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Biomedical subjects

Richard Pacher

Publications and source records attributed to Richard Pacher.

At least 37 records · Page 2Linked to original sources
PubMed2004

Long-term transcutaneous neuromuscular electrical stimulation in patients with bipolar sensing implantable cardioverter defibrillators: a pilot safety study.

Neuromuscular electrical stimulation (NMES) is an option for increasing thigh muscle strength and endurance capacity in patients with chronic heart failure. Electromagnetic interference (EMI) by the signals with sensing of implantable cardioverter defibrillators (ICDs) is possible. The aim of the present pilot safety study was to test the safety of a long-term NMES in patients with ICDs. Six patients with subpectoral ICDs were subjected to long-term NMES of thigh muscles. Four inpatients received NMES to increase muscle strength, and two outpatients performed NMES as a home treatment to increase endurance capacity. During long-term NMES, all patients together received 14 139 799 biphasic electrical pulses and 412 425 on-phases without adverse events. ICD function after the stimulation period revealed no abnormalities in any patient. These results indicate that long-term NMES of thigh muscles seems to be safe in patients with ICDs, providing that an individual risk is excluded before.

Aged↗
PubMed2004

Effect of high-volume and -intensity endurance training in heart transplant recipients.

BACKGROUND: A recommended component of heart transplant recipients (HTR) is endurance-oriented exercise therapy. However, the trainability of HTR after transplantation is vague. We examined the effect of high-volume and -intensity exercise training on exercise performance in HTR, compared with HTR undergoing regular rehabilitation training, and sedentary healthy subjects (SHS). METHODS: We studied four groups of individuals; of those, three groups were HTR. Subjects were a regularly trained HTR group of denervated (HTR-D; N = 15), reinnervated (HTR-R; N = 26) hearts, a high-volume and -intensity endurance-training group (training time 7-20 h.wk(-1); HTR-ET; N = 12), and a group of sedentary healthy subjects (SHS; N = 21). All participants performed cardiopulmonary exercise testing. RESULTS: The HTR-ET achieved a significantly higher performance (255 +/- 47 W, VO(2max) of 45.2 +/- 6.9 mL.kg(-1).min(-1)) in contrast to all other groups (HTR-D: 119 +/- 17 W, VO(2max) of 17.4 +/- 4.5 mL.kg(-1).min(-1); HTR-R: 119 +/- 17 W, VO(2max) of 16.9 +/- 3.7 mL.kg(-1).min(-1); SHS: 184 +/- 19 W, VO(2max) of 35.0 +/- 6.9 mL.kg(-1).min(-1)). The HR at maximal power output in the HTR-ET was 169 +/- 17 bpm and similar to SHS (164 +/- 17 bpm), but significantly higher than HTR-D (125 +/- 16) and HTR-R (142 +/- 10). Maximal lactate concentration (LAmax) of HTR-ET was 9.9 +/- 2.2 mmol.L(-1), comparable to SHS (9.2 +/- 2.1 mmol.L(-1)), and significantly higher than HTR-D (5.5 +/- 1.5 mmol.L(-1)) and HTR-R (5.1 +/- 1.0 mmol.L(-1)). CONCLUSIONS: Data suggest that HTR can perform high-volume and -intensity exercise training, reaching exercise performance comparable to or even exceeding values of sedentary or moderately trained healthy subjects.

Adult↗
PubMed2004

Oncostatin-M in myocardial ischemia/reperfusion injury may regulate tissue repair.

AIM: Oncostatin-M, a member of the gp 130 family of cytokines, has been associated with inflammation, connective tissue production, and extracellular matrix turnover. Since the reperfused heart is associated with an intense inflammatory reaction followed by scar formation, we tested the hypothesis that oncostatin-M is upregulated in response to cardiac injury and may play a part in cardiac repair. METHODS: Using a canine model of myocardial ischemia/reperfusion injury, we examined the expression of oncostatin-M at various time points of reperfusion, ranging from 1 h to 7 days. In situ hybridization was used to determine oncostatin-M mRNA expression. Immunohistochemistry was performed to detect oncostatin-M protein. Stimulatory effects of oncostatin-M on isolated endothelial cells and fibroblasts were investigated. RESULTS: Oncostatin-M mRNA expression was detected in ischemic segments within the first 3 h of reperfusion and was persistent over the whole observation period. At the early time points, infiltrating and endothelial cells were the primary source of oncostatin-M mRNA expression. At later time points, macrophages and myofibroblasts were the main contributors. We previously demonstrated in vivo that monocyte-chemoattractant-protein (MCP-1) mRNA is induced early after reperfusion. We stimulated isolated endothelial cells with oncostatin-M and postischemic lymph, which have both upregulated MCP-1 expression in endothelial cells. In addition, isolated fibroblasts stimulated with oncostatin-M demonstrated a dose-dependent proliferative response. CONCLUSION: Oncostatin-M may contribute to the process of healing after myocardial infarction.

Animals↗
PubMed2003

Safety of a combined strength and endurance training using neuromuscular electrical stimulation of thigh muscles in patients with heart failure and bipolar sensing cardiac pacemakers.

Neuromuscular electrical stimulation (NMES) is an effective and non-strenuous therapy to enhance the strength and endurance capacity of the skeletal muscles in patients with severe chronic heart failure. NMES in patients with pacemakers is controversial because potential electromagnetic interference may result in pacemaker malfunction. Therefore, such patients are in general excluded from NMES. The aim of this pilot study was to evaluate the safety of a combined NMES protocol to increase strength and endurance capacity of the skeletal muscles in patients with heart failure and implanted pacemakers. Seven patients with chronic heart failure and implanted cardiac pacemakers with bipolar sensing leads received NMES treatment of thigh muscles, using a combined protocol comprising biphasic, symmetric, rectangular constant current impulses at different frequencies (8-50 Hz), pulse width up to 60 s (8 Hz), 4 s (15 Hz), 4 s (30 Hz), and 6 s (50 Hz), and amplitudes up to +/- 100 mA (all frequencies) applied to both knee extensor and flexor muscles via surface electrodes (8 x 13 cm each). Acute electromagnetic interference during a safety procedure (telemetric monitoring) before therapeutic NMES application was not observed in any of the patients. The 7 patients received during 20 therapeutic NMES sessions a total of 23,380 on-phases, comprising 2194.08 x 10(3) biphasic electrical pulses, without adverse events. Heart rate monitoring during stimulation and pacemaker interrogation revealed no abnormalities. NMES treatment of thigh muscles using a combined NMES protocol to enhance strength and endurance capacity appears to be safe in patients with heart failure and implanted pacemakers with bipolar sensing, as far as the described electrode configuration and parameter range is applied.

Adult↗
PubMed2003

Glycoprotein 130 ligand oncostatin-M induces expression of vascular endothelial growth factor in human adult cardiac myocytes.

OBJECTIVE: In murine and rat cardiac myocytes the gp130 system transduces survival as well as hypertrophic signals and via induction of the expression of the potent angiogenic factor VEGF in these cells also indirectly contributes to cardiac repair processes through the development of new blood vessels. There are, however, species differences in receptor specificity and receptor crossreactivity in the gp130-gp130 ligand system. We asked whether gp130 signaling is also involved in the regulation of VEGF in human cardiac myocytes and if so which gp130 ligands are critical for such an effect. METHODS: Human adult cardiac myocytes (HACMs) were isolated from myocardial tissue and characterised by positive staining for myocardial actin, troponin-I and cardiotin. HACMs were treated with the gp130 ligands CT-1, IL-6, LIF or OSM and VEGF-1 was determined by a specific ELISA in the conditioned media of these cells. RT-PCR and Western blot analysis was used in order to detect gp130, IL-6-receptor, LIF-receptor or OSM-receptor specific protein and mRNA in human adult cardiac myocytes and for detection of VEGF-1 specific mRNA in cardiac myocytes after incubation with OSM. Pieces of myocardial tissue were incubated ex vivo in the presence and absence of OSM and VEGF was determined in supernatants of these cultures and immunohistochemistry was performed on the tissue using specific antibodies for VEGF-1. Immunohistochemistry was also employed to detect VEGF in sections from a healthy human heart and in a heart from a patient suffering from acute myocarditis. RESULTS: OSM, but not CT-1, IL-6 or LIF increased VEGF-1 production in human adult cardiac myocytes dose-dependently derived from five different donors. This selective stimulation of VEGF by gp130 ligands was also reflected by a specific receptor expression on these cells. We detected high levels of mRNA for gp130 and the OSM receptor in freshly isolated human cardiac myocytes but only low amounts of mRNA for the IL-6 receptor whereas mRNA for the LIF receptor was hardly detectable by RT-PCR. OSM receptor and IL-6 receptor were also detectable by Western blotting whereas LIF receptor was only present as a faint band. OSM also increased the expression of VEGF-1 mRNA in cardiac myocytes. When pieces of human myocardial tissue were incubated with the gp130 ligands in an ex vivo model only OSM resulted in an increase in VEGF-1 in the supernatants of these cultures. Furthermore, VEGF increased in tissue samples treated with OSM in cardiac myocytes as evidenced by immunohistochemistry. In addition, we found increased VEGF-1 expression in myocardial tissue from a patient suffering from acute myocarditis. CONCLUSION: The gp130-gp130 ligand system is also involved in VEGF regulation in human cardiac myocytes and OSM is the gp130 ligand responsible for this effect in the human system whereas LIF and CT-1 which had been shown to regulate VEGF expression in mouse and rat cardiac myocytes had no effect. Thus we have added OSM, which is produced by activated T lymphocytes and monocytes, to the list of regulatory molecules of VEGF production in the human heart. Our results lend further support to the notion that besides hypoxia, inflammation via induction of VEGF through autocrine or paracrine pathways plays a key role in (re)vascularisation of the myocardium.

Adult↗
PubMed2003

Prognostic power of neurohumoral parameters in chronic heart failure depends on clinical stage and observation period.

BACKGROUND: Endothelin (ET) and natriuretic peptides have prognostic significance in chronic heart failure (CHF). Because stimuli for forming these neurohormones differ, this study investigates whether their prognostic power depends on clinical stage and on length of the observation period. METHODS: Plasma big ET, B-type natriuretic peptide (BNP), N-terminal BNP (N-BNP), and N-terminal atrial natriuretic peptide (N-ANP), in addition to 11 clinical and hemodynamic variables, were obtained from 452 patients with left ventricular ejection fraction (LVEF) </=35%. According to their New York Heart Association class and LVEF, patients were stratified into Group A, mild CHF (n = 114); Group B, moderate CHF (n = 210); and Group C, severe CHF (n = 128). To predict the combined end-point of death or urgent heart transplantation, a multivariate analysis was performed after an observation period of up to 1, 2, and 3 years in all patients and in each sub-group. RESULTS: Best independents predictors were as follows: All patients: up to 1 year, big ET (p < 0.0001, chi-square = 59); and 2 and 3 years, log N-ANP (p < 0.0001, chi-square = 68; p < 0.0001, chi-square = 89). Group A: up to 2 and 3 years, log N-ANP (p < 0.001, chi-square = 12; p < 0.0001, chi-square = 25). Group B: up to 1 and 3 years, log N-ANP (p < 0.0001, chi-square = 16; p < 0.0001, chi-square = 22); and 2 years, log N-BNP (p < 0.0001, chi-square = 19). Group C: up to 1, 2, and 3 years, big ET (p < 0.0001, chi-square = 23; p < 0.0001, chi-square = 22; p < 0.0001, chi-square = 20). CONCLUSION: Big ET was the best independent marker for 1-year prognosis in severe CHF, whereas natriuretic peptides (especially N-ANP) were better markers for 2- and 3-year prognoses in mild and moderate CHF.

Biomarkers↗
PubMed2003

Sequential big endothelin plasma levels in heart transplant recipients during bridging therapy and after successful heart transplantation.

BACKGROUND: The purpose of this study was to investigate the impact of successful heart transplantation in patients with refractory heart failure receiving bridging therapy on sequential plasma levels of big endothelin, norepinephrine, atrial natriuretic peptide and aldosterone. METHODS: Fourteen patients (2 women, 12 men) accepted for heart transplantation were studied. All had severe chronic heart failure refractory to optimized oral therapy with angiotensin-converting enzyme inhibitors and furosemide, were in New York Heart Association functional Class IV, and had a left ventricular ejection fraction of <15%, Right heart catheterization was performed in all patients (cardiac index 1.9 +/- 0.1 liters/min. m(2), pulmonary capillary wedge pressure 30 +/- 2 mmHg, systemic vascular resistance index 2,827 +/- 253 dyn. s/cm(5). m(2)). As bridging therapy, patients received either prostaglandin E(1), prostaglandin E(1) and dobutamine or dobutamine alone as a continuous infusion. Neurohumoral variables were measured prior to bridging therapy and 3.5 months before and 7 and 10 months after successful heart transplantation. RESULTS: Big endothelin, norepinephrine and atrial natriuretic peptide plasma levels decreased from 7.4 +/- 2.9 fmol/ml, 1112 +/- 686 pg/ml and 366 +/- 312 pg/ml to 6.0 +/- 4.5 fmol/ml, 720 +/- 503 pg/ml and 198 +/- 160 pg/ml, respectively, after bridging therapy, and further to 2.1 +/- 0.9 fmol/ml (p < 0.00001 vs baseline), 527 +/- 31 pg/ml (p < 0.02 vs baseline) and 115 +/- 70 pg/ml (p < 0.03 vs baseline), respectively, after cardiac transplantation. Aldosterone plasma levels decreased from 242 +/- 220 pg/ml to 183 +/- 142 pg/ml during bridging therapy and increased after heart transplantation to 252 +/- 189 pg/ml. Plasma creatinine levels increased from 1.2 +/- 0.4 mg/dl at baseline to 1.4 +/- 0.2 mg/dl after transplantation (NS). CONCLUSIONS: The study suggests that excessive overproduction of big endothelin, atrial natriuretic peptide and norepinephrine is predominantly related to pump failure and, after cardiac transplantation, a moderate spillover of big endothelin persists. Its specific origin, however, remains to be elucidated. Furthermore, our data suggest a protective effect of prostaglandin E(1) on kidney function after heart transplantation.

Aged↗
PubMed2003

Pathogenesis of bone loss in heart transplant candidates and recipients.

BACKGROUND: Heart transplantation (HTX) is associated with decreased bone mineral density and changes in bone metabolism. We conducted this study to evaluate the pathophysiology of bone metabolism in HTX candidates and recipients. METHODS: Thirty-six HTX recipients were compared with 36 HTX candidates concerning biochemical parameters of bone metabolism and bone mineral density. RESULTS: Osteocalcin, bone-specific alkaline phosphatase, cross-linked-N-telopeptide of type I collagen, estradiol, serum creatinine, and blood urea nitrogen concentrations were significantly higher, whereas the calcium-creatinine ratio, thyrotropin, thyroxine, and bone mineral density were significantly lower in HTX recipients than in HTX candidates. Compared with a control group, HTX candidates had decreased renal function and increased bone resorption, whereas HTX recipients additionally had increased alkaline phosphatase and osteocalcin levels. In HTX recipients, we found positive correlations between creatinine clearance and bone mineral density; daily and cumulative cortisone doses were not associated with bone mineral density. CONCLUSIONS: In HTX candidates, disturbances in bone metabolism with increased bone resorption may be caused partly by existing low-grade renal insufficiency, regular intake of loop diuretics, and restriction of mobility. In HTX recipients, immunosuppressive therapy-glucocorticoids and cyclosporine-seem to be responsible for changes in bone metabolism.

Adult↗
PubMed2003

Revascularization of myocardial scar tissue following prostaglandin E1-therapy in patients with ischemic heart disease.

Prostaglandin E1 (PGE-1) treatment has proved to stimulate angiogenesis in vital non-infarcted myocardium of patients with ischemic cardiomyopathy (ICMP). We investigated infarcted myocardial tissue for a possible angiogenic response to PGE-1. Neovascularization was investigated in infarcted areas of 12 hearts explanted from patients with ICMP who had been treated with PGE-1 before heart transplantation (HTX). In transmural sections containing myocardial scar tissue, CD34 and VEGF were immunohistochemically quantified to estimate capillary density and the extent of angiogenesis. To investigate a possible effect of PGE-1 on collagen turnover, the collagen content was determined in myocardial scar tissue by assessing the intensity of the area positively stained with sirius red. PGE-1-treated patients had significantly more CD34- and VEGF-positive cells in infarcted areas, and showed a significant reduction in collagen content as compared with the non-PGE-1 group (CD34: 120.3 +/- 6.1 vs. 47.7 +/- 6.1 capillary profiles/mm2; VEGF: 52.8 +/- 5.6 vs. 24.0 +/- 4.8 capillary profiles/mm2, and collagen content: 2.18 +/- 0.4 eU vs. 3.59 +/- 0.38 eU). Our data demonstrate that PGE-1 stimulates angiogenesis by upregulating VEGF expression, and reduces fibrosis in cardiac scar tissue of ischemic origin. The induction of therapeutic angiogenesis in vital and at sites of putative dead myocardial scar tissue, along with the hemodynamic improvement in patients with severe ICMP, might explain the favorable clinical outcome in PGE-1-treated patients before HTX.

Alprostadil↗
PubMed2002

Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT).

BACKGROUND: The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ET(A) antagonist darusentan in addition to modern standard therapy in patients with CHF. METHODS AND RESULTS: A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure > or =12 mm Hg, and a cardiac index < or =2.6 L x min(-1) x m(-2) were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages. CONCLUSIONS: This study demonstrates for the first time in a large patient population that 3 weeks of selective ET(A) receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ET(A) blockade is beneficial in CHF.

Blood Pressure↗
PubMed2002

B-type natriuretic peptide predicts sudden death in patients with chronic heart failure.

BACKGROUND: Given the high incidence of sudden death in patients with chronic heart failure (CHF) and the efficacy of implantable cardioverter-defibrillators, an appropriate tool for the prediction of sudden death is desirable. B-type natriuretic peptide (BNP) has prognostic significance in CHF, and the stimuli for its production cause electrophysiological abnormalities. This study tests BNP levels as a predictor of sudden death. METHODS AND RESULTS: BNP levels, in addition to other neurohormonal, clinical, and hemodynamic variables, were obtained from 452 patients with a left ventricular ejection fraction (LVEF) < or =35%. For prediction of sudden death, only survivors without heart transplantation (HTx) or a mechanical assist device and patients who died suddenly were analyzed. Up to 3 years, 293 patients survived without HTx or a mechanical assist device, 89 patients died, and 65 patients underwent HTx. Mode of death was sudden in 44 patients (49%), whereas 31 patients (35%) had pump failure and 14 patients (16%) died from other causes. Univariate risk factors of sudden death were log BNP (P=0.0006), log N-terminal atrial natriuretic peptide (P=0.003), LVEF (P=0.005), log N-terminal BNP (P=0.006), systolic blood pressure (P=0.01), big endothelin (P=0.03), and NYHA class (P=0.04). In the multivariate model, log BNP level was the only independent predictor of sudden death (P=0.0006). Using a cutoff point of log BNP <2.11 (130 pg/mL), Kaplan-Meier sudden death-free survival rates were significantly higher in patients below (99%) compared with patients above (81%) this cutoff point (P=0.0001). CONCLUSION: BNP levels are a strong, independent predictor of sudden death in patients with CHF.

Adrenergic beta-Antagonists↗
PubMed2002

Hypertrophic osteoarthropathy caused by PGE1 in a patient with congestive heart failure during cardiac rehabilitation.

Continuous chronic drug infusion with PGE1 via a portable pump and neuromuscular electrical stimulation (NMES) help to improve the quality of life in patients with severe chronic heart failure waiting for a donor heart, as both treatments can be performed at home. We report a 56-year-old woman suffering from severe chronic heart failure, who was referred for a cardiac rehabilitation program because of progressive muscle weakness and weight loss. Due to her underlying heart disease she was unable to perform voluntary exercise. NMES of both knee extensor muscles was started. Under simultaneous chronic drug infusion with PGE1 via a portable pump the patient developed clinical signs of hypertrophic osteoarthropathy, which prevented her from continuing the rehabilitation program. X-ray examinations and bone scans concurred with the diagnosis of secondary hypertrophic osteoarthropathy. After the PGE1 dose had been reduced, the clinical signs of the osteoarthropathy resolved and the patient was able to continue the rehabilitation program with no difficulty. This case report underlines the importance of being aware of the potential side effects of modern cardiac drugs in the complex treatment of patients waiting for a donor heart.

Alprostadil↗
PubMed2002

Plasminogen activator inhibitor 1 expression is regulated by the inflammatory mediators interleukin-1alpha, tumor necrosis factor-alpha, transforming growth factor-beta and oncostatin M in human cardiac myocytes.

Accumulating evidence points towards a role for proteases and protease inhibitors in tissue remodelling and repair in a variety of organs. In particular-besides the matrix metalloprotease system-the plasminogen activator (PA)/plasmin system has been implicated in these processes in the heart. Urokinase type PA (u-PA) and PA inhibitor type 1 (PAI-1) seem to modulate cardiac rupture and infarct healing. In this study we aimed to investigate whether inflammatory mediators can regulate the expression of components of the PA/plasmin system in human adult cardiac myocytes (HACM). We could demonstrate that HACM, isolated from pieces of myocardial tissue by mechanical dispersion and characterized by positive immunostaining for the cardiac markers troponin I, tropomyosin, cardiotin and myocardial muscle-actin, in vitro express PAI-1 and tissue type PA (t-PA) whereas u-PA was not detectable in these cells. PAI-1 protein production was increased up to twofold by interleukin-1alpha (IL-1alpha) and tumor necrosis factor-alpha (TNF-alpha) and up to fivefold by transforming growth factor-beta (TGF-beta) and oncostatin M (OSM). Similar changes were observed in PAI-1 transcript levels after cytokine treatment. t-PA production in HACM was not affected by these agonists. No effect of these cytokines on PAI-1 production in fibroblasts isolated from human myocardial tissue was seen. In an ex vivo model we could show that incubation of pieces of human myocardial tissue with these cytokines also resulted in an increase in PAI-1 in cardiac myocytes as evidenced by immuno-histochemistry. Furthermore we found increased PAI-1 expression in myocardial tissue from a patient suffering from acute myocarditis. Thus for the first time we provide evidence that inflammatory mediators modulate PAI-1 expression in human adult cardiac myocytes in vitro and ex vivo and could demonstrate that PAI-1 expression is increased in the in vivo setting under inflammatory conditions. If the effect on PAI-1 expression brought about by IL-1alpha, TNF-alpha, TGF-beta and OSM is not only operative under in vitro and ex vivo conditions but also in the in vivo setting one could speculate that these cytokines contribute to upregulation of PAI-1 in myocardial tissue and that PAI-1, when upregulated in myocardial tissue during inflammatory processes, could serve as a defence mechanism against excessive matrix degradation by proteases. Thus we propose a role for PAI-1 produced in the heart by cardiac myocytes in cardiac remodelling and repair processes.

Cells, Cultured↗
PubMed2002

Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease.

OBJECTIVE: Prostaglandin E1 (PGE-1) is a potent vasodilative agent which has been used to bridge patients with chronic heart failure listed for heart transplantation (HTX). In various experimental settings PGE-1 appears to stimulate angiogenesis by inducing vascular endothelial growth factor expression. This observational clinical study sought to investigate the angiogenic effects of PGE-1 in the failing human heart. METHODS: Neovascularization was investigated in 14 explanted hearts from patients with ischemic cardiomyopathy (ICMP) who had been bridged to HTX with PGE-1 (8+/-1 mg/kg/min, 97+/-75.6 days) and compared with 14 hearts who did not receive PGE-1 prior to HTX. In three sectional areas obtained from the left ventricular wall CD34, von Willebrand factor (vWf), nuclear Ki67 (MIB-1), and VEGF were quantified by immunohistochemistry to estimate capillary density and endothelial cell proliferation. Additionally, to investigate a possible angiogenic effect of PGE-1 in vitro, cultured human coronary artery smooth muscle cells (HCASMCs) were treated with PGE-1. RESULTS: PGE-1-treated patients had significantly more CD34- and vWf-positive cells in the subepicardium (both P<0.01), myocardium (both P<0.0001) and subendocardium (P<0.01 and P<0.001) as compared to the nonPGE-1 group. Proliferative endothelial activity expressed by the presence of MIB-1- and VEGF-positive cells (both P<0.0001 in all layers) was increased more than twofold. Addition of PGE-1 to HCASMCs in cell culture resulted in a significant increase in VEGF production (164.0+/-19.7 pg/10(5) cells/24 h, P<0.005) as compared to the control cell line (66.6+/-8.7 pg/10(5) cells/24 h, P<0.005). CONCLUSIONS: Our data demonstrate that PGE-1 is a potent stimulator of angiogenesis via upregulation of VEGF expression. The induction of therapeutic angiogenesis in patients with severe ICMP might explain the favorable clinical outcome in PGE-1 treated patients until HTX.

Adult↗
PubMed2002

Intimal hyperplasia and coronary flow reserve after heart transplantation: association with big endothelin-1.

BACKGROUND: Endothelin, a peptide with strong vasoconstrictive and mitogenic properties, has been found to increase after cardiac transplantation. We therefore assessed the association between its precursor peptide, big endothelin-1, and intimal hyperplasia and coronary flow reserve after heart transplantation. METHODS: Thirty-five patients without hemodynamically significant coronary artery disease after heart transplantation were investigated: Average peak flow velocity in the left anterior descending artery (LAD) was assessed by intracoronary Doppler at baseline as well as after injection of adenosine; coronary flow reserve was calculated as a ratio of both and was corrected for patient age and baseline average peak flow velocity. Lumen, intima + media and total vessel area were measured by intracoronary ultrasound. The plasma concentration of big endothelin-1 in venous blood was determined by radioimmunoassay. RESULTS: Patients with elevated big endothelin-1 levels (>2 fmol/ml) tended to have a decreased corrected coronary flow reserve (2.60 +/- 0.9 vs 3.21 +/- 1.0, p = 0.078). They also had a significantly larger intima + media area (5.82 +/- 2.9 vs 2.37 +/- 2.9 mm(2), p = 0.004) and total vessel area (18.36 +/- 5.8 vs 12.81 +/- 4.8 mm(2), p = 0.012) than those with normal plasma concentrations. CONCLUSIONS: Our study suggests an association between elevated big endothelin-1 plasma levels and the development of intimal hyperplasia and reduction of coronary flow reserve after cardiac transplantation.

Adult↗
PubMed2002

Prognostic impact of workload in patients with congestive heart failure.

AIMS: Recent data underline the prognostic value of cardiopulmonary exercise parameters (eg, peak oxygen consumption [PVO2]), percentage of predicted oxygen consumption [ppVO2], ventilation, and workload) in patients with congestive heart failure. These parameters were not yet compared in a multivariate analysis. METHODS AND RESULTS: To detect the superiority of one of these parameters, in a prospective 1-year follow-up study we investigated 226 patients with heart failure. The end point of the study was combined death and prioritization for urgent cardiac transplantation within 1 year. Cardiopulmonary exercise testing was performed with evaluation of peak oxygen consumption, percentage of predicted peak oxygen consumption, peak carbon dioxide production, ventilation, workload, anaerobic threshold, and ventilation/carbon dioxide production ratio. All variables were univariate predictors of 1-year mortality and urgent transplantation. Multivariate analysis demonstrated that only workload and ventilation were independently related to 1-year mortality and urgent cardiac transplantation, whereas peak oxygen consumption or percentage of predicted peak oxygen consumption did not reach statistical significance in this model. CONCLUSION: Workload on bicycle stress test correlates to 1-year mortality. More important, workload is a more powerful predictor of 1-year survival compared with established markers such as pVO2 or ppVO2.

Anaerobic Threshold↗
PubMed2002

Endothelin receptor antagonists in cardiology clinical trials.

Endothelin-1 (ET-1) is enhanced and has been demonstrated to be a prognostic marker in patients with advanced stages of heart failure, acute ischaemic syndromes, myocardial infarction and pulmonary hypertension. Activation of the endothelin (ET) system is associated with adverse haemodynamic consequences in patients with congestive heart failure and results in coronary vasoconstriction in patients with coronary artery disease (CAD). Moreover, ET-1 raises blood pressure, induces vascular and myocardial hypertrophy and acts as the natural counterpart of nitric oxide (NO), which exerts vasodilating, antithrombotic and antiproliferative effects. This article reviews recently completed and ongoing clinical trials examining the effects of ET receptor antagonists in patients with heart failure, CAD, arterial hypertension and pulmonary hypertension.

Cardiovascular Diseases↗