Socially disadvantaged city districts show a higher incidence of acute ST-elevation myocardial infarctions with elevated cardiovascular risk factors and worse prognosis.

BACKGROUND: The importance of socioeconomic status (SES) for coronary heart disease (CHD)-morbidity is subject of ongoing scientific investigations. This study was to explore the association between SES in different city-districts of Bremen/Germany and incidence, severity, treatment modalities and prognosis for patients with ST-elevation myocardial infarctions (STEMI). METHODS: Since 2006 all STEMI-patients from the metropolitan area of Bremen are documented in the Bremen STEMI-registry. Utilizing postal codes of their home address they were assigned to four groups in accordance to the Bremen social deprivation-index (G1: high, G2: intermediate high, G3: intermediate low, G4: low socioeconomic status). RESULTS: Three thousand four hundred sixty-two consecutive patients with STEMI admitted between 2006 and 2015 entered analysis. City areas with low SES showed higher adjusted STEMI-incidence-rates (IR-ratio 1.56, G4 vs. G1). This elevation could be observed in both sexes (women IRR 1.63, men IRR 1.54) and was most prominent in inhabitants <50 yrs. of age (women IRR 2.18, men IRR 2.17). Smoking (OR 1.7, 95%CI 1.3-2.4) and obesity (1.6, 95%CI 1.1-2.2) was more prevalent in pts. from low SES city-areas. While treatment-modalities did not differ, low SES was associated with more extensive STEMIs (creatine kinase > 3000 U/l, OR 1.95, 95% CI 1.4-2.8) and severe impairment of LV-function post-STEMI (OR 2.0, 95% CI 1.2-3.4). Long term follow-up revealed that lower SES was associated with higher major adverse cardiac or cerebrovascular event (MACCE)-rates after 5 years: G1 30.8%, G2 35.7%, G3 36.0%, G4 41.1%, p (for trend) = 0.02. This worse prognosis could especially be shown for young STEMI-patients (<50 yrs. of age) 5-yr. mortality-rates(G4 vs. G1) 18.4 vs. 3.1%, p = 0.03 and 5-year-MACCE-rates (G4 vs. G1) 32 vs. 6.3%, p = 0.02. CONCLUSIONS: This registry-data confirms the negative association of low socioeconomic status and STEMI-incidence, with higher rates of smoking and obesity, more extensive infarctions and worse prognosis for the socio-economically deprived.

Smoking ban in public areas is associated with a reduced incidence of hospital admissions due to ST-elevation myocardial infarctions in non-smokers. Results from the Bremen STEMI Registry.

INTRODUCTION: Laws banning tobacco smoking from public areas have been passed in several countries, including the region of Bremen, Germany at the end of 2007. The present study analyses the incidence of hospital admissions due to ST-elevation myocardial infarctions (STEMIs) before and after such a smoking ban was implemented, focusing on differences between smokers and non-smokers. In this respect, data of the Bremen STEMI Registry (BSR) give a complete epidemiological overview of a region in northwest Germany with approximately 800,000 inhabitants since all STEMIs are admitted to one central heart centre. METHODS AND RESULTS: Between January 2006 and December 2010, data from the BSR was analysed focusing on date of admission, age, gender, and prior nicotine consumption. A total of 3545 patients with STEMI were admitted in the Bremen Heart Centre during this time period. Comparing 2006-2007 vs. 2008-2010, hence before and after the smoking ban, a 16% decrease of the number of STEMIs was observed: from a mean of 65 STEMI/month in 2006-2007 to 55/month in 2008-2010 (p < 0.01). The group of smokers showed a constant number of STEMIs: 25/month in 2006-2007 to 26/month in 2008-2010 (+4%, p = 0.8). However, in non-smokers, a significant reduction of STEMIs over time was found: 39/month in 2006-2007 to 29/month in 2008-2010 (-26%, p < 0.01). The decline of STEMIs in non-smokers was consistently observed in all age groups and both sexes. Adjusting for potentially confounding factors like hypertension, obesity, and diabetes mellitus did not explain the observed decline. CONCLUSIONS: In the BSR, a significant decline of hospital admissions due to STEMIs in non-smokers was observed after the smoking ban in public areas came into force. No reduction of STEMI-related admissions was found in smokers. These results may be explained by the protection of non-smokers from passive smoking and the absence of such an effect in smokers by the dominant effect of active smoking.

A growth factor mixture that significantly enhances angiogenesis in vivo.

Studies of therapeutic angiogenesis have generally focused on single growth factor strategies. However, multiple factors participate in angiogenesis. We evaluated the angiogenic potential of a growth factor mixture (GFm) derived from bovine bone. The major components of GFm (SDS-polyacrylamide gel electrophoresis, mass spectrometry, and Western blot) include transforming growth factor-beta1-3, bone morphogenic protein-2-7, and fibroblast growth factor-1. GFm was first shown to induce an angiogenic response in chorioallantoic membranes. Next, myocardial ischemia was induced in 21 dogs (ameroid) that were randomized 3 weeks later to received GFm 1 mg/ml (I), GFm 10 mg/ml (II), or placebo (P) (with investigators blinded to conditions) injected in and adjacent to ischemic myocardium. Dogs were assessed 6 weeks later using quantitative and semiquantitative measures. There were GFm concentration-dependent improvements in distal left anterior descending artery (LAD) opacification by angiography (P: 0.4 +/- 0.2, I: 1.1 +/- 0.14, II: 1.6 +/- 0.3, angiographic score p = 0.014). Histologically, there was also concentration-dependent vascular growth response of relatively large vessels (P: 0.21 +/- 0.15, I: 1.00 +/- 0.22, II: 1.71 +/- 0.18, vascular growth score p = 0.001). Resting myocardial blood flow (colored microspheres) was not significantly impaired in any group. However, maximum blood flow (adenosine) was reduced in ischemic territories and did not improve in GFm-treated hearts. GFm, a multiple growth factor mixture, is a potent angiogenic agent that stimulates large vessel growth. Although blood flow did not improve during maximal vasodilatory stress, large intramyocardial collateral vessels developed and angiographic visualization of the occluded distal LAD improved significantly. The use of multiple growth factors may be an effective strategy for therapeutic angiogenesis provided a more effective delivery strategy is devised that can achieve improved maximum blood flow potential.

Effects of exercise training on left ventricular function and peripheral resistance in patients with chronic heart failure: A randomized trial.

CONTEXT: Exercise training in patients with chronic heart failure improves work capacity by enhancing endothelial function and skeletal muscle aerobic metabolism, but effects on central hemodynamic function are not well established. OBJECTIVE: To evaluate the effects of exercise training on left ventricular (LV) function and hemodynamic response to exercise in patients with stable chronic heart failure. DESIGN: Prospective randomized trial conducted in 1994-1999. SETTING: University department of cardiology/outpatient clinic in Germany. PATIENTS: Consecutive sample of 73 men aged 70 years or younger with chronic heart failure (with LV ejection fraction of approximately 0.27). INTERVENTION: Patients were randomly assigned to 2 weeks of in-hospital ergometer exercise for 10 minutes 4 to 6 times per day, followed by 6 months of home-based ergometer exercise training for 20 minutes per day at 70% of peak oxygen uptake (n=36) or to no intervention (control group; n=37). MAIN OUTCOME MEASURES: Ergospirometry with measurement of central hemodynamics by thermodilution at rest and during exercise; echocardiographic determination of LV diameters and volumes, at baseline and 6-month follow-up, for the exercise training vs control groups. RESULTS: After 6 months, patients in the exercise training group had statistically significant improvements compared with controls in New York Heart Association functional class, maximal ventilation, exercise time, and exercise capacity as well as decreased resting heart rate and increased stroke volume at rest. In the exercise training group, an increase from baseline to 6-month follow-up was observed in mean (SD) resting LV ejection fraction (0.30 [0.08] vs 0.35 [0.09]; P=.003). Mean (SD) total peripheral resistance (TPR) during peak exercise was reduced by 157 (306) dyne/s/cm(-5) in the exercise training group vs an increase of 43 (148) dyne/s/cm(-5) in the control group (P=.003), with a concomitant increase in mean (SD) stroke volume of 14 (22) mL vs 1 (19) mL in the control group (P=.03). There was a small but significant reduction in mean (SD) LV end diastolic diameter of 4 (6) mm vs an increase of 1 (4) mm in the control group (P<.001). Changes from baseline in resting TPR for both groups were correlated with changes in stroke volume (r=-0.76; P<.001) and in LV end diastolic diameter (r=0.45; P<.001). CONCLUSIONS: In patients with stable chronic heart failure, exercise training is associated with reduction of peripheral resistance and results in small but significant improvements in stroke volume and reduction in cardiomegaly. JAMA. 2000.

Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.

OBJECTIVES: The aim of this study was to analyze whether L-arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure (CHF). BACKGROUND: Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise. METHODS: Forty patients with severe CHF (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg. and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 microg/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%. RESULTS: At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 microg/min was 2.54 +/- 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 +/- 0.9% after ACh 30 microg/min in L-arg. (p < 0.001 vs. C), by 8.6 +/- 0.9% in T (p < 0.001 vs. C) and by 12.0 +/- 0.3% in L-arg. +/- T (p < 0.005 vs. C, L-arg. and T). Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study. CONCLUSIONS: Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation.

Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance.

OBJECTIVES: The purpose of the study was to investigate if apoptosis occurs in skeletal muscle myocytes and its relation to exercise intolerance in patients with chronic heart failure (CHF). BACKGROUND: Intrinsic abnormalities of skeletal muscle frequently limit exercise tolerance in CHF patients. Recently, apoptosis has been detected in cardiac myocytes of patients with CHF, suggesting that apoptosis may contribute to the reduced contractile force. The presence and regulation of apoptosis in skeletal myocytes of patients with CHF remains to be defined. METHODS: Skeletal muscle biopsies (m. vastus lateralis) of 34 CHF patients (New York Heart Association functional class II-III) and eight age-matched healthy control subjects were analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling for the presence of apoptosis, and by immunohistochemistry and videodensitometrical quantification for inducible nitric oxide synthase (iNOS) and Bcl-2 expression. Maximal oxygen consumption (VO2max) was determined by ergospirometry. RESULTS: Apoptosis was detected in 16/34 (47%) patients with CHF and in none of the healthy subjects. Patients with apoptosis-positive skeletal muscle myocytes exhibited a significantly lower VO2max (12.0 +/- 3.7 vs. 18.2 +/- 4.4 ml/kg/min; p = 0.0005), a higher iNOS expression (6.8 +/- 3.6 vs. 3.7 +/- 2.6% iNOS-positive stained tissue area; p = 0.015) and a lower Bcl-2 expression (1.0 +/- 0.3 vs. 1.4 +/- 0.4% Bcl-2-positive tissue area; p = 0.03) as compared with patients with apoptosis-negative biopsies. CONCLUSIONS: These results indicate that apoptosis is frequently found in skeletal muscle obtained from CHF patients, which is associated with significant impairment of functional work capacity. In skeletal muscle of these patients, iNOS and Bcl-2 are possibly involved in the regulation of apoptosis.

Exercise intolerance in patients with chronic heart failure and increased expression of inducible nitric oxide synthase in the skeletal muscle.

OBJECTIVES: This study was designed to analyze the effect of iNOS on mitochondrial creatine kinase (mi-CK) expression and exercise capacity in chronic heart failure (CHF). BACKGROUND: The molecular mechanisms underlying exercise intolerance in CHF are still unclear. Expression of inducible nitric oxide synthase (iNOS) and reduced phosphocreatine resynthesis have been described in skeletal muscle of patients with CHF. However, it is unknown whether these phenomena are causally related to each other and to exercise tolerance. METHODS: Thirty-eight patients with CHF and 8 healthy controls (C) underwent bicycle ergospirometry and biopsy of the vastus lateralis muscle. Expression of iNOS was quantified by immunohistochemistry and reverse-transcriptase polymerase chain reaction, mi-CK by Western-blot. Intracellular presence of NO was confirmed by immunohistochemical quantification of nitrotyrosine (NT). To corroborate clinical findings, L6 rat skeletal myoblasts were incubated with sodium nitroprusside (SNP). RESULTS: Expression of iNOS was significantly increased in CHF (4.0+/-2.8 vs. 0.8+/-0.7% iNOS positive tissue area, p < 0.001 vs. C) and inversely correlated to maximal oxygen uptake (r=-0.65, p < 0.001). Intracellular NO-accumulation was confirmed by increased NT levels (13.5+/-8.5 vs. 2.0+/-1.7% NT-positive tissue area, p < 0.001 vs. C). Mi-CK was decreased in CHF (0.84+/-0.36 vs. 1.57+/-0.60, p < 0.001 vs. C). The inverse correlation seen between iNOS and mi-CK expression in patients (r=-0.68, p < 0.001) was reproduced in incubation experiments with SNP. CONCLUSIONS: Increased expression of iNOS in skeletal muscle of patients with CHF was inversely correlated with mi-CK expression and exercise capacity. Cell experiments confirmed a causal relationship via NO. These findings extend our knowledge of the pathophysiology of exercise intolerance in CHF.

Regular physical exercise corrects endothelial dysfunction and improves exercise capacity in patients with chronic heart failure.

BACKGROUND: The purpose of this study was to determine the effects of systemic exercise training on endothelium-mediated arteriolar vasodilation of the lower limb and its relation to exercise capacity in chronic heart failure (CHF). Endothelial dysfunction is a key feature of CHF, contributing to increased peripheral vasoconstriction and impaired exercise capacity. Local handgrip exercise has previously been shown to enhance endothelium-dependent vasodilation in conduit and resistance vessels in CHF. METHODS AND RESULTS: Twenty patients were prospectively randomized to a training group (n=10, left ventricular ejection fraction [LVEF] 24+/-4%) or a control group (n=10, LVEF 23+/-3%). At baseline and after 6 months, peak flow velocity was measured in the left femoral artery using a Doppler wire; vessel diameter was determined by quantitative angiography. Peripheral blood flow was calculated from average peak velocity (APV) and arterial cross-sectional area. After exercise training, nitroglycerin-induced endothelium-independent vasodilation remained unaltered (271% versus 281%, P=NS). Peripheral blood flow improved significantly in response to 90 microg/min acetylcholine by 203% (from 152+/-79 to 461+/-104 mL/min, P<0.05 versus control group) and the inhibiting effect of L-NMMA increased by 174% (from -46+/-25 to -126+/-19 mL/min, P<0.05 versus control group). Peak oxygen uptake increased by 26% (P<0.01 versus control group). The increase in peak oxygen uptake was correlated with the endothelium-dependent change in peripheral blood flow (r=0.64, P<0. 005). CONCLUSIONS: Regular physical exercise improves both basal endothelial nitric oxide (NO) formation and agonist-mediated endothelium-dependent vasodilation of the skeletal muscle vasculature in patients with CHF. The correction of endothelium dysfunction is associated with a significant increase in exercise capacity.

Effects of endurance training on mitochondrial ultrastructure and fiber type distribution in skeletal muscle of patients with stable chronic heart failure.

OBJECTIVES: The present study was designed to evaluate the effects of an ambulatory training program in patients with chronic heart failure (CHF) on the ultrastructural morphology of mitochondria and fiber type distribution of skeletal muscle and its relation to peripheral perfusion. BACKGROUND: Recent studies in patients with CHF have suggested that intrinsic abnormalities in skeletal muscle can contribute to the development of early lactic acidosis and fatigue during exercise. METHODS; Patients were prospectively randomized to either a training group (n = 9; mean [+/- SD] left ventricular ejection fraction [LVEF] 26 +/- 10) participating in an ambulatory training program or to a physically inactive control group (n = 9; LVEF 28 +/- 10%). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing with measurement of central and peripheral hemodynamic variables as well as percutaneous needle biopsies of the vastus lateralis muscle. The mitochondrial ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry; cytochrome c oxidase activity was visualized by histochemistry and subsequently quantitated by morphometry. The fiber type distribution was determined by adenosine triphosphatase staining. RESULTS: After 6 months of exercise training there was a significant increase of 41% in the surface density of cytochrome c oxidase-positive mitochondria (SVMOcox+) (p < 0.05 vs. control) and of 43% in the surface density of mitochondrial cristae (SVMC) (p < 0.05 vs. control). Furthermore, exercise training induced a 92% increase in the surface density of the mitochondrial inner border membrane (p < 0.05 vs. control). In contrast, the total number of cytochrome c oxidase-positive mitochondria remained essentially unchanged. Exercise-induced improvement in peak oxygen uptake was closely linked to changes in SVMOcox+ (p < 0.01, r = 0.66). After exercise training, changes in submaximal femoral venous lactate levels were not related to changes in submaximal leg blood flow (r = -0.4), but were inversely related to changes in the volume density of mitochondria (p = 0.01; r = -0.6) as well as to changes in SVMC (p < 0.05; r = -0.5). After exercise training there was a "reshift" from type II to type I fibers (p < 0.05 vs. control). CONCLUSIONS: Patients with CHF who engage in regular physical exercise show enhanced oxidative enzyme activity in the working skeletal muscle and a concomitant reshift to type I fibers. These exercise-induced changes in oxidative capacity appear to be unrelated to changes in peripheral perfusion.

Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural abnormalities of leg muscles.

OBJECTIVES: The present study was designed to evaluate the effect of an ambulatory training program on ultrastructural morphology and the oxidative capacity of skeletal muscle and its relation to central and peripheral hemodynamic variables in patients with chronic heart failure. BACKGROUND: Clinical evidence supports the hypothesis that exercise intolerance in patients with chronic heart failure is not only a consequence of low cardiac output, but is also a result of alterations in oxidative metabolism of skeletal muscle. METHODS: Twenty-two patients were prospectively randomized either to a training group (mean [+/-SD] ejection fraction 26 +/- 9%, n = 12) participating in an ambulatory training program or to a physically inactive control group (ejection fraction 27 +/- 10%, n = 10). At baseline and after 6 months, patients underwent symptom-limited bicycle exercise testing, and central and peripheral hemodynamic variables were measured. Percutaneous needle biopsy samples of the vastus lateralis muscle were obtained at baseline and after 6 months. The ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry. RESULTS: After 6 months, patients in the training group achieved an increase in oxygen uptake at the ventilatory threshold of 23% (from 0.86 +/- 0.2 to 1.07 +/- 0.2 liters/min, p < 0.01 vs. control group) and at peak exercise of 31% (from 1.49 +/- 0.4 to 1.95 +/- 0.4 liters/min, p < 0.01 vs. control group). There was no significant change in oxygen uptake at the ventilatory threshold and at peak exercise in the control group. The total volume density of mitochondria and volume density of cytochrome c oxidase-positive mitochondria increased significantly by 19% (from 4.7 +/- 1.5 to 5.6 +/- 1.5 vol%, p < 0.05 vs. control group) and by 41% (from 2.2 +/- 1.0 to 3.1 +/- 1.0 vol%, p < 0.05 vs. control group) after 6 months of regular physical exercise. Cardiac output at rest and at submaximal exercise remained unchanged but increased during maximal symptom-limited exercise from 11.9 +/- 4.0 to 14.1 +/- 3.3 liters/min in the training group (p < 0.05 vs. baseline; p = NS vs. control group). Peak leg oxygen consumption increased significantly by 45% (from 510 +/- 172 to 740 +/- 254 ml/min, p < 0.01 vs. control group). Changes in cytochrome c oxidase-positive mitochondria were significantly related to changes in oxygen uptake at the ventilatory threshold (r = 0.82, p < 0.0001) and at peak exercise (r = 0.87, p < 0.0001). CONCLUSIONS: Regular physical training increases maximal exercise tolerance and delays anaerobic metabolism during submaximal exercise in patients with stable chronic heart failure. Improved functional capacity is closely linked to an exercise-induced increase in the oxidative capacity of skeletal muscle.

Effect of an acute beta-adrenergic blockade on the relationship between ventilatory and plasma lactate threshold.

The present study assesses interobserver variability and day-to-day reproducibility of ventilatory threshold T(ven) and lactate threshold T(lac) in healthy young men. The data were obtained before and after acute beta-adrenergic blockade with metoprolol (100 mg/d p.o.). Fifteen healthy young men underwent progressively increased treadmill ergometry tests on two separate days (day 1, 2). Ten out of fifteen subjects participated in a third exercise test under an acute beta-adrenergic blockade (day 3). Interobserver variability of oxygen uptake at T(ven) (8%; +/- 0.136 l/min) and T(lac) (5%; +/- 0.984 l/min) was small and day-to-day reproducibility of T(ven) (7%; +/- 0.131 l/min) and T(lac) (7%; +/- 0.133 l/min) high. Under acute beta-adrenergic blockade T(ven) occurred at a significantly lower work load (360 +/- 117 s) as compared with T(ven) of days 1 and 2 (477 +/- 153 s; p < 0.05), and T(lac) of day 3 after beta-adrenergic blockade (456 +/- 76 s; p < 0.05). Therefore, a significantly lower oxygen uptake (1.409 +/- 0.29 l/min) could be observed at T(ven) of day 3 as compared with T(ven) of days 1 and 2 (1.852 +/- 0.30; p < 0.001), and T(lac) of days 1 and 2 (1.724 +/- 0.22; p < 0.001). There was a significant linear correlation between oxygen uptake at T(ven) and T(lac) before beta-adrenergic blockade (r = 0.86; p < 0.001). This correlation, however, was lost following an acute beta-adrenergic blockade (r = 0.56; n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

[Successful lysis therapy in acute unilateral renal vein thrombosis]. / Erfolgreiche Lysetherapie bei akuter einseitiger Nierenvenenthrombose.

A nephrotic syndrome developed in a 50-year-old man who, because of rheumatoid arthritis for the last three years, had been receiving gold therapy (30-50 mg sodium aurothiomalate weekly for 10 months). Treatment for the nephrotic syndrome was initiated with 100 mg prednisone daily. Ten days later he complained of severe pain in his right flank and haematuria was noted. Serum creatinine concentration increased from 1.0 to 1.8 mg/dl, while creatinine clearance fell to 62 ml/min. Computed tomography demonstrated significant enlargement of the right kidney and a thrombus in the right renal vein which extended cranial into the inferior vena cava. High dosage infusion of urokinase (4.5-7.5 mill. IU daily for nine days) achieved complete lysis of the thrombus. The creatinine concentration fell to 1.1 mg/dl, while creatinine clearance rose to 104 ml/min. On the 5th day the right kidney had 25% of total function, several days later 40%.--This case illustrates that, as long as there are no contraindications, adequately high doses of urokinase can be appropriate treatment of acute renal vein thrombosis associated with the nephrotic syndrome.