Peri-interventional coronary vasomotion.

A percutaneous coronary intervention (PCI) is a unique condition to study the effects of ischemia and reperfusion in patients with severe coronary atherosclerosis when coronary vasomotor function is compromised by loss of endothelial and autoregulatory vasodilation. We studied the effects of intracoronary non-selective α-, as well as selective α(1)- and α(2)-blockade in counteracting the observed vasoconstriction in patients with stable and unstable angina and in patients with acute myocardial infarction. Coronary vasoconstriction in our studies was a diffuse phenomenon and involved not only the culprit lesion but also vessels with angiographically not visible plaques. Post-PCI vasoconstriction was reflected by increased coronary vascular resistance and associated with decreased LV-function. α (1)-Blockade with urapidil dilated epicardial coronary arteries, improved coronary flow reserve and counteracted LV dysfunction. Non-selective α-blockade with phentolamine induced epicardial and microvascular dilation, while selective α(2)-blockade with yohimbine had only minor vasodilator and functional effects. Intracoronary α-blockade also attenuated the no-reflow phenomenon following primary PCI. This article is part of a Special Issue entitled "Coronary Blood Flow".

Non infective severe aortic paravalvular leakage 7 years after surgery: the role of suture technique.

We report a case of redo aortic prosthesis replacement for a severe paravalvular leak (PVL) in a man operated with continuous suture technique 7 years earlier. The severe aortic regurgitation was due to the rupture of the suture. In spite of operations to replace malfunctioning heart valves are common procedures and performed all over the world from more than 50 years, there is still an open debate about the most suitable suture technique. In this case report, we'll discuss if the suture technique has a role in preventing or leading complications as severe PVL.

Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients' skin which are normalized by kidney-pancreas transplantation.

BACKGROUND: In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold. METHODS AND FINDINGS: We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase delta chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant. CONCLUSIONS: Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.

Disproportionate hyperproinsulinemia, beta-cell restricted prohormone convertase 2 deficiency, and cell cycle inhibitors expression by human islets transplanted into athymic nude mice: insights into nonimmune-mediated mechanisms of delayed islet graft failure.

To learn more about nonimmune-mediated islet graft failure, we transplanted different preparations (preps) of isolated human islets under the kidney capsule of streptozotocin (STZ)-diabetic nude mice. One month after the implantation of 1,000 or 2,000 islets, grafts were harvested for morphological, immunohistochemical, and ultrastructural analysis. Only a single islet prep cured the diabetes out of all the recipients, while the remaining preps showed only partial function after the implantation of 2,000 islets. Transplanted mice showed high circulating proinsulin levels but, with the exclusion of those bearing curative grafts, relatively low mature insulin levels. Engrafted beta-cells showed positive carboxypeptidase E (CPE) and prohormone convertase 1 (PC1) staining, while prohormone convertase 2 (PC2) was undetectable. In contrast, PC2 was abundantly expressed by engrafted alpha-cells. Moreover, engrafted beta-cells did not show evidence of replication, and preapoptotic beta-cells, with intra- and extracellular amyloid deposition, were detected with electron microscopy. Cell cycle inhibitors p16(INK4), p21(WAF1), and p27(Kip1) were abundantly expressed in the islet grafts and showed a predominant nuclear localization. In conclusion, diabetic nude mice transplanted with human islets showed disproportionate hyperproinsulinemia and graft evidence of beta-cell restricted PC2 depletion, amyloid deposition and beta-cell death, and lack of beta-cell replication with nuclear translocation of p27(Kip1) and p21(WAF1) that together may contribute to delayed graft failure.

Impaired bradykinin response to ischaemia and exercise in patients with mild congestive heart failure during angiotensin-converting enzyme treatment. Relationships with endothelial function, coagulation and inflammation.

Inflammation and endothelial dysfunction play important roles in the pathophysiology of congestive heart failure (CHF), and the peptide bradykinin, generated during inflammation, may act as a defence mechanism by inducing vasodilation. Plasma bradykinin levels are increased in experimental heart failure but low in patients with advanced chronic CHF despite treatment with angiotensin-converting enzyme (ACE) inhibitors. It is not currently known how bradykinin behaves in less severe phases of CHF controlled by long-term ACE inhibitor treatment. We studied 10 male patients with clinically stable chronic CHF [New York Heart Association (NYHA) class II] on long-term ACE inhibitor treatment and 10 normal sex- and age-matched control subjects. High performance liquid chromatography/radioimmunoassay methods were used to evaluate plasma levels of bradykinin in relation to an array of parameters of endothelial function, coagulation and inflammation before and after stimuli of forearm arterial occlusion and physical exercise. CHF patients had higher levels of bradykinin (P = 0.008), activated factor XII (P = 0.049), interleukin-6 (P = 0.050) and tumour necrosis factor receptor II (sTNFRII) (P = 0.026) than controls. Arterial occlusion and exercise significantly increased bradykinin and von Willebrand factor levels in controls but not in CHF patients. The increase in brachial artery diameter after arterial occlusion was less in CHF patients (P = 0.036) and inversely related to baseline plasma levels of bradykinin (r = -0.855, P = 0.002) and sTNFRII (r = -0.780, P = 0.008). NYHA class II CHF patients during long-term treatment with ACE inhibitors have increased bradykinin levels and signs of inflammation. They are unable to respond adequately to stimuli of ischaemia and physical exercise which both require vasodilation.

Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role of oral anticoagulants and successful heart transplantation.

Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and inflammation, but it is not known how these abnormalities are related, whether they are modified by oral anticoagulants (OAT), or if they persist after successful heart transplantation. We studied 25 patients with CHF (New York Heart Association class IV, 10 of whom underwent heart transplantation) and 25 age- and sex-matched healthy controls by measuring their plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelial-selectin (E-selectin) and thrombomodulin. CHF patients had higher plasma levels of TAT, D-dimer, t-PA, fibrinogen, VWF, TNF, IL-6, sTNFRII, sVCAM-1 (P = 0.0001), sICAM-1 (P = 0.003) and thrombomodulin (P = 0.007) than controls. There were significant correlations (r = 0.414-0.595) between coagulation, fibrinolysis, endothelial dysfunction and inflammation parameters, which were lower in those patients treated with OATs. Heart transplantation led to reductions in fibrinogen (P = 0.001), VWF (P = 0.05), D-dimer (P = 0.05) and IL-6 levels (P = 0.05), but all the parameters remained significantly higher (P = 0.01-0.0001) than in the controls. Advanced CHF is associated with coagulation activation, endothelial dysfunction and increased proinflammatory cytokine levels. Most of these abnormalities parallel each other, tend to normalize in patients treated with OATs and, although reduced, persist in patients undergoing successful heart transplantation, despite the absence of clinical signs of CHF.

The alpha1-adrenergic blocker urapidil improves contractile function in patients 3 months after coronary stenting: a randomized, double-blinded study.

BACKGROUND: The recovery of left ventricular function (LVF) after revascularization takes time. alpha-Adrenergic blockade acutely improves coronary blood flow and LVF, whereas the effects of more prolonged alpha-adrenergic blockade on LVF recovery after stenting are unknown. METHODS: In 32 patients (age 58 +/- 12 y) with an 82% +/- 6% stenosis, ejection fraction (EF) and systolic thickening (%Th) were measured by transthoracic echocardiography before and 30 minutes to 2 hours after revascularization. In a double-blinded protocol, either 200 microg/kg urapidil or placebo was given intravenously, and LVF was measured 10 minutes later. Two hours later, oral treatment with 30 mg/d drug or placebo was started, and LVF measured again after 24 hours and 3 months. RESULTS: Before revascularization, EF was 49.4% +/- 8.5% (+/-SD) and 51.3% +/- 8.8% in the urapidil-treated and the placebo groups, respectively. Thirty minutes to 2 hours after coronary stenting, EF was unchanged. After intravenous drug administration, EF increased to 56.5% +/- 9.7%). At 24 hours and 3 months after revascularization, EF became 59.5% +/- 7.9% and 59.6% +/- 8.2% in the urapidil-treated group, respectively, whereas EF in the placebo group did not change (50.4% +/- 5.7% and 49.7% +/- 4.9%, respectively). Revascularization did not acutely improve %Th. Intravenous urapidil improved %Th from 31.4% +/- 17.6% to 44.2% +/- 11.6%, whereas there was no change in the placebo group. At 3 months, %Th was 49.5% +/- 12.9% in the urapidil-treated group and 39.7% +/- 8.9% in the placebo group. CONCLUSIONS: These data suggest that long-term alpha-adrenergic blockade might improve LVF at midterm after coronary revascularization.

Effects of selective alpha1- and alpha2-adrenergic blockade on coronary flow reserve after coronary stenting.

BACKGROUND: Coronary flow reserve (CFR) is not normalized shortly after coronary stenting. We hypothesized that alpha-adrenergic coronary vasoconstriction acts to limit CFR. METHODS AND RESULTS: We assessed flow velocity by Doppler wires and cross-sectional area by angiography in 46 patients undergoing coronary culprit lesion stenting (81+/-4% stenosis). Hyperemia was induced by adenosine (24 micro g IC or 140 micro g/kg per minute IV) before and after stenting. Finally, either the alpha(1)-antagonist urapidil (10 mg IC) or the alpha(2)-antagonist yohimbine (3 mg IC) was randomly combined with adenosine. In 8 subjects with angiographically normal coronary arteries, CFR was increased from 3.21+/-0.30 to 3.74+/-0.43 by yohimbine and to 4.58+/-0.65 by urapidil, respectively (P=0.0001). Patients were divided according to the cutoff of CFR > or =3.0 (n=18) or <2.5 (n=28). Revascularization per se did not change CFR. However, 15 minutes after stenting, CFR decreased to 2.05+/-0.55 from CFR 3.64+/-0.58, whereas in patients with CFR 2.39+/-0.51, it remained unchanged. Yohimbine improved CFR to 3.26+/-0.42 and to 3.41+/-0.58 in patients with >3.0 and <2.05+/-0.55 baseline CFR, respectively. Urapidil improved CFR to 3.52+/-0.30 and 3.98+/-1.07, respectively. CONCLUSIONS: Urapidil and yohimbine attenuated the CFR impairment occurring after revascularization by increasing both the epicardial vasodilator effect of adenosine and the blood flow velocity, thus suggesting that the adrenergic system plays an important role in limiting the capacity of the coronary circulation to dilate.