Differential expression of vascular smooth muscle-modulating microRNAs in human peripheral blood mononuclear cells: novel targets in essential hypertension.

Vascular smooth muscle cell (VSMC) phenotypic plasticity has a critical role in the pathophysiology of arterial remodeling in essential hypertension. MicroRNAs are emerging as potential biomarkers and therapeutic targets in cardiovascular disease. We assessed the expression levels of the microRNAs miR-143, miR-145, miR-21, miR-133 and miR-1, which are implicated in VSMC phenotypic modulation, in 60 patients with essential hypertension and 29 healthy individuals. All patients underwent 24-h ambulatory blood pressure (BP) monitoring. MicroRNA levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed lower miR-143 (2.20±0.25 versus 4.19±0.57, P<0.001), miR-145 (13.51±1.73 versus 22.38±3.31, P=0.010) and miR-133 (8.15±1.32 versus 37.03±8.18, P<0.001) and higher miR-21 (3.08±0.32 versus 2.06±0.31, P=0.048) and miR-1 (33.94±5.19 versus 12.35±2.13 P=0.006) expression levels compared with controls. In hypertensive patients, we observed correlations of miR-143 (r = -0.380, P=0.003), miR-145 (r=-0.405, P=0.001), miR-21 (r=-0.486, P<0.001) and miR-133 (r=0.479, P<0.001) expression levels with 24-h diastolic BP. Furthermore, we observed correlations of miR-21 (r=-0.291, P=0.024), miR-1 (r=-0.312, P=0.015) and miR-133 (r=0.310, P=0.016) levels with the dipping status. Associations of miR-143 (r=-0.292, P=0.025), miR-145 (r=-0.399, P=0.002), miR-21 (r=-0.343, P=0.008) and miR-133 (r=0.370, P=0.004) levels with 24-h mean pulse pressure were also found. Our data provide important evidence that VSMC-modulating microRNAs are closely related to essential hypertension in humans and they may represent potential therapeutic targets in essential hypertension.

Arterial stiffness in hypertensives in relation to expression of angiopoietin-1 and 2 genes in peripheral monocytes.

Angiopoietins (Angs) are important angiogenic and endothelial cell growth factors with many functions, including influence on the vascular wall. Pulse-wave velocity (pwv) is an independent marker of cardiovascular adverse outcome in hypertensives, although all the pathophysiological mechanisms that affect it have not yet been determined. We investigated the relationship between arterial stiffness and Ang-1 and Ang-2 gene expression in the peripheral blood monocytes of hypertensive patients. We studied 53 patients who had untreated grade-1 or grade-2 essential hypertension and no indications of other organic heart disease. Carotid-femoral (c-f) and carotid-radial (c-r) artery waveforms were measured and pwv was determined. The monocytes were isolated using anti-CD14(+) antibodies and mRNAs were estimated by real-time quantitative reverse transcription-PCR. Ang-1 gene expression was strongly correlated with both c-f-pwv (r=0.952, P<0.001) and c-r-pwv (r=0.898, P<0.001). Similarly, Ang-2 gene expression was significantly correlated with both c-f-pwv (r=0.471, P=0.002) and c-r-pwv (r=0.437, P=0.003). Our data provide important evidence that Ang-1 and Ang-2 gene expression levels in peripheral monocytes are closely related with pwv in patients with essential hypertension. This positive correlation may suggest a link between angiogenesis and arterial stiffness in those patients.

Effect of angiotensin-converting enzyme inhibitors on systemic inflammation and myocardial sympathetic innervation in normotensive patients with type 2 diabetes mellitus.

Diabetes mellitus (DM) may cause an increase in the inflammatory status and oxidative stress as well as sympathetic nervous system overactivity, even in the absence of any other organic heart disease. We investigated the effect of perindopril, an angiotensin-converting enzyme inhibitor (ACE-i), on indexes of systemic inflammation and oxidative stress in normotensive patients with type 2 DM. We also examined the effect of the drug on the disturbances of left ventricular myocardial adrenergic innervation that may be seen in these patients. We studied 62 normotensive patients with type 2 DM, who were randomized to receive perindopril (n=32) or placebo (n=30). At the start of the study and after 6 months' therapy blood samples were taken to evaluate total peroxides (TP), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha), and the patients underwent a (123)I-metaiodobenzylguanidine myocardial scintigraphy study. ACE-i caused a significant reduction in levels of cytokines and TP (P<0.001 for IL-6 and TNF-alpha, P=0.001 for TP). There was also a reduction in total defect score (P<0.001) and the heart to mediastinum ratio at 10 min and 4 h was improved (P<0.001 for both). No significant alterations were observed in the placebo group. Our data indicate that the addition of ACE-i to the medication of normotensive diabetic type 2 patients may improve the disturbed myocardial adrenergic innervation, the systemic inflammatory status and oxidative stress. Our findings indicate the cardioprotective action of ACE-i and suggest that earlier treatment might be appropriate in those patients.

Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: relationship to regional wall motion and myocardial perfusion abnormalities.

BACKGROUND: Iodine 123-labeled metaiodobenzylguanidine (MIBG) has been used to study cardiac adrenergic nerve activity. Cardiac MIBG uptake is diminished in patients with heart failure. However, it is not known how this reduction is related to regional abnormalities of myocardial wall motion or perfusion. METHODS AND RESULTS: We studied 24 patients with idiopathic dilated cardiomyopathy (ejection fraction <45%) and 15 healthy control subjects using I-123 MIBG cardiac imaging, echocardiographic assessment of wall motion abnormalities, technetium 99m sestamibi perfusion scintigraphy, and hemodynamic assessment. Cardiac MIBG was significantly correlated with ejection fraction (r = 0.67), cardiac index (r = 0.57), left ventricular wall motion score index (r = -0.68), and systolic wall stress (r = -0.61). MIBG was lower in patients than in control subjects (1.43 +/- 0.19 vs 2.05 +/- 0.02; P <.01), whereas the washout rate was higher (P <.01). Moreover, a significant correlation was found between the reduction in MIBG uptake and the severity of echocardiographic wall motion abnormalities in the anterior wall (r = 0.543), apex (r = 0.530), and septum (r = 0.675), as well as with the severity of decrease in resting myocardial perfusion in the anterior wall (r = 0.480) and septum (r = 0.580). CONCLUSIONS: Patients with idiopathic dilated cardiomyopathy show not only global but also regional abnormalities of cardiac sympathetic innervation. The severity of these changes is partially correlated with abnormalities of regional wall motion and myocardial perfusion.

Pulmonary tumor embolism from primary cardiac B-cell lymphoma.

We report the case of a 54-year-old man with pulmonary embolism during convalescence from "idiopathic" pericarditis. A transthoracic echocardiographic examination indicated a large mass within the right atrium. Subsequently, he died from refractory hypotension. On autopsy, two large whitish nodules were found in the right atrium; there was also nodular epicardial infiltration. Both lungs showed multiple, grossly visible tumor emboli with pulmonary infarction and no evidence of conventional thromboembolism. This is the first report of pulmonary tumor embolism due to large cell B-cell primary cardiac lymphoma. Refractory unexplained pericardial effusion, pulmonary embolism without risk factors for venous thrombosis, and/or the existence of a mass in the right heart should arouse clinical suspicion for this rare malignancy.

Assessment of left ventricular ejection dynamics in patients with coronary artery disease during dipyridamole-stress Doppler echocardiography.

OBJECTIVES: To investigate the contribution of Doppler-echocardiographically derived aortic indexes of left ventricular systolic function during dipyridamole-stress to the diagnosis of coronary artery disease (CAD). DESIGN: This was a clinical study. METHODS: Echocardiographic studies under baseline and peak dipyridamole stresses were performed on 15 normal subjects and 32 patients with angiographically confirmed CAD. Peak Doppler velocity, acceleration, and acceleration time of the ascending aorta, as well as segmental left ventricular wall motion, were analyzed. RESULTS: The sensitivity, specificity and overall accuracy of wall-motion abnormalities induced by dipyridamole for the detection of CAD were 62.5, 100, and 74.5%, respectively. When wall-motion abnormalities were combined with the percentage changes in peak aortic velocity and acceleration, the overall sensitivities were 84.38 and 78.15%, respectively, the specificities were 66.7 and 80.00%, respectively, and the accuracy was 78.72% for both models. When all three parameters were combined, the sensitivity, specificity and overall accuracy of the method were 87.5, 86.7, and 87.2%, respectively. CONCLUSIONS: Doppler-echocardiographically derived aortic indexes of left ventricular systolic function during dipyridamole stress could be a useful adjunct to two-dimensional echocardiography by improving its sensitivity in the diagnosis of CAD.