Nitroglycerin withdrawal increases endothelium-dependent vasomotor response to acetylcholine

OBJECTIVES: We sought to determine whether nitroglycerin (NTG) withdrawal contributes to worsening of endothelial dysfunction and development of the rebound phenomenon during intermittent transdermal NTG therapy. BACKGROUND: Intermittent transdermal NTG therapy is recommended to avoid the development of tolerance. However, this regimen may precipitate worsening angina in the NTG-free interval. METHODS: Twenty patients were randomized to intermittent transdermal NTG (0.6 mg/h; NTG group) or no treatment (control group) five days before angiography. The risk factors for endothelial dysfunction were similar in both groups. After diagnostic angiography, the patients underwent quantitative angiography before and after intracoronary acetylcholine (ACh), 10(-4) mol/liter. Immediately after the morning study, the patch was removed from the NTG group, and 3 h later, the ACh infusion was repeated in both groups. All patients had mild to moderate coronary artery disease (CAD). RESULTS: The diameter of the left anterior descending coronary artery at baseline was 2.0 +/- 0.1 mm in the control group and 2.6 +/- 0.1 mm in the NTG group (p < 0.05). Acetylcholine caused mild vasoconstriction in the control group in the morning and afternoon (2.7 +/- 5.3% and 2.4 +/- 3.9%, respectively; p = NS). The NTG group demonstrated mild vasoconstriction to ACh in the morning (3.2 +/- 2.8%; p = NS vs. control group). After patch removal, there was a significant increase in the magnitude ofvasoconstriction in the NTG group (11.6 +/- 3.9%, p = 0.04 vs. morning constriction). CONCLUSIONS: These results confirm that NTG withdrawal increases the coronary vasomotor response to ACh in patients with mild CAD and suggests that the rebound phenomena may be secondary to the development of endothelial dysfunction after discontinuation of NTG therapy.     

The effect of apolipoprotein E genotype on serum lipoprotein particle response to exercise

Exercise affects lipoprotein metabolism and apolipoprotein E (Apo E) genotype may alter changes in lipoprotein subclasses that occur with exercise. The present study examined the effects of Apo E genotype (APOE) on the response of lipoprotein subclass concentrations to long-term exercise. A prospective longitudinal study, conducted at seven centers, genetically screened 566 individuals to create three cohorts of healthy adults, equal for gender and the most common APOE variants: E2/3 (n = 35), E3/3 (n = 40), and E3/4 (n = 31). Subjects with body mass index (BMI) > or = 31 or evidence of dyslipidemia or metabolic disease were excluded. All subjects exercised aerobically at 75% of maximal heart rate for 40 min, four times weekly for 6 months. Fasting lipoprotein subpopulations were measured before and after exercise training using proton nuclear magnetic resonance spectroscopy. Serum lipids for the entire cohort did not change with exercise training, but the LDL subpopulation response varied by APOE. Small-sized LDL particles decreased only in the APOE3 homozygotes whereas medium-sized LDL particles increased only in this group. These changes were directionally different from the responses in the E2/3 and E3/4 subjects (p < 0.05). Neither exercise nor APOE variant affected overall LDL or HDL size or cholesterol concentration, but exercise decreased VLDL diameter by 3.5 nm (p < 0.001) attributable to decreases in large VLDL in each APOE group. In conclusion, APOE variants influence the serum LDL subpopulation response to exercise training in normolipidemic subjects. Subjects homozygous for APOE3 experienced the most beneficial lipid effects from exercise training.     

The effect of aspirin on the ventilatory response to exercise in chronic heart failure

INTRODUCTION: Patients with chronic heart failure (CHF) experience breathlessness and fatigue on exercise. One of the abnormalities seen on maximal exercise testing is an increased ventilatory response to exercise (VE/VCO(2) slope). The cause of this is unknown, but is likely to be due to a combination of interacting peripheral and central factors. Recent data have demonstrated a relation between VE/VCO(2) slope and prostaglandin levels in contracting muscles. The present study examined the influence of the presence of a potent non-selective prostaglandin inhibitor, aspirin, on the ventilatory response to exercise in a group of patients with CHF. METHODS: We investigated the ventilatory response to exercise of 120 consecutive patients in sinus rhythm attending a specialist heart failure clinic. We excluded those taking clopidogrel (six patients) and those on both warfarin and aspirin or taking other non-steroidal anti-inflammatory agents (five patients). The other 109 patients were grouped according to whether they were taking aspirin (n=52 (48%)) or not (n=57 (52%)). Each patient underwent echocardiography to assess left ventricular function, and exercise testing with metabolic gas exchange to derive peak oxygen consumption (pVO(2)) and the VE/VCO(2) slope. RESULTS: The groups were similar in terms of age, (67 (13) vs. 66 (12) years; P=0.34) drug use, heart failure aetiology, left ventricular function (ejection fraction; 33.3 (9.4) vs. 31.8 (9.9)%; P=0.05)) and exercise tolerance (pVO(2); 20.4 (5.3) vs. 19.9 (6.0); P=0.68, and VE/VCO(2) slope; 35.4 (6.2) vs. 35.7 (9.3); P=0.73). There was no difference in the ventilatory response to exercise or the symptoms of breathlessness between the two groups. CONCLUSIONS: Aspirin does not appear to affect exercise performance in CHF.     

Metabolic response to exercise

At the beginning, the survival of humans was strictly related to their physical capacity. There was the need to resist predators and to provide food and water for life. Achieving these goals required a prompt and efficient energy system capable of sustaining either high intensity or maintaining prolonged physical activity. Energy for skeletal muscle contraction is supplied by anaerobic and aerobic metabolic pathways. The former can allow short bursts of intense physical activity (60-90 sec) and utilizes as energetic source the phosphocreatine shuttle and anaerobic glycolysis. The aerobic system is the most efficient ATP source for skeletal muscle. The oxidative phosporylation of carbohydrates, fats and, to a minor extent, proteins, can sustain physical activity for many hours. Carbohydrates are the most efficient fuel for working muscle and their contribution to total fuel oxidation is positively related to the intensity of exercise. The first metabolic pathways of carbohydrate metabolism to be involved are skeletal muscle glycogenolysis and glycolysis. Later circulating glucose, formed through activated gluconeogenesis, becomes an important energetic source. Among glucose metabolites, lactate plays a primary role as either direct or indirect (gluconeogenesis) energy source for contracting skeletal muscle. Fat oxidation plays a primary role during either low-moderate intensity exercise or protracted physical activity (over 90-120 min). Severe muscle glycogen depletion results in increased rates of muscle proteolysis and branched chain amino acid oxidation. Endurance training ameliorates physical performance by improving cardiopulmonary efficiency and optimizing skeletal muscle supply and oxidation of substrates.     

Effect of exercise protocol on the left ventricular response to exercise

The purpose of this study was to determine whether the left ventricular response during exercise radionuclide angiography would be influenced by exercise protocol. One hundred twenty healthy volunteers (aged 18 to 40 years) performed upright bicycle exercise using 1 of 5 protocols. Ejection fraction was measured using first-pass radionuclide angiography. Exercise protocols were as follows: (1) graded exercise (25 W increase every 2 minutes) to fatigue, heart rate greater than 85% of age-predicted maximum, n = 53; (2) graded exercise to 85% of age-predicted maximal heart rate or to fatigue with heart rate less than 85% of age-predicted maximum, n = 26; (3) graded exercise to fatigue, with "exercise" imaging performed immediately after exercise, n = 15; (4) abrupt presentation of a supermaximal work load (400 W), n = 10; (5) graded exercise to a work load of 75 W preceding the abrupt presentation of a supermaximal work load (300 to 400 W), n = 16. Protocols 2 and 3, representing less than maximal stress, yield higher ejection fractions than Protocol 1 and may reduce the sensitivity of exercise radionuclide angiography. Protocols 4 and 5, representing supermaximal stress, yield lower ejection fractions than Protocol 1 and may reduce the specificity of exercise radionuclide angiography. Thus, exercise protocol has a significant influence on the left ventricular response during exercise radionuclide angiography.     

The effect of pantothenate deficiency in mice on their metabolic response to fast and exercise

The changes in fuel metabolism during fast and exercise were compared to the tissue total CoA levels in mice maintained on pantothenate-deficient and pantothenate-supplemented (control) diets. In nonexercised mice maintained on a pantothenate-deficient diet for 65 to 105 days, the total CoA levels of many tissues were significantly lower than in controls (liver 18%, kidney 23%, spleen 21%, heart 38%, and leg skeletal muscle 66%). However, no differences in total CoA levels in brain or epididymal fat pads were observed. During a 48-hour fast, the total CoA levels increased in the heart and liver of both pantothenate-deficient and control mice (heart 32 and 19%, respectively; liver 39 and 45%, respectively), but the level of total CoA remained lower in the deficient mice. Liver glycogen levels were 17% lower in deficient mice than in controls and liver ketone bodies were 17% higher in pantothenate deficient mice than in controls. Separate groups of mice on deficient and supplemented diets were trained to run to exhaustion. Compared to trained mice on pantothenate-supplemented diets, the trained pantothenate-deficient mice had lower running times until exhaustion, lower body weights, lower liver and muscle glycogen content (even after rest), and elevated liver ketone bodies both during rest and after running. In summary, the pantothenate-deficient mice were unable to maintain normal glycogen stores, but had a normal ketogenic response to fast and exercise in spite of the lower levels of liver total CoA.     

The effect of beta-blockade therapy on the response to exercise training in postmyocardial infarction patients

Cardiac rehabilitation after a myocardial infarction has been shown to improve exercise capacity. Beta blockade has been shown to be effective in treating angina and reducing mortality, but studies are controversial as to whether beta-blockade therapy attenuates the effects of training. We attempted to study the effects of beta blockade (metoprolol) on the response to training in patients enrolled in a cardiac rehabilitation program after an uncomplicated myocardial infarction. We studied 27 patients with a recent uncomplicated myocardial infarction who were subdivided in two groups: Group 1 (13 patients) not taking a beta blocker, and Group 2 (14 patients) taking metoprolol (mean 142 ± 57 mg daily). All patients underwent a maximal cardiopulmonary exercise test before and after a 3-month training program. The training intensity was designed to approximate the ventilatory threshold. Results showed an increase in peak VO₂ in both Group 1 (27%, p<0.01) and Group 2 (33%, p<0.001), and an increase in VO₂ at the ventilatory threshold (39% in Group 1 and 28% in Group 2, p<0.01). The mean changes in exercise capacity were not different between groups. It was concluded that metoprolol did not influence the beneficial effects of a cardiac rehabilitation program in postmyocardial infarction patients.     

Proximal coronary vasomotor reactivity after exercise training in dogs

The effects of exercise on large coronary vasoreactivity were determined in eight dogs trained by treadmill running for 8 weeks. Six nontrained dogs comprised the control group. The trained group showed a significant reduction in heart rate during graded submaximal exercise testing when compared with the controls, and resting plasma levels of norepinephrine (nontrained group, 331 +/- 99 pg/ml; trained group, 142 +/- 30 pg/ml; p less than .05) and epinephrine (nontrained, 424 +/- 105; trained, 258 +/- 45 pg/ml; p less than .05) were reduced significantly in the trained group. Epicardial coronary responses to intracoronary infusion of serotonin and phenylephrine were evaluated by quantitative coronary angiography, and myocardial blood flow was measured with 15 microns radioactive microspheres. Left ventricular/body weight ratio was similar in the trained (4.81 +/- 0.24 g/kg) and nontrained groups (4.79 +/- 0.17), and no differences were noted in resting myocardial oxygen consumption or coronary arteriovenous oxygen difference. The constriction of the proximal left anterior descending artery (LAD) in response to serotonin infusion was not different in the two groups, but the LAD and circumflex artery constrictor responses to phenylephrine were attenuated in the trained when compared with the nontrained dogs. The data indicate that endurance exercise diminishes the large epicardial coronary vasoconstrictor response to alpha-adrenergic stimulation, but not to serotonin. The blunted constrictor response in the trained animals suggests that exercise may be useful in reducing epicardial coronary vasoconstriction, which is thought to be important in some patients with coronary artery disease.     

Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension

BACKGROUND & AIMS: It has been suggested that beta-blockers might be harmful in pulmonary arterial hypertension. However, no study has evaluated the effect of beta-blockers in these patients. The aim of this study was to investigate the effect of beta-blockers on exercise capacity and pulmonary hemodynamics in patients with portopulmonary hypertension receiving beta-blockers for the prophylaxis of variceal bleeding. METHODS: Ten consecutive patients with moderate to severe portopulmonary hypertension (mean pulmonary artery pressure of 52 [10] mm Hg) underwent a 6-minute walk test and a right heart catheterization at baseline and 2 (1) months after beta-blocker withdrawal. RESULTS: Following beta-blocker withdrawal, 9 of 10 patients increased their 6-minute walked distance with a mean increase in the whole group of 79 (78) meters (P = .01). Cardiac output increased by 28% (P < .01) with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance (P < .01). Increases in cardiac output were related to a 25% increase in heart rate (P < .01), whereas stroke volume was unchanged (P = .65). The improvements in exercise tolerance were associated with increases in chronotropic response (maximal heart rate minus resting heart rate) from 18 (9) to 34 (12) beats/min (P < .01) during the 6-minute walk test. CONCLUSIONS: In patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening in exercise capacity and pulmonary hemodynamics. These deleterious effects support the contraindication of beta-blockers in patients with portopulmonary hypertension.     

Influence of differential vascular remodeling on the coronary vasomotor response

OBJECTIVES: Arterial remodeling may increase or decrease the luminal encroachment of atherosclerotic plaques in the coronary circulation. However, the factors determining the nature and consequences of the remodeling process remain poorly characterized. The study aims were to assess whether the pattern of vascular remodeling influences the physical and vasomotor responses of the coronary arteries in vivo in man. METHODS: Coronary vessel area, distensibility and stiffness were determined in positively, negatively and non-remodeled arterial segments using intravascular ultrasound and Doppler flow measurement. Epicardial vasomotor responses were determined following intracoronary boluses of acetylcholine (10(-6) and 10(-4) M), adenosine (24-30 microg) and nitroglycerin (200 microg). RESULTS: Fifty-six coronary arterial segments were studied in 25 patients. In comparison to non- and positively remodeled segments, negatively remodeled segments had a higher stiffness index (67+/-16 vs. 33+/-5 and 38+/-8, respectively; P<0.02) and appeared to have lower compliance and distensibility (0.66+/-0.17 vs. 1.65+/-0.54 and 0.94+/-0.18/mmHg; P=NS). Non-remodeled segments had a greater change in vessel area with 10(-6) M acetylcholine (4.9+/-0.8%), compared to positively and negatively remodeled segments (0.6+/-1.8% and -4.9+/-1.8%, respectively, P<0.05). A significant degree of preservation of vasodilatation to 10(-6) M acetylcholine was evident in positively remodeled compared with negatively remodeled segments (P<0.05). Nitroglycerin caused greater vasodilatation in non-remodeled segments (7.2+/-3.8%) than either positively or negatively remodeled segments (4.7+/-0.9 and 3.7+/-0.6%, respectively, P<0.05). CONCLUSIONS: Vascular remodeling is an important and major determinant of local epicardial vasomotor responses. Both structural and functional abnormalities are associated with negative remodeling that may contribute to the adverse effects of such lesions.     

High level of cholesterol increases coronary vasomotor tone during exercise

BACKGROUND: Coronary vasomotor tone plays an important role in the regulation of myocardial perfusion and influences ischemic threshold significantly. Endothelial dysfunction occurs in the presence of coronary risk factors and is closely linked to the development of atherosclerosis affecting myocardial perfusion and decreasing ischemic threshold. OBJECTIVE: To study the effect of hypercholesterolemia on coronary vasomotor tone in normal and stenotic coronary arteries at rest and during exercise. PATIENTS AND METHODS: In total 48 patients were included in the present analysis. Patients were divided into two groups according to the actual levels of serum cholesterol: 18 patients had normal (mean 181 +/- 28 mg%; group 1) and 30 had elevated (mean 263 +/- 46 mg%; group 2) levels of serum cholesterol according to the 4S criteria with a cutoff level of 213 mg% (5.5 mmol/l). Coronary vasomotor tone at rest and during supine bicycle exercise was calculated by dividing mean aortic pressure by radius of coronary vessel obtained using biplanar quantitative coronary angiography. A normal as well as a stenotic vessel segment in each patient were studied. RESULTS: Normal vessel segments in patients with normal levels of cholesterol (group 1) exhibited no exercise-induced change in coronary vascular tone (+3%, NS), whereas a significant increase in tone (+24%, P < 0.01 versus rest) occurred in those with high levels of cholesterol (group 2). In contrast, stenotic segments in members of both groups exhibited an increase in vascular tone irrespective of the actual level of serum cholesterol. CONCLUSIONS: Hypercholesterolemia causes a pathologic increase in coronary vasomotor tone of angiographically normal vessel segments during exercise. A similar pathologic response occurs in stenotic arteries, but this is independent of the actual level of serum cholesterol. These findings suggest that hypercholesterolemia influences vasomotor tone of the nonstenosed coronary arteries in patients with coronary artery disease probably through the occurrence of endothelial dysfunction.