Dimitrios Tousoulis

Inflammatory and thrombotic mechanisms in coronary atherosclerosis

Many molecular and cellular mechanisms link inflammation and haemostatic mechanisms. Inflammation, and perhaps chronic infection, may play important roles in the initiation and progression of atherosclerosis. Atherosclerotic lesions are heavily infiltrated by cellular components associated with inflammation (macrophages and T lymphocytes), and acute plaque rupture is also associated with inflammatory components. Several markers of systemic inflammation may predict future cardiovascular events in apparently healthy subjects as well as in patients with chronic and acute syndromes. There may thus be therapeutic potential in modifying the atherosclerotic, vasomotor, and thrombotic components of ischaemic heart disease.

Incremental Predictive Value of Carotid Inflammation in Acute Ischemic Stroke

Background and Purpose— Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (&Dgr;T), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification. Methods— Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR. Results— In total, 50 patients were included in the study. Culprit carotid arteries had higher &Dgr;T compared with nonculprit (0.93±0.58 versus 0.58±0.35°C; P<0.001). The addition of &Dgr;T to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768; Pdif=0.05). Conclusions— Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

BACKGROUND Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications. METHODS SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749. FINDINGS Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group. INTERPRETATION Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation. FUNDING Medtronic.

Effects of atorvastatin on reactive hyperaemia and the thrombosis–fibrinolysis system in patients with heart failure

Objective: To investigate the effects of short term atorvastatin treatment on forearm vasodilatory response to reactive hyperaemia (RH%) and on components of the thrombosis–fibrinolysis system (antithrombin III, proteins and S, factors V and VII, von Willebrand factor, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1)) in patients with heart failure. Patients and methods: 35 patients with heart failure were enrolled in this study; 17 patients received atorvastatin 10 mg/day and 18 patients received no statin for four weeks. Forearm blood flow (FBF) was measured by venous occlusion strain gauge plethysmography. RH% and forearm vasodilatory response to nitrate were defined as the percentage change of FBF from rest to the maximum flow during reactive hyperaemia and after nitrate administration, respectively. Plasma concentrations of antithrombin III, protein C, protein S, factor V, factor VII, von Willebrand factor, tPA, and PAI-1 were determined before and after treatment. Results: Maximum hyperaemic FBF remained unchanged in both groups. Baseline FBF was slightly but not significantly decreased in the atorvastatin treated group. RH% was significantly increased only in the atorvastatin treated group, from mean (SD) 42.44 (18.9)% to 83.7 (36.1)% (p < 0.01). Plasma concentrations of antithrombin III (from mean (SD) 81.7 (11.37)% to 73.5 (13.8)%), protein C (from mean (SD) 88.3 (26.9)% to 63.9 (25.0)%), factor V (from mean (SD) 126.2 (33.4)% to 94.9 (29.8)%), tPA (from median (25th–75th percentile) 11.68 (8.60–20.95) ng/ml to 10.30 (8.65–15.12) ng/ml), and PAI-1 (from median (25th–75th percentile) 3.10 (2.15–4.40) IU/l to 1.90 (0.75–3.0) IU/l) were significantly decreased in the atorvastatin treated group (p < 0.05) but not in the control group. Plasma concentrations of von Willebrand factor, factor VII, and protein S remained unaffected in both groups. Conclusion: Atorvastatin did not change the maximum hyperaemic flow, although it decreased plasma concentrations of antithrombin III, protein C, factor V, tPA, and PAI-1 in patients with heart failure. Therefore, short term treatment with atorvastatin may affect the expression of both endothelium and liver derived components of the thrombosis–fibrinolysis system in patients with heart failure.

New insights by optical coherence tomography into the differences and similarities of culprit ruptured plaque morphology in non-ST-elevation myocardial infarction and ST-elevation myocardial infarction.

BACKGROUND Plaque rupture is the most common pathology associated with non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). However, limited data are available regarding ruptured plaque morphology and its relationship with the clinical syndrome. This study aimed (1) to provide a morphologic description of ruptured culprit lesions by optical coherence tomography (OCT) and (2) to investigate whether ruptured plaque morphology differs between NSTEMI and STEMI. METHODS We included 84 consecutive patients with NSTEMI and STEMI undergoing OCT study of the culprit lesion. We identified patients with plaque rupture in the OCT study and used them as the study population. Qualitative and quantitative analysis of ruptured plaque morphology was then performed, followed by a comparison of the morphological characteristics in patients with STEMI and NSTEMI. RESULTS Fifty-five patients (70.5%) with rupture, 25 with NSTEMI, and 30 with STEMI were used for analysis. Plaque was ruptured at the minimal lumen in 34.5% of the cases, whereas 69% of the ruptures occurred at the plaque shoulder. Ruptured cap thickness was ≤90 μm in 96% of ruptured plaques. Patients with NSTEMI had greater minimal luminal area (P < .001), less lipid content (P = .01), and lower rupture length (P < .001) and length of missing fibrous cap (P < .05) compared with patients with STEMI. CONCLUSIONS Rupture of the plaque in myocardial infarction usually occurs in sites different than the minimal lumen and at the shoulder of areas with fibrous cap measuring ≤90 μm. Patients with STEMI have greater plaque disruption and smaller minimal lumen area than patients with NSTEMI.

Anti-Inflammatory Treatment With Colchicine in Acute Myocardial Infarction: A Pilot Study

Background— Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST‐segment‐elevation myocardial infarction. Colchicine is a substance with potent anti‐inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results— Patients presenting with ST‐segment‐elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase‐myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST‐segment‐elevation myocardial infarction. One hundred fifty‐one patients were included (60 in the MRI substudy). The area under the creatine kinase‐myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754‐6940) ng·h‐1·mL‐1 in the colchicine group in comparison with 6184 (IQR, 4456‐6980) ng·h‐1·mL‐1 in controls (P<0.001). Indexed MRI‐late gadolinium enhancement‐defined infarct size was 18.3 (IQR, 7.6‐29.9) mL/1.73 m2 in the colchicine group versus 23.2 (18.5‐33.4) mL/1.73 m2 in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0‐25.3) % and 19.8 (IQR, 13.7‐29.8) %, respectively (P=0.034). Conclusions— These results suggest a potential benefit of colchicine in ST‐segment‐elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285.

Exercise Blood Pressure Response, Albuminuria and Arterial Stiffness in Hypertension

BACKGROUND A hypertensive response to exercise is associated with high cardiovascular risk, whereas the data about its relation to surrogates of subclinical atherosclerosis are scarce. We investigated the relationships of a hypertensive response to exercise with urinary albumin excretion and arterial stiffness in hypertensives. METHODS There were 171 untreated males (mean age 52 years, all Caucasian) with stage I-II essential hypertension and a negative treadmill exercise test divided into those with a hypertensive response to exercise (n=48) (peak exercise systolic blood pressure > or =210 mm Hg) and to those with normal blood pressure response (n=123). Albumin-to-creatinine ratio values were determined as the mean of 3 nonconsecutive morning spot urine samples, and arterial stiffness was evaluated on the basis of carotid-to-femoral pulse wave velocity. RESULTS Patients with a hypertensive response to exercise compared with those with normal blood pressure response exhibited greater log albumin-to-creatinine ratio (1.52+/-0.59 vs 0.97+/-0.33 mg/g) and higher pulse wave velocity (8.7+/-1.6 vs 7.7+/-1.2 m/s), independent of potentially confounding demographic and clinical factors. Resting systolic blood pressure (odds ratio [OR] 1.11, 95% confidence interval [CI], 1.06-1.16), body mass index (OR 1.12, 95% CI, 1.02-1.23), resting heart rate (OR 0.96, 95% CI, 0.93-0.99), and albumin-to-creatinine ratio (OR 7.45, 95% CI, 2.54-21.83) were independently associated with a hypertensive response to exercise. CONCLUSION A hypertensive response to exercise is related to augmented albumin-to-creatinine ratio and arterial stiffness, reflecting accelerated subclinical atherosclerosis. The association of albumin excretion with exercise blood pressure response suggests that albuminuria constitutes an important factor in the interpretation of the hypertensive response to exercise-associated risk.

First In Vivo Application of Microwave Radiometry in Human Carotids: A New Noninvasive Method for Detection of Local Inflammatory Activation

OBJECTIVES This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings. BACKGROUND Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues. METHODS Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (ΔT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed. RESULTS ΔT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher ΔT compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher ΔT compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher ΔT compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher ΔT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01). CONCLUSIONS MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation.

Microalbuminuria is closely related to impaired arterial elasticity in untreated Patients with essential hypertension

Background/Aim: Although an increase in urinary albumin excretion (UAE) and impaired arterial mechanics have both been identified as predictors of cardiovascular events in hypertensive subjects, the interaction between arterial pressure wave contour and microalbuminuria (MA) has not been well defined. Methods: MA was determined from three nonconsecutive 24-hour urine samples in a group of 130 untreated hypertensive subjects. The arterial pressure waveform was recorded by carotid artery applanation tonometry and expressed as the augmentation index (AIx), the ratio of the augmented pressure (the difference between the early and late systolic shoulder) to pulse pressure. The subjects were classified according to their arterial pressure waveform into type A (Aix >0.12), type B (0 < Aix ≤ 0.12), and type C (Aix ≤ 0). Results: Patients with MA (n = 48) were matched for demographics with those without MA (n = 82). Subjects with MA had significantly increased left ventricular mass index (101 vs. 85 g/m2, p < 0.0001), blood pressure (164/100 vs. 146/94 mm Hg, p < 0.005), and AIx (0.16 vs. 0.04, p < 0.03). Hypertensive patients with type A arterial pressure waveform had significantly increased values of the log 24-hour UAE as compared with those with type B and C pressure waveforms. The proportion of patients with type A waveform was significantly higher in microalbuminuric patients as compared with normoalbuminuric patients (67 vs. 33%, p < 0.005); in contrast, the proportion of patients with type B or C waveform was significantly higher in normoalbuminuric patients as compared with microalbuminuric patients (68 vs. 36%, p < 0.005). By multiple regression analysis and analysis of variance, it was revealed that an increased AIx was significantly and independently associated with increased values of UAE (p < 0.05). Conclusions: Hypertensive patients with MA exhibited an earlier systolic augmentation of the arterial pressure, reflecting a more impaired arterial elasticity as compared with hypertensive subjects without MA. These findings suggest that worse cardiovascular outcomes may be associated with the presence of an increased UAE in hypertensive subjects.

Microalbuminuria is associated with unfavourable cardiac geometric adaptations in essential hypertensive subjects

We sought in this study to examine the relationship between microalbuminuria and cardiac geometry since a slight increased urinary albumin excretion (UAE) and increased left ventricular (LV) mass have both been identified as predictors of cardiovascular events in hypertensive subjects. For this purpose, microalbuminuria was determined in three non-consecutive 24-h urine samples as UAE of 20–200 mg/24 h in a group of 249 untreated hypertensive subjects. Echocardiographic classification of patients into LV geometric patterns was based on relative wall thickness values and on gender-specific values for LV mass index (LVMI). The group of patients with microalbuminuria (n = 119) was matched for age, sex, body mass index, smoking status and plasma cholesterol level with the group of patients without microalbuminuria (n = 130). Subjects with microalbuminuria had significantly increased LVMI (111 vs 90 g/m2, P < 0.0001), relative wall thickness (0.46 vs 0.41, P < 0.001) and office systolic and diastolic blood pressure (161 vs 148 and 101 vs 97 mmHg, respectively, P < 0.005). For the pooled population, UAE was positively correlated to LVMI (r = 0.46, P < 0.001) and relative wall thickness (r = 0.47, P < 0.001). In the entire population, normal LV geometry, concentric LV remodelling, eccentric and concentric LV hypertrophy was found in 34%, 33%, 12% and 21%, respectively. The prevalence of normal LV geometry was significantly higher in normoalbuminuric compared with microalbumnuric subjects (55 vs 14%, P < 0.001) while the prevalence of concentric LV hypertrophy was significantly higher in microalbuminuric compared with normoalbuminuric subjects (32 vs 5%, P < 0.0001). Multiple regression analysis revealed that concentric LV hypertrophy was significantly associated with increased values of UAE and mean arterial pressure. In conclusion, the higher prevalence of unfavourable LV geometric patterns in hypertensive subjects with microalbuminuria compared with those without microalbuminura, may account for the worse cardiovascular outcomes associated with the presence of an increased UAE in hypertensive subjects.