Gene therapy for therapeutic myocardial angiogenesis: a promising synthesis of two emerging technologies.
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Biotechnology↗
Biomedical subjects
A M Feldman
Publications and source records attributed to A M Feldman.
IL-1 beta alters the expression of the receptor tyrosine kinase gene r-EphA3 in neonatal rat cardiomyocytes.
To identify proinflammatory cytokine responsive genes in the myocardium, we used differential display to study RNA isolated from neonatal rat cardiac myocytes treated with tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). Sequence analysis of differential display products confirmed by reverse Northern blots revealed one clone as the partial sequence of an Eph-related receptor tyrosine kinase (r-EphA3). In cardiac myocytes, 36-h exposure to TNF-alpha and IL-1 beta reduced r-EphA3 transcripts to 59.9% (P < 0.01) of control levels; this effect was largely dependent on IL-1 beta. Western blot analysis showed that changes in r-EphA3 protein levels reflect that seen for transcripts. Cardiac nonmyocytes expressed substantially lower levels of r-EphA3. Full-length r-EphA3 cDNA clone (3,077 base pair) yielded an amino acid sequence with 90-98% homology to the Eph receptor human EphA3, chick EphA3, and mouse EphA3. In the adult rat, r-EphA3 transcripts were most abundant in the heart, brain, and lung. These results suggest that IL-1 beta may exert its effect on cardiac myocytes at least in part by altering r-EphA3 expression.
Amino Acid Sequence↗
Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy.
BACKGROUND: Although an autoimmune pathogenesis has been postulated for dilated cardiomyopathy, immunosuppressive therapy has not been shown to be effective in clinical trials. Immune modulatory therapy with immune globulin is an effective therapy for Kawasaki disease in children, and recent data suggest that it improves ventricular function in children with new-onset dilated cardiomyopathies. The role of immune globulin therapy in adults with this disorder has not previously been evaluated. METHODS AND RESULTS: Ten patients were treated with high-dose intravenous immune globulin infusions (2 g/kg). All were hospitalized with NYHA class III to IV heart failure, left ventricular ejection fraction (LVEF) < 0.40, and symptoms for < 6 months at the time of presentation. One patient died before the completion of therapy. The remaining 9 were discharged, and LVEF was reassessed 12 months after therapy. LVEF improved from 0.24 +/- 0.02 (mean +/- SEM) at baseline to 0.41 +/- 0.04 at follow-up (P = .003). All 9 patients improved functionally to NYHA class I to II, and there have been no subsequent hospitalizations for heart failure during the course of follow-up. CONCLUSIONS: In this series of patients with new-onset dilated cardiomyopathy treated with high-dose immune globulin, LVEF improved 17 EF units. The effectiveness of intravenous immune globulin therapy in this disorder should be evaluated in a randomized, multicenter trial.
Acute Disease↗
Circulating interleukin-6 in severe heart failure.
In a group of patients with New York Heart Association class IV heart failure, significant relations between interleukin-6 and tumor necrosis factor-alpha, and between levels of both interleukin-6 and tumor necrosis factor-alpha and plasma levels of norepinephrine were observed. The present study also demonstrates that in patients with heart failure, elevated levels of tumor necrosis factor-alpha and interleukin-6 may be present even without cachexia.
Adult↗
Academic cardiology division in the era of managed care. A paradigm for survival.
The ability of academic divisions of cardiology to pursue educational and research missions in an era of market-driven managed care is being increasingly jeopardized. Indeed, several academic medical centers have been sold to for-profit entities, and many cardiology divisions have been forced to decrease staff and faculty reimbursements. Despite these threats, the academic division has unique strengths: (1) premium quality of care, (2) a single employer, (3) a somewhat uniform practice culture, (4) high-volume operators performing interventional procedures, (5) expertise in highly technical aspects of cardiology, and (6) the availability of physicians for outreach ventures. Therefore, we hypothesized that the cardiology division could be strengthened by collaborating with the medical center in the development of an aggressive and proactive managed care strategy. To this end, we developed a cardiovascular network having the academic center as its central focus but including a group of high-quality and geographically dispersed community-based physicians. These physicians were attracted by an economic package that provided protection from downside risk, participation in our managed care initiatives, and geographic exclusivity in an over-crowded market. In turn, the community-based physicians increasingly used the academic medical center for tertiary care, resulting in increased volumes and incremental profitability. Using this paradigm, we have now recruited approximately 40 community cardiologists. The resulting network provides access to a university cardiologist in most of the surrounding urban and rural counties and will allow us to compete effectively for capitated contracts.
Academic Medical Centers↗
Treatment of patients admitted to the hospital with congestive heart failure: specialty-related disparities in practice patterns and outcomes.
OBJECTIVES: This study sought to define specialty-related differences in the care and outcome of patients admitted to the hospital with congestive heart failure (CHF). BACKGROUND: Congestive heart failure is the leading diagnosis-related group (DRG) discharge diagnosis in the United States and accounts for an estimated annual hospital cost in excess of $7 billion. The clinical impact of aggressive CHF management and the importance of the subspecialist in guiding this care have not been evaluated. METHODS: To define differences in physician practice patterns, we performed a chart review of consecutive patients admitted to a university teaching hospital with a primary DRG discharge diagnosis of CHF. We compared treatment and outcome of patients cared for by a generalist (n = 160) and those whose care was guided by a cardiologist (n = 138) during their index hospital period with CHF and over the next 6 months. RESULTS: At our institution, > 50% of patients admitted to the hospital with CHF cared for by generalists alone had minimal (New York Heart Association functional class I or II) symptoms, compared with < 15% of those cared for by a cardiologist (p < 0.01). Although generalists' patients underwent significantly fewer in-hospital diagnostic tests and had shorter lengths of stay, they had a 1.7-fold increased risk of readmission for CHF within 6 months (p < 0.05). Six-month cardiac and all-cause mortality were not significantly different between the groups. The type of physician caring for the patient and a history of diabetes, previous CHF or myocardial infarction were independent predictors of readmission for CHF. CONCLUSIONS: Involvement of a cardiologist in the care of patients admitted to the hospital with CHF is associated with increased use of diagnostic testing, longer hospital stays and improved clinical outcome. These results substantiate practice guidelines that suggest a role for cardiologists in the care of symptomatic patients with CHF.
Aged↗
Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice.
BACKGROUND: Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine with negative inotropic effects, can be detected in myocardium with end-stage heart failure, after endotoxin administration, and during transplant rejection. Various studies suggest that TNF-alpha participates in the pathogenesis of cardiac dysfunction. To test this hypothesis, transgenic mice were made that selectively overexpress TNF-alpha in cardiomyocytes. METHODS AND RESULTS: A transgene construct was made containing the murine alpha-myosin heavy chain promoter and the coding sequence of murine TNF-alpha, followed by the simian virus 40 T-antigen intron and polyadenylation signals. Injection of this construct into fertilized eggs yielded three transgenic mice, all of which died spontaneously before the completion of weaning. Gross pathologic analysis of these mice demonstrated a decrease in body weight with markedly increased heart weight. Histologic examination of the heart revealed a substantial, diffuse lymphohistiocytic inflammatory infiltrate, associated with interstitial edema. Reverse transcriptase polymerase chain reaction showed that the transgene was expressed in the heart. Enzyme-linked immunosorbent assay demonstrated a substantial amount of TNF-alpha protein in the transgenic heart. CONCLUSION: Overexpression of TNF-alpha in the heart leads to severe myocarditis and cardiomegaly. These results support the hypothesis that myocardial expression of TNF-alpha can contribute to the pathogenesis of cardiac dysfunction.
Animals↗
Interleukin-1 beta inhibits phospholamban gene expression in cultured cardiomyocytes.
Phospholamban is a key regulatory protein that defines diastolic function. Proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) can depress contractility and intracellular Ca2+ currents and transients. An alteration in phospholamban expression is a possible pathway by which these cytokines modulate cardiac function. To test this hypothesis, primary cultures of neonatal rat cardiomyocytes were incubated with IL-1 beta, TNF-alpha, or both, and the level of phospholamban transcripts was examined by Northern blot analyses. Phospholamban transcript levels were decreased approximately equal to 50% (P < .0001) in cells exposed to 2 ng/mL IL-1 beta (20 hours), whereas TNF-alpha had no effect. Western blot analyses showed that IL-1 beta also reduced phospholamban protein levels (60% of control, P < .0001). The effects on transcript levels were gene specific; IL-1 beta induced transcripts for inducible NO synthase (iNOS), did not alter GAPDH transcripts, and reduced sarcoplasmic reticulum Ca(2+)-ATPase (65% of control, P < .001) transcripts. Cardiomyocytes treated with IL-1 beta showed no alterations in basal contractile parameters (maximum velocity of contraction and relaxation and maximal amplitude of contraction) but were unresponsive to beta-adrenergic stimulation. Studies performed in the presence of second-messenger inhibitors showed that the effect of IL-1 beta on phospholamban transcript levels was blocked by dexamethasone, was insensitive to inhibitors of iNOS, cyclooxygenase, or tyrosine kinases, but was enhanced by the addition of the protein kinase inhibitor staurosporine. These data demonstrate that IL-1 beta alters the expression of phospholamban, a key regulator of cardiac contractility, at both the transcript and protein levels. The results suggest novel mechanisms by which IL-1 beta may modify cardiac function.
Animals↗
Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha.
The failing human heart expresses tumor necrosis factor-alpha (TNF-alpha). However, its pathophysiological significance is not clear. We previously reported that robust overexpression of TNF-alpha in the murine heart causes lethal myocarditis. In this study, we modified the transgene to reduce the production of TNF-alpha by preserving the destabilizing sequence in TNF-alpha cDNA. Expression was driven by the murine alpha-myosin heavy chain promoter. Use of this modified construct allowed to the establish a mutine transgenic line (TG). TG offspring were examined at 6, 12, and 24 weeks. All showed a significantly higher heart weight-to-body weight ratio. Northern blot analysis confirmed the expression of transgene in the heart, and enzyme-linked immunosorbent assay demonstrated the presence of TNF-alpha protein. The TG heart demonstrated a mild, diffuse, lymphohistiocytic interstitial inflammatory infiltrate. Cardiomyocyte necrosis and apoptosis were present but not abundant. Magnetic resonance imaging showed that the TG heart was significantly dilated with reduced ejection fraction. Although the left ventricular dP/dtmax was not different at baseline, its responsiveness to isoproterenol was significantly blunted in TG. Atrial natriuretic factor was expressed in the TG ventricle. A group of TG died spontaneously, and subsequent autopsies revealed exceptional dilation of the heart, increased lung weight, and pleural effusion, suggesting that they died of congestive heart failure. The cumulative mortality rate at 6 months was 23%. In conclusion, the mouse overexpressing TNF-alpha recapitulated the phenotype of congestive heart failure. This provides a novel model to elucidate the role of this cytokine in the development of congestive heart failure.
Animals↗
Dose dependence of chronic positive inotropic effect of vesnarinone in patients with congestive heart failure due to idiopathic or ischemic cardiomyopathy.
Vesnarinone is a novel oral agent that improves survival and symptoms of patients with dilated cardiomyopathy. Although it is thought to have positive inotropic effects, clinical data supporting this mechanism in patients with severe heart failure remain scant. The present study tested whether 3 months of oral vesnarinone therapy increases the inotropic state and whether this response is dose dependent. Twenty-one patients with dilated cardiomyopathy (New York Heart Association class III to IV) were randomized to 30 mg/day (n = 11) or to 60 mg/day (n = 10) of vesnarinone. Cardiac function was assessed before and after therapy by radionuclide ventriculography to measure left ventricular volume and flow and by noninvasive measurement of the central aortic pressure wave. The inotropic effect of vesnarinone was assessed by a recently validated index equal to the ratio of left ventricular maximal ventricular power divided by the square of end-diastolic volume (PWRmax/ EDV2). This ratio is sensitive to inotropic change but is minimally altered by chamber loading. After 3 months of 60 mg/day therapy, PWRmax/EDV2 increased by 28 +/- 32%. Ejection fraction and cardiac output also increased by 21 +/- 14% and 14 +/- 14%, respectively, and arterial load decreased by 10.5 +/- 12.4% (all p < 0.005). End-systolic volume also declined by 7 +/- 10%, suggesting reverse remodeling. These changes were smaller and none achieved statistical significance at the 30 mg/day dose (e.g., 14.2 +/- 35.4% for PWRmax/ EDV2). Heart rate was unchanged with either dose. Thus, chronic vesnarinone treatment dose modestly raises the inotropic state and lowers afterload in patients with dilated cardiomyopathy in a dose-dependent fashion.
Administration, Oral↗
Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations.
BACKGROUND: OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS: Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS: OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.
Blood Pressure↗
Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy.
PURPOSE: To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). METHODS AND MATERIALS: Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). RESULTS: When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. CONCLUSIONS: These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.
Adult↗
Strategies for pharmacologic modulation of the heart failure phenotype.
The end-stage heart failure phenotype is characterized by marked dyspnea on exertion, edema, and overwhelming fatigue, and by a high incidence of sudden death. Patients who display the end-stage phenotype have transitioned from a normal phenotype with myocardial damage at a cellular level. This transition appears to be mediated by events at both the cellular and molecular levels. Until recently, it was generally believed that this transition was irreversible. However, recent clinical trials have demonstrated that the phenotype can be changed with pharmacologic agents. These agents have been demonstrated to improve exercise capability, increase ventricular function, and improve symptoms. Important recent studies have shown that pharmacologic agents can substantially alter the high mortality rates associated with the end-stage heart failure phenotype. As we learn more about the molecular and cellular events that initiate and support the transition from cardiac compensation to decompensation, we will be able to improve our pharmacologic targeting and, we hope, be able to delay the development of the end-stage heart failure phenotype to an even greater degree.
Adrenergic beta-Antagonists↗
Decreased adenylate cyclase activity and expression of Gs alpha in human myocardium after orthotopic cardiac transplantation.
We studied several aspects of guanine nucleotide-stimulated adenylate cyclase function in patients after orthotopic cardiac transplantation. In 28 patients, adenylate cyclase activity was measured in endomyocardial biopsy samples obtained just before and at monthly intervals after cardiac transplantation. In biopsies obtained > or = 6 months after transplantation, basal adenylate cyclase activity was decreased by 67% (n = 12; P < .05), GTP gamma S-stimulated adenylate cyclase activity was decreased by 78% (n = 12; P < .05), Mn+2+forskolin-stimulated adenylate cyclase activity was decreased by 80% (n = 8; P < .05), and Mn+2-stimulated adenylate cyclase activity (a measure of activity of the catalytic subunit of adenylate cyclase) was decreased by 83% (n = 8, P < .05). Western blot analysis demonstrated that 6 months after cardiac transplantation, the level of Gs alpha protein was decreased by 61 +/- 12% (n = 8; P < .001). There was no change in the level of Gi alpha as assessed by pertussis toxin-catalyzed ADP-ribosylation (n = 4; P = NS). With the use of the quantitative polymerase chain reaction, a 50 +/- 10% (n = 6; P < .001) reduction in the steady-state level of Gs alpha mRNA was observed. There was no change in the level of mRNA for Gi-3 alpha. Thus, after orthotopic cardiac transplantation in humans, guanine nucleotide-stimulated adenylate cyclase activity is decreased in parallel with decreased levels of Gs alpha protein and mRNA.
Adenylyl Cyclases↗
Malignant melanoma and other second cutaneous malignancies in cutaneous T-cell lymphoma. The influence of additional therapy after total skin electron beam radiation.
BACKGROUND: Previous large studies have shown that patients with cutaneous T-cell lymphoma are at increased risk for basal cell carcinoma and squamous cell carcinoma, and anecdotal case reports have suggested an association with malignant melanoma. It has been postulated that the exposure of cutaneous structures to potentially carcinogenic therapies, such as ionizing radiation or alkylating agents, might be causally associated with the development of these second cutaneous malignancies, but, to date, no study has directly addressed this issue. The purpose of this study was to evaluate the occurrence of second cutaneous malignancies in a group of patients with cutaneous T-cell lymphoma treated with total skin electron beam therapy and to examine the additional effects of oral psoralen with UV-A phototherapy, topical mechlorethamine hydrochloride therapy, and further radiation therapy. One hundred sixty-four patients with cutaneous T-cell lymphoma who had received total skin electron beam therapy between 1974 and 1990 were identified, and information was abstracted from their records. RESULTS: Six patients developed malignant melanoma 12 to 95 months after total skin electron beam therapy. Of the six patients, three had received oral psoralen with UV-A as additional therapy and two had received topical mechlorethamine. None had received additional radiation therapy. Twenty-four patients developed more than 37 basal cell carcinomas and 34 squamous cell carcinomas from 11 months to more than 10 years after total skin electron beam therapy. Of the 24 patients, 15 had received oral psoralen with UV-A and 12 had received mechlorethamine as additional therapy. Additional radiation therapy had been administered to nine patients. During a median follow-up of 6 years, no patients died of any second cutaneous malignancy. CONCLUSION: We found a high rate of both melanoma and nonmelanoma skin cancer. The additional use of mechlorethamine or oral psoralen plus UV-A, but not radiation, was significantly associated with the development of basal cell carcinoma and squamous cell carcinoma, but not malignant melanoma.
Adult↗
Impact of non-CTCL dermatologic diagnoses and adjuvant therapies on cutaneous T-cell lymphoma patients treated with total skin electron beam radiation therapy.
PURPOSE: To evaluate the impact of pre-cutaneous T-cell lymphoma dermatologic diagnoses and adjuvant therapies on the relapse-free and overall survivals of patients treated with total skin electron beam therapy. METHODS AND MATERIALS: Between 1974 and 1990, 164 patients were evaluated by members of Yale University School of Medicine departments of Dermatology and Therapeutic Radiology and treated with total skin electron beam therapy to a total dose of 3600 cGy. Patients who achieved a clinical complete response were offered doxorubicin/cyclophosphamide chemotherapy, extracorporeal photopheresis, or no systemic adjuvant therapy. The effects of TNM stage, antecedent non-T-cell lymphoma dermatologic diagnoses, and systemic adjuvant therapies were analyzed for their impact on relapse-free and overall survival. RESULTS: In this cohort of patients, an antecedent dermatologic diagnosis of follicular mucinosis or lymphomatoid papulosis was significantly associated with a shorter relapse-free survival for T1 and T2 patients, while antecedent "non-specific" dermatitides were associated with a somewhat better relapse-free survival. When the impact of systemic adjuvant therapies was analyzed, neither systemic doxorubicin/cyclophosphamide chemotherapy nor systemic extracorporeal photopheresis were found to delay cutaneous relapse. CONCLUSION: Our results suggest that antecedent follicular mucinosis and lymphomatoid papulosis may be associated with short relapse-free survival in T1 and T2 patients treated with total skin electron beam therapy. They also imply that neither adjuvant chemotherapy nor extracorporeal photopheresis delay cutaneous relapse after total skin electron beam therapy.
Adult↗
New therapeutic agents for the management of congestive heart failure.
During the past year, several important studies have strongly supported the use of what we now view as the three-pronged, "standard" approach to the treatment of symptomatic heart failure: diuretics, digoxin, and angiotensin-converting enzyme inhibitors. New information regarding the latter two agents is reviewed elsewhere in this issue of Current Opinion in Cardiology. However, despite obvious advances in our management of this important clinical syndrome and the substantial body of evidence supporting the beneficial effects of the angiotensin-converting enzyme inhibitors, the prognosis for patients with symptomatic congestive heart failure remains abysmal. For this reason, new and novel agents for the pharmacologic treatment of patients with heart failure continue to be developed and clinically evaluated. This article reviews the results of recent clinical trials with some of these new investigational pharmacologic agents. To facilitate categorization of these new agents, they will be grouped according to their primary pharmacologic action. However, it should be noted that those pharmacologic actions may not necessarily be responsible for either the beneficial or deleterious effects associated with these agents.
Calcium Channel Blockers↗
Quinolinone derivatives in the management of congestive heart failure.
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Animals↗