Inflammation and atrial remodeling after a mountain marathon.

Endurance athletes have an increased risk of atrial fibrillation. We performed a longitudinal study on elite runners of the 2010 Jungfrau Marathon, a Swiss mountain marathon, to determine acute effects of long-distance running on the atrial myocardium. Ten healthy male athletes were included and examined 9 to 1 week prior to the race, immediately after, and 1, 5, and 8 days after the race. Mean age was 34.9 ± 4.2 years, and maximum oxygen consumption was 66.8 ± 5.8 mL/kg*min. Mean race time was 243.9 ± 17.7 min. Electrocardiographic-determined signal-averaged P-wave duration (SAPWD) increased significantly after the race and returned to baseline levels during follow-up (128.7 ± 10.9 vs. 137.6 ± 9.8 vs. 131.5 ± 8.6 ms; P < 0.001). Left and right atrial volumes showed no significant differences over time, and there were no correlations of atrial volumes and SAPWD. Prolongation of the SAPWD was accompanied by a transient increase in levels of high-sensitivity C-reactive protein, proinflammatory cytokines, total leucocytes, neutrophil granulocytes, pro atrial natriuretic peptide and high-sensitivity troponin. In conclusion, marathon running was associated with a transient conduction delay in the atria, acute inflammation and increased atrial wall tension. This may reflect exercise-induced atrial myocardial edema and may contribute to atrial remodeling over time, generating a substrate for atrial arrhythmias.

Young adults with coeliac disease may be at increased risk of early atherosclerosis.

BACKGROUND: Accelerated progression of atherosclerosis and increased cardiovascular risk have been described in immune-mediated disorders, but few data are available in coeliac disease. AIM: To evaluate instrumental and biochemical signs of atherosclerosis risk in 20 adults at first diagnosis of coeliac disease and after 6-8 months of gluten-free diet with mucosal recovery. METHODS: We analysed total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, homocysteine, C-reactive protein, folate and vitamin B12; ultrasound measurement of carotid intima-media thickness (IMT) and endothelium-dependent dilatation were both carried on at diagnosis and after gluten withdrawal. Twenty-two healthy members of the hospital staff served as matched controls for vascular examinations. RESULTS: At baseline, mean total and HDL-cholesterol (HDL-C) were both within normal range, while mean LDL-cholesterol concentration was slightly increased; diet was associated with an increment in total and HDL-C (68.2 ± 17.4 vs. 51.4 ± 18.6 mg/dL; P < 0.001) and a significant improvement in total/HDL-C ratio (3.05 ± 0.71 vs. 3.77 ± 0.92; P < 0.02). Mean plasma homocysteine was elevated and not influenced by diet. C-reactive protein significantly decreased with diet (1.073 ± 0.51 vs. 1.92 ± 1.38 mg/dL; P < 0.05). At baseline, in coeliacs, IMT was increased (0.082 ± 0.011 vs. 0.058 ± 0.012 cm; P < 0.005), while endothelium-dependent dilatation was decreased (9.3 ± 1.3 vs. 11.2 ± 1.2%; P < 0.05). Both parameters improved after gluten abstinence. CONCLUSIONS: Adults with coeliac disease seem to be at potentially increased risk of early atherosclerosis as suggested by vascular impairment and unfavourable biochemical risk pattern. Chronic inflammation might play a determining role. Gluten abstinence with mucosal normalisation reverts to normal the observed alterations.

Propionyl-L-carnitine improves endothelial function, microcirculation and pain management in critical limb ischemia.

INTRODUCTION: Chronic critical limb ischemia (CLI) is a severe condition of hypo-perfusion of lower limbs, which is associated with inflammation and a pro-coagulative state. It is a disease at high risk of amputation and cardiovascular death. Propionyl-L-carnitine (PLC) is efficacious in improving pain free walking distance in peripheral arterial disease with claudication; it also exerts favorable effects on the arterial wall and on endothelial function. The purpose of this study was to evaluate the effects of PLC on microcirculation, endothelial function and pain relief in patients affected by CLI not suitable for surgical intervention. PATIENTS AND METHODS: We enrolled 48 patients with CLI. Patients were randomized into two groups: the first group was treated with PLC, the second was treated with saline solution. All of them underwent the following tests: laser Doppler flowmetry at the forefoot at rest and after ischemia, trans cutaneous oxygen partial pressure and carbon dioxide partial pressure at the forefoot at rest and after ischemia, endothelium dependent dilation of the brachial artery. All tests were repeated after treatments. Pain was assessed by visual analog pain scale. RESULTS: Endothelium dependent dilation increased after PLC (9.5 ± 3.2 vs 4.9 ± 1.4 %; p < 0.05). Post-ischemic peak flow with laser-Doppler flow increased after PLC. TcPO2 increased, while TcPCO2 decreased after PLC; CO2 production decreased after PLC. VAS showed a significant reduction in pain perception after active treatment. CONCLUSIONS: In CLI patients, PLC can improve microcirculation (post ischemic hyperemia, TcPO2 and TcPCO2 production). PLC also enhances endothelium dependent dilation and reduces analgesic consumption and pain perception.

Effects of smoking on cardiopulmonary baroreceptor activation and peripheral vascular resistance.

PATIENTS AND METHODS: We studied 16 healthy smokers and 16 nonsmokers acting as controls. We subjected smokers and nonsmokers to cardiopulmonary baroreceptor stimulation by studying forearm and common carotid haemodynamic and sympathovagal balance. Smokers repeated the tests after smoking one cigarette. Smokers and controls were subjected to passive elevation of the legs and the trunk in a horizontal position with pressure monitoring and measurement of the calibre and flow in the brachial and common carotid arteries using a colourDoppler ultrasound. We calculated forearm resistance and carotid wall tension. We also studied R-R variability, calculating the ratio between low frequency (LF) and high frequency (HF) R-R interval variability. RESULTS: During stimulation diastolic blood pressure values decreased in controls and in smokers at rest. After smoking one cigarette, smokers showed an increase in systolic and diastolic blood pressure as well as in the heart rate during stimulation. Humeral artery increased the calibre during stimulation in both groups; after cigarette smoking the calibre declined throughout the study phases. Forearm resistance decreased in both groups during stimulation at rest, but increased after cigarette smoking. The LF/HF ratio decreased during stimulation in both groups, and it increased at rest after smoking. Carotid diameter did not change in either group, and wall tension increased in smokers after smoking one cigarette. CONCLUSIONS: Smoking one cigarette increases resistance, impairs baroreflex and increases carotid wall tension in mild smokers. These findings may explain the higher rate of a cardiovascular event in smokers.

Haemodynamic effects of AT1 inhibition and Ca2+-channel blockade in hypertensive patients during isometric stress.

To assess the effects of valsartan and amlodipine on the haemodynamics of forearm circulation in hypertensive patients undergoing isometric stress. A total of 24 patients with essential hypertension were subjected to a double blind-cross-over study. The artery left arm flow (strain gauge plethysmography), distensibility of digital arteries (piezoelectric plethysmography) and blood pressure were measured. District resistance was calculated as the ratio between mean arterial pressure and blood flow. The tests were performed at basal conditions (T0) and after 8 days (T8) of therapy with valsartan (160 mg) or amlodipine (10 mg), at rest and during handgrip (HG); treatments were inverted after 15 days of washout. Valsartan and amlodipine reduced blood pressure after 8 days (P<0.05), handgrip increased systolic and diastolic values and heart rate at T0 and only a slight raising in diastolic values at T8. The recovery time of pressure values was longer in hypertensives treated with amlodipine (P<0.05). The forearm flow increased after HG (at T0 an T8) and increased even further after valsartan (P<0.005). Valsartan increased arteriolar distensibility, expressed by the ratio between time to peak and total time (PT/TT) calculated on the sphygmic wave. Amlodipine did not affect PT/TT ratio, whereas it reduced local resistance (T8 vs T0, P<0.05). The reduction effect of valsartan on resistance was detectable also during handgrip, on the contrary amlodipine did not control the increase. Inhibition of AT1 is able to reduce haemodynamic modifications elicited by isometric stress in hypertensive patients.

Quantitative contrast echocardiographic assessment of collateral derived myocardial perfusion during elective coronary angioplasty.

OBJECTIVE: To determine whether myocardial contrast echocardiography can be used to quantify collateral derived myocardial flow in humans. METHODS: In 25 patients undergoing coronary angioplasty, a collateral flow index (CFI) was determined using intracoronary wedge pressure distal to the stenosis to be dilated, with simultaneous mean aortic pressure measurements. During balloon occlusion, echo contrast was injected into both main coronary arteries simultaneously. Echocardiography of the collateral receiving myocardial area was performed. The time course of myocardial contrast enhancement in images acquired at end diastole was quantified by measuring pixel intensities (256 grey units) within a region of interest. Perfusion variables, such as background subtracted peak pixel intensity and contrast transit rate, were obtained from a fitted gamma variate curve. RESULTS: 16 patients had a left anterior descending coronary artery stenosis, four had a left circumflex coronary artery stenosis, and five had a right coronary artery stenosis. The mean (SD) CFI was 19 (12)% (range 0-47%). Mean contrast transit rate was 11 (8) seconds. In 17 patients, a significant collateral contrast effect was observed (defined as peak pixel intensity more than the mean + 2 SD of background). Peak pixel intensity was linearly related to CFI in patients with a significant contrast effect (p = 0.002, r = 0.69) as well as in all patients (p = 0.0003, r = 0.66). CONCLUSIONS: Collateral derived perfusion of myocardial areas at risk can be demonstrated using intracoronary echo contrast injections. The peak echo contrast effect is directly related to the magnitude of collateral flow.

Sympathetic stimulation using the cold pressor test increases coronary collateral flow.

BACKGROUND: Little is known about the vasomotor function of human coronary collateral vessels. The purpose of this study was to examine collateral flow under a strong sympathetic stimulus (cold pressor test, CPT). METHODS: In 30 patients (62 +/- 12 years) with coronary artery disease, two subsequent coronary artery occlusions were performed with random CPT during one of them. Two minutes before and during the 1 minute-occlusion, the patient's hand was immerged in ice water. For the calculation of a perfusion pressure-independent collateral flow index (CFI), the aortic (Pao), the central venous (CVP) and the coronary wedge pressure (Poccl) were measured: CFI = (Poccl - CVP)/(Pao - CVP). RESULTS: CPT lead to an increase in Pao from 98 +/- 14 to 105 +/- 15 mm Hg (p = 0.002). Without and with CPT, CFI increased during occlusion from 14% +/- 10% to 16% +/- 10% (p = 0.03) and from 17% +/- 9% to 19% +/- 9% (p = 0.006), respectively, relative to normal flow. During CPT, CFI was significantly higher at the beginning as well as at the end of the occlusion compared to identical instants without CPT. CFI at the end of the control occlusion did not differ significantly from the CFI at the beginning of occlusion with CPT. CONCLUSIONS: During balloon occlusion, collateral flow increased due to collateral recruitment independent of external sympathetic stimulation. Sympathetic stimulation using CPT additionally augmented collateral flow. The collateral-flow-increasing effect of CPT is comparable to the recruitment effect of the occlusion itself. This may reflect a coronary collateral vasodilation mediated by the sympathetic nervous system.

Vascular adhesion molecule-1 and markers of platelet function before and after a treatment with iloprost or a supervised physical exercise program in patients with peripheral arterial disease.

Platelet function and levels of vascular adhesion molecule-1 (VCAM-1) were investigated in 24 patients with peripheral arterial disease at Fontaine stage II undergoing a 2 weeks treatment with iloprost (0.5-2 ng/kg/h i.v. infused, 6 h/day) or a 2 weeks supervised physical training, randomly assigned. Patients were studied before (T0) and after (T14) treatments and 10 days later (T24). The adhesion of washed platelets to fibrinogen coated microwells was reduced after treatment both with iloprost (1.9+/-0.4 vs 6.8+/-0.7%; T24 vs T0; M+/-SEM; p<0.05) and physical exercise (3.0+/-1.0 vs 6.7+/-0.7; p<0.05) while adhesion to human plasma coated microwells was reduced only after treatment with iloprost (1.9+/-0.8 vs 5.8+/-0.9; p<0.05). The expression of fibrinogen receptor (glycoprotein IIb/IIIa) on platelets, measured by flow-cytometry was also reduced after iloprost treatment (17.1+/-1.5 vs 31.8+/-4.8 AU; p<0.05) and physical exercise (14.6+/-1.5 vs 34.0+/-3.3; p<0.05). Theurinaryexcretion of platelet thromboxane A2 metabolite 2,3-dinor-thromboxane B2 decreased only in patients treated with iloprost (154.7+/-97.9 vs 256.2+/-106.4 pg mg creatinine(-1); p<0.05). Similarly plasma VCAM-1 was lower in patients who were treated with iloprost (827.7+/-77.4 vs 999.0+/-83.8 ng ml(-1); p<0.05). In conclusion, both iloprost and physical exercise seem to act on reversible phenomena such as the expression of adhesion molecules or ex vivo adhesion, whereas only iloprost reduces thromboxane A2 biosynthesis in vivo. This anti-platelet activity seems to be extended in time and to be associated with an improvement in vascular function.

Relationship of lipoprotein(a) to variables of coagulation in hypertensive subjects.

BACKGROUND: Coagulation factors are independent predictors of cardiovascular damage in the general population. The purpose of this study was to investigate the relationships between general cardiovascular risk factors, lipoprotein(a) (Lp(a)), and some hemostatic variables, and to characterize the isoforms of apolipoprotein(a) (apo(a)) in hypertensive subjects. METHODS: Plasma lipids, apolipoproteins, Lp(a), apo(a) isoforms, fibrinogen, and parameters that directly reflect the coagulation activation were measured in 389 untreated essential hypertensive patients recruited at a hypertension clinic. Hypertensive patients were compared with 323 normotensive controls. RESULTS: In normotensive subjects, Lp(a) concentrations were significantly correlated with fibrinogen (r = 0.138; P < 0.02) but not D-dimer (r = 0.074; not significant). In hypertensive subjects, log Lp(a) concentrations were significantly correlated with age (r = 0.127; P < 0.02), apo-B (r = 0.128; P < 0.02), plasma fibrinogen (r = 0.193; P < 0.001), and fibrin D-dimer (r = 0.200; P < 0.001) levels, but not with body mass index, blood pressure, cholesterol, triglycerides, apo-AI, prothrombin fragment 1 + 2, and antithrombin III. The relationship of Lp(a) with fibrinogen (male: r = 0.198, P < 0.002; female: r = 0.177, P < 0.01) and D-dimer (male: r = 0.211, P < 0.002; female: r = 0.188, P < 0.01) was significant in both sexes, whereas the relationship of Lp(a) with age and apo-B was found only in males. Multivariate analysis showed that both fibrinogen and D-dimer were independently related with Lp(a). Elevated fibrinogen, D-dimer, and Lp(a) levels were significantly and independently associated with clinical evidence of atherosclerotic disease. Apo(a) phenotypes were analyzed to investigate the genetic background of the relationships between Lp(a) and coagulation parameters. In both hypertensive and normotensive subjects, Lp(a) levels were inversely correlated with apo(a) isoform protein size, whereas fibrinogen and D-dimer concentrations were comparable in patients with apo(a) isoforms of different size. CONCLUSIONS: The relationship between Lp(a) and clotting variables is significantly stronger in hypertensive than in normotensive subjects, providing a compelling argument for accelerated progression of atherothrombosis in these patients.

Pulmonary venous flow velocity patterns in 404 individuals without cardiovascular disease.

OBJECTIVE: To determine the pulmonary venous flow velocity (PVFV) values in a large normal population. DESIGN: Prospective study in consecutive individuals. SETTING: University hospital. METHODS: Among 404 normal individuals, the flow velocity pattern in the right upper pulmonary vein was recorded in 315 subjects using transthoracic echocardiography, and in both upper pulmonary veins in 100 subjects using transoesophageal echocardiography. Subjects were divided into five age groups. The PVFV values were compared between transthoracic and transoesophageal echocardiography within the age groups, and intraindividually between the right and left upper pulmonary veins in transoesophageal echocardiography. RESULTS: Normal PVFV values for the right upper pulmonary vein in transthoracic and transoesophageal echocardiography are presented. The duration of flow reversal at atrial contraction was overestimated using transthoracic echocardiography (mean (SD): 96 (21) ms in transoesophageal echocardiography, 120 (28) ms in transthoracic echocardiography, p < 0.0001). Systolic to diastolic peak flow velocity ratio (S:D) increased earlier with advancing age with transoesophageal echocardiography than with transthoracic echocardiography. Similar results were found for the corresponding time-velocity integrals. Data from the left and right upper pulmonary veins differed with respect to onset and deceleration of flow velocities, but not for flow durations or peak velocities. CONCLUSIONS: Normal PVFV values generally show a wide range. The data presented will be of value in assessing left ventricular diastolic function and mitral regurgitation using the PVFV pattern.

Increased fibrinogen levels and hemostatic abnormalities in patients with arteriolar nephrosclerosis: association with cardiovascular events.

Increased plasma fibrinogen levels and hemostatic abnormalities suggestive of a prothrombotic state are present in patients with end-stage renal failure and could contribute to increased cardiovascular morbidity in these patients. We investigated the relationship between abnormalities of the hemostatic system and the degree of renal failure and whether these abnormalities are associated with increased prevalence of cardiovascular events in patients with arteriolar nephrosclerosis. In 425 patients recruited at a hypertension clinic we assessed the renal function by creatinine clearance, urinary protein excretion, and microalbuminuria, the prevalence of atherosclerotic disease, and measured prothrombin time, activated partial thromboplastin time. fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, and antithrombin. Early impairment of renal function (creatinine clearance, 30 to 89 ml/min per 1.73 m2 of body surface area) caused by arteriolar nephrosclerosis was found in 172 patients. Patients with early renal failure were significantly older and had significantly greater values of blood pressure, plasma fibrinogen, F1+2, and D-dimer than patients with normal renal function. Elevated D-dimer and fibrinogen levels were independently associated with the presence of decreased creatinine clearance. Log fibrinogen, log F1+2, and log D-dimer were inversely correlated with creatinine clearance. The prevalence of coronary artery, cerebrovascular, and peripheral vascular disease was significantly greater in patients with mild renal failure than in those with normal renal function. Elevated levels of fibrinogen and D-dimer were associated with the presence of atherosclerotic disease independent of renal function and other risk factors. In conclusion, changes in hemostatic parameters occur early in the course of renal failure in patients with arteriolar nephrosclerosis, suggesting a prothrombotic state that may contribute to the risk for atherosclerotic disease at all levels of renal function.

Activity of cardiopulmonary baroreceptors, peripheral resistance and cutaneous microcirculation in patients with peripheral obstructive arterial disease.

OBJECTIVES: To assess the effects of cardiopulmonary baroreceptors on the haemodynamics of the humeral and common carotid arteries in patients suffering from peripheral artery disease (PAD) and to discover whether the stimulation of these receptors modifies the cutaneous microcirculation in the forearm. DESIGN: We studied a group of patients suffering from peripheral artery disease and two groups as controls. SETTING: Patients were examined at the ambulatory for Vascular Research, Division of Vascular Medicine and Rehabilitation, University of Verona. PATIENTS: We studied 15 patients with peripheral artery disease of the lower limbs at Fontaine stage II (group C), 10 free of arterial pathologies (group B) and 10 young people (group A). MAIN OUTCOME MEASURES: We subjected the patients to passive elevation of the legs and the trunk in a horizontal position with pressure monitoring and measurement of the calibre and flow in the brachial and common carotid arteries using a colourDoppler ultrasound. We also studied the cutaneous microcirculation with laserDoppler flowmetry. RESULTS: During the test, arterial pressure and cardiac frequency remained constant in group A, systolic pressure values showed a slight, but statistically significant increase in group B, whilst the increase in systolic pressure values at this stage was marked in group C. Diastolic pressure values and cardiac frequency remained unchanged in all groups. The calibre of the humeral artery increased in the control groups. Carotid resistance was unchanged in the three groups. Humeral resistance during the test decreased in the two control groups whilst it increased in group C. The number of perfusion units felt in the control groups; no variations in group C. CONCLUSIONS: Our study demonstrates, in patients with peripheral artery disease, a reduction in the activity of the cardiopulmonary baroreceptors with an increase in the humeral resistance during the test and impairment of the mechanisms of cutaneous microcirculatory vasoregulation in the forearm.

Relaxation in hypertrophic cardiomyopathy and hypertensive heart disease: relations between hypertrophy and diastolic function.

AIM: To determine the relation between the extent and distribution of left ventricular hypertrophy and the degree of disturbance of regional relaxation and global left ventricular filling. METHODS: Regional wall thickness (rWT) was measured in eight myocardial regions in 17 patients with hypertrophic cardiomyopathy, 12 patients with hypertensive heart disease, and 10 age matched normal subjects, and an asymmetry index calculated. Regional relaxation was assessed in these eight regions using regional isovolumetric relaxation time (rIVRT) and early to late peak filling velocity ratio (rE/A) derived from Doppler tissue imaging. Asynchrony of rIVRT was calculated. Doppler left ventricular filling indices were assessed using the isovolumetric relaxation time, the deceleration time of early diastolic filling (E-DT), and the E/A ratio. RESULTS: There was a correlation between rWT and both rIVRT and rE/A in the two types of heart disease (hypertrophic cardiomyopathy: r = 0.47, p < 0.0001 for rIVRT; r = -0.20, p < 0.05 for rE/A; hypertensive heart disease: r = 0.21, p < 0.05 for rIVRT; r = -0.30, p = 0.003 for rE/A). The degree of left ventricular asymmetry was related to prolonged E-DT (r = 0. 50, p = 0.001) and increased asynchrony (r = 0.42, p = 0.002) in all patients combined, but not within individual groups. Asynchrony itself was associated with decreased E/A (r = -0.39, p = 0.01) and protracted E-DT (r = 0.69, p < 0.0001) and isovolumetric relaxation time (r = 0.51, p = 0.001) in all patients. These correlations were still significant for E-DT in hypertrophic cardiomyopathy (r = 0.56, p = 0.02) and hypertensive heart disease (r = 0.59, p < 0.05) and for isovolumetric relaxation time in non-obstructive hypertrophic cardiomyopathy (n = 8, r = 0.87, p = 0.005). CONCLUSIONS: Non-invasive ultrasonographic examination of the left ventricle shows that in both hypertrophic cardiomyopathy and hypertensive heart disease, the local extent of left ventricular hypertrophy is associated with regional left ventricular relaxation abnormalities. Asymmetrical distribution of left ventricular hypertrophy is indirectly related to global left ventricular early filling abnormalities through regional asynchrony of left ventricular relaxation.

Relationship of fibrinogen levels and hemostatic abnormalities with organ damage in hypertension.

Elevated plasma levels of fibrinogen and activated coagulation pathways are risk factors of cardiovascular disease in the general population. In a cross-sectional study of a case series, we investigated the relationship between fibrinogen and hemostatic markers with target-organ damage (TOD) in patients with arterial hypertension. Prothrombin time, partial thromboplastin time, fibrinogen, fibrin D-dimer, prothrombin fragment 1+2 (F1+2), and antithrombin III were measured in 352 untreated patients with mild to moderate essential hypertension and 92 normotensive controls. Staging of TOD was assessed according to W.H.O. guidelines by clinical evaluation and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries. F1+2 concentrations were significantly greater in hypertensive patients than normotensive controls and were positively correlated with blood pressure. Age, blood pressure levels, duration of hypertension, smoking, HDL-cholesterol, triglycerides, and plasma fibrinogen, fibrin D-dimer, and F1+2 levels were significantly related to the presence and severity of TOD in univariate analysis. Plasma fibrinogen and D-dimer levels were related to organ damage independent of age, blood pressure, duration of hypertension, and smoking status. Separate analysis indicated significant association of fibrinogen and D-dimer levels with cardiac, cerebrovascular, peripheral vascular, and renal damage. In conclusion, elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence and severity of TOD in patients with essential hypertension and may contribute to the development of atherosclerotic disease in these patients.