Immunomediated and ischemia-independent inflammation of coronary microvessels in unstable angina.

This study investigated whether the myocardium is involved in the acute inflammatory reaction associated with bursts of unstable angina (UA). We looked for the presence of activated DR+ inflammatory cells and the expression patterns, localization, and immunostaining identification of genes for cytokines (IL-1beta, TNF-alpha, IL-6, and IFN-gamma), MCP-1, and iNOS in the left ventricle biopsies from 2-vessel disease anginal patients, 24 with UA and 12 with stable angina (SA), who underwent coronary bypass surgery. Biopsy specimens from 6 patients with mitral stenosis who underwent valve replacement were examined as control hearts (CHs). Plasma levels of IL-2 soluble receptor (sIL-2R) were measured as a marker of systemic immune reaction. In CHs, DR+ cells were undetectable, and cytokine and iNOS mRNA expression were negligible. UA patients had higher sIL-2R levels than SA patients (P<0.01), and their biopsy specimens showed both numerous DR+ cells identified as lymphocytes, macrophages, endothelial cells, and elevated expression levels of cytokine and iNOS genes (from 2.4- to 6.1-fold vs SA; P<0.01). Cytokine and iNOS genes and proteins were localized in endothelial cells without involvement of myocytes. IL-1beta and MCP-1 mRNAs were nearly undetectable. No significant differences were found in the number of DR+ cells, levels of cytokine, and iNOS genes between potentially ischemic and nonischemic left ventricle areas. In SA specimens, DR+ cells were very rare and only mRNAs for TNF-alpha and iNOS genes were overexpressed versus CHs. These results indicated that an acute immunomediated inflammatory reaction, essentially involving coronary microvessels, is demonstrable in UA patients.

Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component.

Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-alpha, IL-6, IFN-gamma, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-alpha, IL-6, and iNOS, and, to a lesser extent, of IFN-gamma genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.

Thromboxane inhibition improves renal perfusion and excretory function in severe congestive heart failure.

OBJECTIVES: The aim of this study was to evaluate whether thromboxane inhibition can favorably affect renal perfusion and clinical conditions in patients affected by severe heart failure. BACKGROUND: The renal formation of the vasoconstrictor thromboxane A(2) (TxA(2)) is increased during cardiac failure. METHODS: By oral administration of picotamide (a renal TxA(2) synthase and TxA(2)/prostaglandin H(2) receptor inhibitor), we blocked renal TxA(2). Fourteen patients in New York Heart Association functional class IV were studied according to a randomized, double-blinded, cross-over design. Each of the two eight-day periods of testing was preceded by a three-day period during which certain vasoactive medications were stopped. RESULTS: Daily 24-h total urinary thromboxane B(2) (TxB(2)), the stable metabolite of TxA(2), dropped at the end of picotamide treatment (p < 0.01 vs. baseline). Compared with placebo, effective renal plasma flow and the glomerular filtration rate increased (p < 0.01 and p < 0.05, respectively), thus leading to a significant decrease in the filtration fraction (p < 0.01). Renal vascular resistance decreased consistently (p < 0.01). In all patients, picotamide treatment was associated with an increase in diuresis and natriuresis (p < 0.001 vs. baseline). Plasma creatinine decreased (p < 0.05 vs. baseline). Patients also showed improvement in several clinical parameters, including a significant decrease in both pulmonary and venous pressure (p < 0.01 vs. baseline). CONCLUSIONS: These results indicate that renal thromboxane formation plays an important role in renal vascular resistance in patients with severe heart failure, such as those described in the present study. Inhibition of TxA(2) improves renal hemodynamics and kidney function and favorably affects indexes of cardiac performance.

Exaggerated myocardial oxLDL amount and LOX-1 receptor over-expression associated with coronary microvessel inflammation in unstable angina.

The pathophysiological relationship between coronary atherosclerosis and coronary microvessels remains undefined and the specific causative role of oxidatively modified low density lipoprotein (oxLDL) in human atherosclerosis is debated. The purposes of this study are to investigate whether coronary microvessels are involved in coronary atherosclerosis and whether increased myocardial oxLDL amount can be associated with coronary microvessel inflammation. A combination of immunohistochemical, RT-PCR and real-time PCR studies performed on myocardial biopsy specimens from patients with mitral stenosis (control hearts, CHs) and from unstable and stable angina patients (UAP and SAP), demonstrated that myocardial oxLDL was associated with a chronic low-grade inflammation in SAP and with a severe high grade inflammation in UAP. oxLDL amount was notably higher in UAP than in SAP and in UAP the high grade of inflammation was correlated with the increased amount of oxLDL in endothelial cells and macrophages. The exaggerated amount of oxLDL in UAP and the interaction of oxLDL with lectin-like oxLDL (LOX-1) receptor are amplified by the activation of transcriptional factor octamere 1 (OCT-1) with consequent activation of a series of inflammatory endothelial feed-back mechanisms resulting in LOX-1 gene over-expression, endothelial inflammation as well as uncontrolled nuclear factor kappa B (NFkB) activation. Moreover, in UAP genes for signal transducer and activator transcriptional factor 1α (STAT1α), angiotensin converting enzyme (ACE) and numerous pro-inflammatory cytokines were over-expressed. The present results may have clinical relevance because they show that coronary atherosclerosis is a disease not confined to the large arteries but involving the whole coronary tree. In UAP the exaggerated amount of myocardial oxLDL is associated with widespread high grade microvessel inflammation.

Abnormal pressure passive dilatation of cerebral arterioles in the elderly with isolated systolic hypertension.

The aim of this study was to investigate the cerebrovascular adaptability to 2 sequential pressor stimuli in elderly patients with isolated systolic hypertension. Ten healthy elderly normotensive subjects (68 to 82 years), 10 elderly subjects with isolated systolic hypertension (63 to 82 years), and 10 young normotensive subjects (24 to 40 years) took part in the study. A pressor reaction, using sequential cold pressor and handgrip stimulation, was induced. The cerebrovascular response to the pressor stimulation was measured by transcranial Doppler determination of the mean flow velocity in the middle cerebral arteries. In all of the subjects, blood pressure increased during handgrip (+12 mm Hg, P<0.001 in the young; +18 mm Hg, P<0.01 in the elderly normotensive subjects; +19 mm Hg, P<0.001 in the hypertensive patients versus baseline). In the hypertensive subjects, the pressure increase persisted well into the recovery period. The pressure increase caused a significant increase in mean flow velocity in the middle cerebral arteries only in the elderly subjects. Cold pressor test increased blood pressure in all of the subjects during stimulation and the first 2 minutes of the recovery period (at whole-curve ANOVA: F=22.03, P<0.001 in the young participants; F=18.3, P<0.001 in the normotensive elderly; and F=13.04, P<0.001 in the hypertensive elderly). Mean flow velocity in the middle cerebral arteries significantly increased only in the hypertensive subjects. In the elderly hypertensive patients, the cerebrovascular reaction to adrenergic stimuli was more impaired than in the elderly normotensive subjects. This event can amplify the pressure insult on cerebral hemodynamics and increase the predisposition to cerebral damage, such as vascular cognitive impairment or stroke.

Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study.

AIMS: Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD). METHODS AND RESULTS: A total of 1209 adults aged 40-75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31-0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance. CONCLUSION: Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.