failing human heart respond differently to adenosine.
Animals↗
Differential expression of tissue inhibitors of metalloproteinases in the failing human heart.
BACKGROUND: Extracellular matrix turnover is regulated by matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs). Together, these proteins may contribute to myocardial remodeling in congestive heart failure. We hypothesized that the expression of MMPs and TIMPs might be differentially regulated in the failing human heart. METHODS AND RESULTS: Northern blot analyses were performed with probes to TIMP-1 to -4 and GAPDH with poly A+ mRNA from ventricular tissues of patients with ischemic cardiomyopathy (ICM, n=16) or idiopathic dilated cardiomyopathy (DCM, n=15) and nonfailing control hearts (n=15). TIMP-1 to -4 and MMP-9 proteins were quantified by ELISA and/or Western blot, and the total gelatinolytic activity was studied by gelatin zymography. The results showed that cardiac expression of TIMP-1 and -3 transcripts and proteins was significantly reduced in ICM and DCM. No significant difference was observed in TIMP-2 and -4 transcripts. However, TIMP-4 protein was significantly reduced in ICM myocardium. MMP-9 protein content and total gelatinolytic activity were upregulated in the same samples. CONCLUSIONS: These studies demonstrated a selective downregulation of TIMPs along with upregulation of MMP-9 and gelatinolytic activity in the failing hearts, alterations that favor matrix degradation and turnover. These findings might be of pathophysiological significance and might suggest new therapeutic targets for limiting the ventricular remodeling and dilatation process characteristic of the failing human heart.
Adult↗
Feasibility of combined percutaneous transluminal angioplasty and minimally invasive direct coronary artery bypass in patients with multivessel coronary artery disease.
BACKGROUND: Angioplasty has become an accepted treatment of patients with coronary artery disease and is now commonly used to treat patients with multivessel disease. The major disadvantage of angioplasty has been restenosis requiring repeat interventions with resultant loss of initial cost savings. Compared with the right and the circumflex coronary arteries, the left anterior descending artery (LAD) has been more adversely affected by restenosis. Recently, minimally invasive direct coronary artery bypass (MIDCAB) to the LAD through a small left anterior thoracotomy using the left internal mammary artery has been performed in some centers with excellent early results and with reduced costs compared with standard bypass surgery. METHODS AND RESULTS: We retrospectively reviewed the first 31 consecutive patients treated in our institution with integrated coronary revascularization (ICR): MIDCAB to the LAD combined with PTCA of the other diseased vessels in patients with multivessel disease. Postoperative angiography in 84% of patients revealed a patent anastomosis and normal flow in the graft and bypassed vessel. Thirty-eight (97%) of 39 vessels were successfully treated percutaneously. At a mean follow-up of 7 months, all patients are currently asymptomatic. There have been 2 adverse clinical events, both related to angioplasty and not to MIDCAB. The average length of stay at the hospital after MIDCAB was 2.79+/-1.05 days. CONCLUSIONS: These preliminary results with ICR are encouraging and suggest that a randomized, prospective clinical trial comparing ICR with standard coronary artery bypass surgery for the revascularization of symptomatic patients with multivessel disease involving the LAD is warranted.
Angioplasty, Balloon, Coronary↗
Effects of tumor necrosis factor gene polymorphisms on patients with congestive heart failure. VEST Investigators for TNF Genotype Analysis. Vesnarinone Survival Trial.
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known to be elevated in patients with congestive heart failure (CHF). Two biallelic polymorphisms have been identified in the TNF gene locus: one in the promoter region of TNF-alpha (TNFA1/2), and the other in the first intron of TNF-beta (TNFB1/2). Both TNFA2 and TNFB2 alleles are associated with high TNF-alpha production in vitro and susceptibility to inflammatory diseases. Given the importance of TNF-alpha in the pathogenesis of CHF, we studied the prevalence of TNF gene polymorphisms in CHF patients and the correlation of genotypes to in vivo TNF-alpha levels. METHODS AND RESULTS: TNFA and TNFB genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism technique. There were no differences in the TNF allele frequencies between CHF (n=229; TNFA1/2=0.84/0.16, TNFB1/2=0.33/0.67) and control subjects (n=139; TNFA1/2=0.84/0.16, TNFB1/2=0.32/0.68). In 211 patients with CHF, circulating levels of TNF-alpha and the soluble receptors type I and type II were measured by ELISA: 6.18+/-3.59 pg/mL, 1768+/-761 pg/mL, and 4484+/-1750 pg/mL, respectively. There were no correlations between TNFA or TNFB genotypes and circulating levels of TNF-alpha or its soluble receptors in the CHF patients. CONCLUSIONS: Despite their association with other inflammatory diseases, neither TNFA nor TNFB polymorphisms are related to the presence of CHF or the elevation of circulating TNF-alpha. Thus, other factors may be more important in determining the circulating levels of TNF-alpha in CHF.
Adult↗
Heterogeneous immediate effects of partial left ventriculectomy on cardiac performance.
BACKGROUND: Partial left ventriculectomy (PLV) is a novel surgical treatment for severe heart failure consisting of resection of a large wedge of myocardium to reduce wall stress and restore the normal mass-volume ratio. Although ejection fraction (EF) has been shown to improve after PLV, few other physiological data describing its immediate effects on left ventricular (LV) performance are available. METHODS AND RESULTS: Eight patients, 58+/-5 years old, with severe clinical heart failure and EF of 12+/-3% were studied before and immediately after PLV. LV performance was assessed by the predominantly load-insensitive measures of pressure-area relations with high-fidelity pressure catheters and transesophageal automated echocardiographic measures of cross-sectional area as a surrogate for volume. LV end-diastolic volume decreased from 200+/-60 to 89+/-17 mL, EF increased from 12+/-3% to 41+/-8%, and right ventricular (RV) fractional area change increased from 24+/-12% to 37+/-16% (all P<.05 versus before). Changes in pressure-area relations were variable: end-systolic elastance, 6.5+/-3.4 to 4.3+/-2.5 mm Hg/cm2 and preload recruitable stroke work, 33+/-16 to 34+/-19 mm Hg (P=NS versus before). End-diastolic stiffness increased from 0.13+/-0.06 to 0.19+/-0.07 mm Hg/cm2 (P<.05 versus before). Improvement in LV performance was inversely correlated with semiquantitative histological assessment of myocardial fibrosis and positively correlated with nuclear enlargement and hyperchromasia, indicative of myocyte hypertrophy. No long-term follow-up data were available. CONCLUSIONS: PLV resulted in reductions in LV volumes, increases in EF and RV ejection, but increases in LV stiffness. Estimates of LV performance revealed variable results associated with the degree of myocardial fibrosis. Further study of these effects in relation to patient outcome is warranted.
Aged↗
Adenosine inhibits lipopolysaccharide-induced secretion of tumor necrosis factor-alpha in the failing human heart.
BACKGROUND: The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of congestive heart failure. Recent studies have shown that adenosine inhibits lipopolysaccharide (LPS)-induced expression of TNF-alpha in macrophages and rat cardiomyocytes. The aim of this study was to determine whether adenosine has a similar effect in the failing human heart. METHODS AND RESULTS: Left ventricular muscle strips were obtained from seven patients with end-stage congestive heart failure undergoing heart transplantation or insertion of a left ventricular assist device. The muscle strips were incubated at 37 degrees C in 95% O2/5% CO2 and stimulated with LPS (10 microg/mL). TNF-alpha release in the supernatant was measured with ELISA, and muscle sections were stained for TNF-alpha. Muscle strips released TNF-alpha in the absence of LPS (0.22+/-0.05 pg x mL(-1) x mg wet wt[-1]). TNF-alpha was immunolocalized to the cardiac myocyte, suggesting that the myocyte is a source for TNF-alpha production. Adenosine (10 micromol/L) decreased TNF-alpha by 40% (P<.05). The selective adenosine A2 receptor agonist DPMA (10 micromol/L) decreased TNF-alpha release by 87% (P<.001), whereas ITu (10 micromol/L), an adenosine-regulating agent that increases endogenous adenosine concentration, inhibited TNF-alpha release by 93% (P<.001). CONCLUSIONS: Adenosine can significantly diminish TNF levels in the failing human heart and may represent a new pharmacological intervention in congestive heart failure.
Adenosine↗
Unstable angina: specialty-related disparities in implementation of practice guidelines.
BACKGROUND: The agency for Health Care Policy and Research (AHCPR) has published practice guidelines to improve the quality of care patients with unstable angina. Prior to publication, studies demonstrated that when compared with cardiologists, internists were less likely to use effective pharmacologic therapies or revascularization in patients with unstable angina. HYPOTHESIS: The study was undertaken to determine whether the AHCPR guideline publication abolished specialty-related disparities in care. METHODS: We performed a chart review of consecutive patients hospitalized at a university-affiliated institution with an admission diagnosis of chest pain in the absence of myocardial infarction and a noncardiac etiology. Treatment and diagnostic cardiac testing were compared between risk-stratified patients cared for by a generalist (n = 125) and those whose care was guided by a cardiologist (n = 211). RESULTS: In those with low-risk unstable angina, generalists were less likely to prescribe recommended aspirin (71 vs. 88%, p < 0.01) and beta blockers (9 vs. 37%, p < 0.001), and heparin (20 vs. 49%, p < 0.001), and to perform a recommended diagnostic stress test or cardiac catheterization (28 vs. 60%, p < 0.001). In those with at least intermediate risk, generalists were less likely to prescribe beta blockers (19 vs. 52%, p < 0.001), heparin (19 vs. 66%, p < 0.001), and nitrates (77 vs. 96%, p < 0.001), and to refer for diagnostic testing (19 vs. 65%, p < 0.001). Generalists' care was associated with significantly lower hospital charges. CONCLUSIONS: AHCPR guidelines for the evaluation and treatment of unstable angina are implemented more effectively, but not uniformly, by cardiologists at our institution. Further studies are necessary to evaluate the barriers to implementation of the AHCPR guidelines.
Aged↗
End-systolic pressure-dimension relationship of in situ mouse left ventricle.
The increasing popularity of genetically engineered mice in cardiovascular research has made it important to evaluate cardiac function in small animals. We have developed a system to enable simultaneous pressure-dimension analysis of the mouse left ventricle. The chest was opened under anesthesia, and a 1.4 F micromanometer catheter was inserted into the left ventricle through the apex. A pair of sonomicrometry crystals were attached to the anterior and posterior walls using tissue adhesive. Pressure and dimension were recorded simultaneously at baseline and after isoproterenol injection (1 micro g, intraperitoneally). The ascending aorta was occluded transiently to estimate the end-systolic pressure-dimension relationship (ESPDR), which was parameterized subsequently by the quadratic equation: Pes=C2 X (Des-D0)2+E0 X (Des-D0), where Pes is end-systolic pressure, Des is end-systolic dimension, D0 is the dimension axis intercept, E0 is the local slope at D0, and C2 is the curvilinearity coefficient. The maximum and minimum external dimensions at baseline were 5.82+/-0.50 (s.d.) mm and 5.49+/-0.46 mm with fractional shortening of 0.057+/-0.014 (n=12). The ESPDR was significantly curvilinear and increased convexity after isoproterenol injection (C2, -444+/-281 to -1113+/-780 mmHg/mm2, P<0. 05; E0, 536+/-175 to 889+/-276 mmHg/mm, P<0.001), while the dimension axis intercept remained relatively constant (D0, 5.39+/-0. 46 to 5.37+/-0.52 mm). In conclusion, the combination of miniature piezo-electric crystals and a micromanometer enables continuous measurement of pressure and dimension of in situ mouse left ventricle. This technology may be useful in evaluating the cardiac phenotype of genetically engineered mice.
Animals↗
Evidence of phenotypic alteration as a cause of systolic dysfunction in the failing heart.
This article describes the phenotype of dilated cardiomyopathy in humans and describes parallel studies in experimental models that support or refute the relevance of these changes to the development of the heart failure phenotype.
Adenylyl Cyclases↗
Predicting short-term outcome in severely ill heart failure patients: implications regarding listing for urgent cardiac transplantation and patient selection for temporary ventricular assist device support.
BACKGROUND: The purpose of this study was to determine which patients on a cardiac transplantation list required a ventricular assist device. METHODS AND RESULTS: In a preliminary study, 26 patients with decompensated severe New York Heart Association class IV chronic heart failure were studied. Blood levels for sodium, hemoglobin, cytokines, neurohormones, and hemodynamics were obtained. During short-term follow-up of 40 days, 12 patients had undergone emergent implantation of a ventricular assist device (range 1-27 days, mean 5 days), 4 died (range 14-38 days, mean 26 days), and 5 were alive and receiving only medical therapy while waiting for a transplantation. In addition, five patients had undergone transplantation (range 5-29 days, mean 18 days, excluded from further analysis). Survival curves were constructed by comparing the incidence of death and the implantation of an emergent ventricular assist device in patients with values of a variable above or below the mean value (or median for nonnormally distributed data). There was a significantly greater incidence of death or need for a ventricular assist device in patients with higher levels of tumor necrosis factor-alpha (P = .008), lower levels of serum sodium and hemoglobin (P = .02 and P = .03, respectively), higher heart rates (P = .03), and higher plasma norepinephrine levels (P = .01). The Cox proportional hazards model demonstrated that only serum sodium (P = .03) independently predicted those patients who died or who required emergent left ventricular assist device. CONCLUSION: Numerous variables, particularly serum sodium, need to be considered when evaluating which patients on the transplant list require early assist device implantation or urgent transplantation. These preliminary observations merit confirmation in a larger patient population.
Adult↗