Exercise recommendation and catecholamines in patients with coronary artery disease

Exercise training for patients with coronary artery disease (CAD) is recommended in a wide range between 40-85% of maximum functional capacity (MFC) or 55-90% of maximum heart rate (HR). During exercise, high levels of catecholamines and metabolic acidosis could induce arrhythmia and ischemia. But catecholamines have never been determined in CAD during constant load exercise in the upper range of recommended intensities. In 11 CAD patients (age 58+/-8 years, BMI 26.1+/-4.0 kg x m(-2), NYHA I n=7, II n=4) we tested the maximum functional capacity (MFC), norepinephrine (NE), epinephrine (E) and blood lactate ([Lac(-)](B)) in a symptom-limited incremental ergometer test. Related to the exercise recommendation, the kinetics of NE, E and [Lac(-)](B) were determined in two 30 min constant load tests in randomized order: one was performed at the anaerobic lactate threshold (CTAT), a second was performed 10% above the individual threshold intensity (CT+10%). In the incremental tests maximum workload and VO(2) were 141+/-54 W and 1766+/-532 ml x min(-1), respectively (85+/-22% of normal; [Lac(-)](B) 5.7+/-1.9 mmol x l(-1), HR 138+/-28 b x min(-1), NE 11.7+/-5.1, E 1.6+/-1.4 nmol x l(-1)). In CTAT the anaerobic threshold (63+/-7% of MFC) represented the mean range of recommended exercise intensity for CAD (40-85%) and could be validated as steady-state intensity because catecholamines and [Lac(-)](B) concentrations remained constant after the initial increase (workload 88+/-35 W, [Lac(-)](B) 3.3+/-1.4 mmol x l(-1), HR 117+/- 23 b x min(-1), NE 8.3+/-3.5, E 0.8+/- 0.7 nmol x l(-1)). In all patients CT+10% (71+/-7% of MFC) led to a continuous rise in [Lac(-)](B), to a NE overload and to earlier exhaustion, although the intensities were in the recommended training range (workload 100+/-38 W, [Lac(-)](B) 5.8+/- 1.9 mmol x l(-1), HR 129+/- 29 b x min(-1), NE 13.9+/-6.9, E 1.5+/- 1.7 nmol x l(-1); p<0.01 against CTAT for all except E). Conclusions In the upper range of recommended training intensity for CAD patients, norepinephrine and lactate were higher during endurance exercise than at MFC in incremental tests. Endurance exercise with intensities >70% of MFC could overload the cardiac patient and increase the risk of arryhthmia and ischemia. Therefore, endurance exercise should be performed below 70% of MFC or below 85% of maximum HR, respectively, whereas higher intensities should apply to interval exercise.     

Thrombopoietin and platelet aggregation in patients with stable coronary artery disease

Thrombopoietin (TPO) may facilitate platelet activation and aggregation. However, data on the impact of TPO on platelet aggregation in patients with stable coronary artery disease (CAD) are scarce. We aimed to investigate associations between TPO and platelet aggregation and activation in patients with stable coronary artery disease (CAD). We studied 900 stable CAD patients. Serum TPO was assessed by ELISA. Platelet aggregation was evaluated using the Multiplate Analyzer (agonists: arachidonic acid [AA] and collagen) and the VerifyNow Aspirin Assay. Platelet activation was evaluated by soluble (s)P-selectin. Cyclooxygenase-1 inhibition was evaluated by serum thromboxane B₂ (TXB₂). We found that TPO correlated weakly with platelet aggregation evaluated by Multiplate using AA (r = ?0.09, p = 0.01) and collagen as agonists (r = ?0.03, p = 0.43) and by VerifyNow (r = 0.07, p = 0.03). We found no correlation between TPO and sP-selectin (r = ?0.01, p = 0.70). Independent predictors of AA-induced platelet aggregation by Multiplate included high levels of sP-selectin and serum TXB₂, high platelet count, increasing age and body mass index, female sex, and active smoking. Independent predictors of TPO included low AA-induced platelet aggregation by Multiplate, high levels of hs-CRP, active smoking, and high platelet aggregation evaluated by VerifyNow. In conclusion, TPO levels did not correlate with platelet activation and only weak associations were found between TPO and platelet aggregation, suggesting that TPO did not substantially facilitate platelet aggregation in stable CAD patients.     

Heparin-releasable platelet factor 4 in patients with coronary artery disease.

Recently, platelet factor 4 (PF4) release by heparin (heparin-releasable PF4) has been examined as a useful marker of the interaction between the substances liberated from circulating platelets and the vascular endothelium. We compared the plasma levels of PF4 and beta-thromboglobulin (beta-TG) after intravenous heparin injection in patients with coronary artery disease (CAD) and normal control subjects. We also studied the effects of low-dose aspirin (81 mg/day) on the plasma level of heparin-releasable PF4 in the CAD patients. Blood samples were obtained before and 5 min after the intravenous injection of heparin (1,000 IU) from 23 patients with CAD and 15 normal control subjects. Although the plasma beta-TG level remained unchanged after heparin injection, the plasma PF4 level markedly increased in both groups. There was a significant difference in plasma PF4 levels at 5 min after heparin injection between the CAD group (100.1 +/- 38.1) and the control group (61.0 +/- 24.0) (p less than 0.01). The PF4/beta-TG ratio after heparin injection was also higher in the CAD group than in the control group (p less than 0.01). There was a correlation between the PF4/beta-TG ratio after heparin and the Gensini CAD score, which defines the severity of coronary atherosclerosis (r = 0.489, n = 23, p less than 0.01). Low-dose aspirin was administered to 11 CAD patients for 246.0 +/- 28.8 days. Blood samples for the assay of PF4 and beta-TG were obtained as stated above, and platelet aggregation, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels were also measured before and during aspirin administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise training improves lipoprotein lipid profiles in patients with coronary artery disease

The effects of endurance exercise training on plasma lipoprotein lipids were determined in 10 men, ages 46 to 62 years, with coronary artery disease (CAD). Patients maintained body weight, health-related behaviors, and stable diets throughout the program. Training was at 50% to 85% of maximal oxygen consumption (V?O₂ max) for 40 to 60 minutes, 3 to 5 days/week for 29 ± 7 weeks. Training increased V?O₂ max (31 ± 19%, p < 0.001), reduced plasma cholesterol (C) (?8 ± 4%, p < 0.01), low-density lipoprotein-C (LDL-C) (?9 ± 9%, p < 0.01), and triglyceride (TG) (?13 ± 32%, p < 0.05) concentrations, and increased high-density lipoprotein-C (HDL-C) levels (11 ± 13%, p < 0.05) and $\text{HDL-C}\text{LDL-C}$ ratios (25 ± 20%, p < 0.01). Changes in LDL-C and V?O₂ max were correlated (r = ?0.73, p ± 0.01), while the changes in LDL-C and HDL-C each correlated inversely with pretraining lipoprotein levels (^rLDL-C = ?0.77, p < 0.01; ^rHDL-C = ?0.68, p < 0.05). Thus potentially “antiatherogenic” benefits of exercise seem to be due to a training effect, since they correlate best with changes in V?O₂ max and are maximal in patients with initially low V?O₂ max, high LDL-C, and low HDL-C levels.     

Exercise training improves diastolic perfusion time in patients with coronary artery disease

Exercise training elicits an improvement in work capacity and in left-ventricular function in patients with coronary artery disease. An improvement in myocardial oxygen supply accounts for these effects. The aim of this study was to test the hypothesis that exercise training could favorably influence diastolic perfusion time, a major determinant of subendocardial perfusion. Twenty-two male patients with coronary artery disease were randomized to a training or control group. At the study entry and after one year, all patients underwent an exercise stress test. After one year, rest heart rate was lower and diastolic perfusion time was higher in the training group but not in the control group. At peak of exercise, diastolic perfusion time increased and ST-segment depression decreased significantly in the training group but not in the control group. A significant relation was found between the R-R interval and the diastolic perfusion time either before or after training, with a difference in the intercepts of two regressions. Training shifted updown-line regression, effecting a higher value of diastolic perfusion time for a given value of heart rate. Thus, training increases diastolic perfusion time, independently from the effect on heart rate. This mechanism may contribute to the improvement of myocardial perfusion.     

Exercise training in coronary artery disease and coronary vasomotion

Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.     

Homocysteine levels and platelet reactivity in coronary artery disease patients treated with ticagrelor

Background and aimRecurrent atherothrombotic events have been reported in certain higher risk subsets of patients even with ticagrelor, a potent first-line antiplatelet agent for the management of patients with acute coronary syndrome (ACS). Hyperhomocysteinemia is a known determinant of platelet function abnormalities. Therefore, the aim of our study was to evaluate the impact of homocysteine (Hcy) levels on platelet reactivity in patients receiving Ticagrelor.Methods and resultsPatients with ACS undergoing percutaneous coronary revascularization and on dual antiplatelet therapy with ASA + Ticagrelor (90mg/twice a day) were scheduled for platelet function assessment 30–90 days post-discharge. Aggregation tests were performed by Multiple Electrode Aggregometry (MEA). Suboptimal platelet inhibition HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min).We included 432 patients, divided according to Hcy tertiles. Higher Hcy levels were associated with age, renal failure, creatinine levels and use diuretics (p < 0.001).Patients with higher Hcy levels displayed a higher platelet reactivity at COL test (p = 0.002), and ADP test (p = 0.04), with a linear relationship between Hcy and platelet aggregation after stimulation with collagen (r = 0.202, p < 0.001), thrombin receptor peptide (r = 0.104, p = 0.05) and ADP (r = 0.145, p = 0.006).However, Hcy levels did not significantly affect the rate of HRPR with Ticagrelor (9.9% vs 13.7% vs 10.7%, p = 0.89; adjusted OR [95% CI] = [0.616–1.51], p = 0.99).ConclusionsAmong patients with ACS, despite the elevated platelet reactivity associated to hyperhomocysteinemia, DAPT with ticagrelor could overcome such phenomenon, achieving an adequate platelet inhibition in the majority of the patients.     

Effects of low osmolar contrast (iomeprol) on haemorheology and platelet activation in patients with coronary artery disease

Background Non-ionic low osmolar contrast agents are widely used during coronary angiography. As these agents cause activation of thrombotic pathways in vitro, this may have potentially significant clinical impact. However, limited evidence exists as to their in vivo effects from selective coronary cannulation. Methods We initially performed an in vitro experiment to assess the effect of serial contrast (Iomeprol 300, Bracco) dilution on platelet indices [mean platelet count (MPC), platelet volume (MPV), platelet granularity (MPG)]. The in vivo effect of contrast injection on platelet activation markers [soluble P-selectin (sPsel), soluble CD40 ligand (sCD40L)], MPC, MPV, MPG, haemoglobin and haematocrit was subsequently determined in 35 patients (mean age 58 ± 11; 22 males) undergoing cardiac catheterisaton. Results No significant in vitro effect of contrast on MPC or MPV was seen but there was a significant increase in MPG (p = 0.40, 0.10 and 0.01, respectively). In the in vivo study, there was a reduction in mean haemoglobin and haematocrit levels, suggesting an average increase in plasma volume of 6.5 ± 5.8%. The in vivo effect of Iomeprol was associated with an unadjusted reduction in sPsel concentrations (p = 0.04) and MPV (p < 0.05), with denser platelets (p < 0.05). There was no difference in MPC or sCD40L concentration (both p = NS). After adjustment for the haemodilution effect, no significant reduction in P-sel levels was seen with contrast (p = 0.27), although the adjusted post-contrast change in MPG (p = 0.01), MPC (p = 0.01) and sCD40L (p < 0.05) levels were significant. Conclusion Low osmolar contrast led to a minimal effect on soluble and physical indices of platelets within the coronary artery, primarily due to plasma volume expansion.     

Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty

Objectives. This study sought to investigate changes in the expression of activation-dependent adhesion receptors on neutrophils and platelets after exposure to the balloon-injured coronary artery plaque.Background. Activation of blood cells at the balloon-injured coronary artery plaque may contribute to abrupt vessel closure and late restenosis after percutaneous transluminal coronary angioplasty.Methods. In 30 patients undergoing elective coronary angioplasty, blood specimens were obtained through the balloon catheter proximal to the plaque before dilation and distal to the plaque after dilation. Simultaneous blood samples obtained through the guiding catheter served as control samples. Total surface expression of the inducible fibrinogen receptor (CD41) and surface expression of the activated fibrinogen receptor (LIBS1) on platelets as well as Mac-1 (CD11b) and L-selectin (CD62L) surface expression on neutrophils were assessed by flow cytometry.Results. After exposure to the dilated coronary artery plaque, surface expression of LIBS1 on platelets increased by 40.5 ± 11.0 mean (±SE) fluorescence (p = 0.001) and that of CD11b on neutrophils increased by 20.1 ± 4.4 mean fluorescence (p = 0.018). Concomitantly, anti-CD62L binding on neutrophils decreased by 6.6 ± 2.4 mean fluorescence (p = 0.022). In contrast, surface expression of the adhesion receptors did not change significantly between the coronary ostium and the prestenotic coronary segment.Conclusions. The results of this study demonstrate neutrophil and platelet activation at the balloon-injured coronary artery plaque. This cellular activation may serve as a target for pharmacologic interventions to improve the outcome of coronary angioplasty.     

Functional interplay between platelet activation and endothelial dysfunction in patients with coronary heart disease

Platelet–monocyte binding and surface P-selectin expression are sensitive markers of platelet activation. Endothelium-derived factors are known to inhibit platelet activation and may confer important anti-atherothrombotic effects. We assessed the relationship between platelet activation and endothelium-dependent vasomotion in patients with coronary heart disease (CHD). Twenty male patients with stable CHD were compared with 20 healthy men. Platelet–monocyte binding and platelet surface expression of P-selectin were assessed using two-colour flow cytometry on whole blood. Forearm blood flow was assessed in patients using venous occlusion plethysmography during intra-arterial infusions of substance P, acetylcholine and sodium nitroprusside. Platelet activation was higher in patients than healthy men (platelet–monocyte binding, 27?±?3 vs. 20?±?1%; P?<?0.05). In patients with CHD, there was an inverse correlation between maximal substance P induced vasodilatation and both platelet–monocyte binding (P?=?0.003) and P-selectin expression (P?=?0.02). A similar correlation was observed between platelet–monocyte binding and the vasomotor response to acetylcholine (P?=?0.08) but not with sodium nitroprusside. In patients with stable coronary heart disease, there is a strong inverse relationship between markers of platelet activation and endothelium-dependent vasomotor function. This may explain the pathophysiological mechanism linking endothelial vasomotor dysfunction and the risk of acute atherothrombotic events.     

Functional interplay between platelet activation and endothelial dysfunction in patients with coronary heart disease

Platelet-monocyte binding and surface P-selectin expression are sensitive markers of platelet activation. Endothelium-derived factors are known to inhibit platelet activation and may confer important anti-atherothrombotic effects. We assessed the relationship between platelet activation and endothelium-dependent vasomotion in patients with coronary heart disease (CHD). Twenty male patients with stable CHD were compared with 20 healthy men. Platelet-monocyte binding and platelet surface expression of P-selectin were assessed using two-colour flow cytometry on whole blood. Forearm blood flow was assessed in patients using venous occlusion plethysmography during intra-arterial infusions of substance P, acetylcholine and sodium nitroprusside. Platelet activation was higher in patients than healthy men (platelet-monocyte binding, 27 +/- 3 vs. 20 +/- 1%; P < 0.05). In patients with CHD, there was an inverse correlation between maximal substance P induced vasodilatation and both platelet-monocyte binding (P = 0.003) and P-selectin expression (P = 0.02). A similar correlation was observed between platelet-monocyte binding and the vasomotor response to acetylcholine (P = 0.08) but not with sodium nitroprusside. In patients with stable coronary heart disease, there is a strong inverse relationship between markers of platelet activation and endothelium-dependent vasomotor function. This may explain the pathophysiological mechanism linking endothelial vasomotor dysfunction and the risk of acute atherothrombotic events.