Catheter-based renal denervation in the treatment of resistant hypertension.

Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time.

Hemodynamic findings in severe tricuspid regurgitation.

Tricuspid regurgitation (TR) most commonly occurs in response to right ventricular (RV) dilation with structural abnormalities in the tricuspid valve being rarer. In addition to RV size and valvular integrity, the amount of TR is influenced by RV preload and afterload, the respiratory cycle, left heart function and atrial fibrillation. Hemodynamic changes in right atrial (RA) pressures in severe TR include elevated mean pressures, a large systolic wave called an "s" wave, a prominent 'Y' descent and a blunted 'X' descent. In addition, RV end diastolic pressure is elevated and cardiac output is reduced, especially with exercise. "Ventricularization" of the RA pressure tracing, in which the contour of the RA pressure is similar to, but of lower amplitude than, the contour of the RV pressure is the most specific finding but is found in a minority of patients with severe TR. In summary, alterations in the RA pressure tracing are common in patients with severe TR but specific hemodynamic findings lack sensitivity, which may in part be due to the large effects of RV preload, RV afterload and RA compliance on the amount of TR.

Unilateral renal artery stenosis causes a chronic vascular inflammatory response in ApoE-/- mice.

UNLABELLED: Unilateral renal artery ligation (RAL) causes a short-term vascular inflammatory reaction in ApoE-/- mice, but whether this persists is unknown. Partial constriction of the right renal artery resulted in a mild, sustained increase in systolic blood pressure over the 90 days of the study, whereas there was no change in blood pressure in mice that underwent sham-surgery. Atheroma was present in the abdominal aorta, with pronounced staining for macrophages (39% +/- 9% of area of atheroma) and monocyte chemoattractant-1 (MCP-1; 40%+/-15%) in mice with unilateral RAL. Atheroma was also present in the carotid arteries, with pronounced staining for macrophages (56%+/-15%) and MCP-1 (53%+/-21%). Non-muscle myosin-A, a marker of smooth muscle cell dedifferentiation, was observed in atheroma within the abdominal aorta and carotid arteries in mice that underwent unilateral RAL. There were no atheroma and minimal staining for macrophages, MCP-1 or non-muscle myosin A in carotid arteries or abdominal aorta of mice that underwent sham surgery. CONCLUSIONS: Chronic unilateral partial RAL results in the formation of atheroma in the aorta and carotid arteries of ApoE-/- mice that is characterized by chronic inflammation and dedifferentiation of smooth muscle cells.

Left ventricular hypertrophy in patients with renal artery stenosis.

Left ventricular hypertrophy (LVH) has been shown to be 3 times more prevalent in patients with renal artery stenosis (RAS) compared to essential hypertension, but factors that predict LVH in this population are not known. We identified 66 patients with unilateral renal artery stenosis and an interpretable electrocardiogram (ECG). LVH by either Cornell voltage-duration product or Sokolow-Lyon voltage criteria was present in 18 of the 66 patients (27%). The mean intra-aortic blood pressure was 100 +/- 14 mm Hg in patients with LVH, and 104 +/- 23 mm Hg in those without LVH (P = 0.37). The average stenosis by quantitative computerized angiography was 68 +/- 17% in patients with LVH, and 64 +/- 13% in those without LVH (P = 0.34). The mean translesional pressure gradient was 11 +/- 15 mm Hg in patients with LVH, and 13 +/- 20 mm Hg in those without LVH (P = 0.60). Using linear regression models, there was no correlation between intra-aortic blood pressure, percentage of stenosis, or translesional pressure gradient and either Cornell voltage-duration product or Sokolow-Lyon voltage criteria. In summary, LVH using ECG criteria was present in 27% of patients with unilateral RAS but was not associated with blood pressure at the time of the procedure or severity of renal artery stenosis.

Coronary artery fistulae.

Coronary artery fistulae are abnormal communications between a coronary artery and a cardiac chamber or major vessel (vena cava, pulmonary veins, pulmonary artery). They are usually diagnosed by coronary arteriography. Clinical presentations are variable depending on the type of fistula, shunt volume, site of the shunt, and presence of other cardiac conditions. In this article, we review the literature regarding etiology, incidence, clinical manifestation, image studies, and management.

Thrombin generation in vascular tissue.

BACKGROUND: Classically, it is thought that the vast majority of thrombin is generated on the surface of platelets, however, thrombotic events occur in patients despite treatment with potent antiplatelet agents. METHODS AND RESULTS: In freshly harvested left internal mammary artery (IMA) sections, addition of CaCl2 and platelet-poor plasma (PPP) were sufficient to stimulate a profound burst of thrombin and this effect was inhibited by antitissue factor antibodies. Ultracentrifugation of PPP to remove platelet microparticles had no effect on thrombin generation. Both the extrinsic and factor VIII-dependent pathways were necessary for IMA-supported thrombin generation as PPP derived from individuals deficient in factors V, VII, VIII or X did not support thrombin production. Small amounts of thrombin were generated utilizing factor IX (FIX)-deficient plasma, however, thrombin was not generated by aorta from FIX-deficient mice when FIX-deficient plasma was used. The addition of non-lipidated tissue factor (0.6 pM) and CaCl2 to actively proliferating cultured human aortic smooth muscle cells (SMC) resulted in a pronounced burst of thrombin generation occurring between 3 and 15 min after treatment. In the absence of tissue factor, thrombin was generated but at a slower rate and with a peak value 26% of that observed in the presence of tissue factor. CONCLUSION: Significant thrombin generation can occur on vascular tissue in the absence of platelets or platelet microparticles and on the surface of non-apoptotic SMC.

Incidence and management of "no-reflow" following percutaneous coronary interventions.

No-reflow is a complex condition associated with inadequate myocardial perfusion of the coronary artery in the absence of epicardial obstruction. It can occur in several settings, including percutaneous coronary intervention, especially in complex thrombotic lesions of native arteries and vein grafts and in primary angioplasty. The causes of no-reflow are not completely understood, and current treatments consist of intracoronary vasodilators, antithrombotic therapies, and mechanical devices (including aspiration thrombectomy catheters and embolic protection devices).

The no-reflow phenomenon in coronary arteries.

No reflow occurs when there is inadequate myocardial perfusion of a given segment of the coronary circulation without evidence of epicardial vessel obstruction. It is a rare but clinically significant condition associated with myocardial infarction and coronary interventions. Diagnosis is usually based on clinical signs of myocardial ischemia (symptoms and/or ECG changes) combined with coronary angiography. Management can be difficult and primarily consists of intracoronary administration of vasodilators. One interesting etiology is thromboembolism and this has become the focus for new potential treatments, including distal embolic protection devices.

Effects of thrombin on interactions between beta3-integrins and extracellular matrix in platelets and vascular cells.

The beta3-integrin family consists of alphaIIbbeta3 (also known as glycoprotein IIb/IIIa) and alpha(v)beta3. alphaIIbbeta3 is found on platelets and megakaryocytes and has an essential role in hemostasis. alpha(v)beta3 has a broader distribution, and it functions in angiogenesis, neointimal formation after vascular injury, and leukocyte trafficking. There are important interactions between thrombin and beta3-integrins relative to both "inside-out" (integrin activation) and "outside-in" (modification of cellular events by ligand binding to integrins) signaling. Thrombin, by binding to G protein-coupled, protease-activated receptors, is a potent activator of alphaIIbbeta3. Conversely, outside-in signaling through alphaIIbbeta3 amplifies events initiated by thrombin and is necessary for full platelet spreading, platelet aggregation, granule secretion, and the formation of a stable platelet thrombus. In smooth muscle cells, alpha(v)beta3-integrins influence various responses to thrombin, including proliferation, c-Jun NH2-terminal kinase-1 activation, and focal adhesion formation. Other interactions between beta3-integrins and thrombin include beta3-integrin promotion of the generation of thrombin by localizing prothrombin to cellular surfaces and/or enhancing the formation of procoagulant microparticles and the requirement of beta3-integrin function for platelet-dependent clot retraction. In summary, there is increasing evidence that interactions between beta3-integrins and thrombin play important roles in the regulation of hemostatic and vascular functions.

Alphavbeta3-integrin antagonists inhibit thrombin-induced proliferation and focal adhesion formation in smooth muscle cells.

Alphavbeta3-integrin antagonists reduced neointimal formation following vascular injury in eight different animal models. Because alpha-thrombin contributes to neointimal formation, we examined the hypothesis that alphavbeta3-integrins influence alpha-thrombin-induced signaling. Cultured rat aortic smooth muscle cells (RASMC) expressed alphavbeta3-integrins as demonstrated by immunofluorescence microscopy and fluorescence-activated cell sorting analysis. Proliferative responses to alpha-thrombin were partially inhibited by anti-beta3-integrin monoclonal antibody F11 and by cyclic RGD peptides. Immunofluorescence microscopy showed that alpha-thrombin stimulated a rapid increase in the formation of focal adhesions as identified by vinculin staining and that this effect was partially inhibited by alphavbeta3 antagonists. Beta3-integrin staining was diffuse in quiescent RASMC and did not concentrate at sites of focal adhesions following thrombin treatment. Alpha-thrombin elicited a time-dependent increase in activation of c-Jun NH2-terminal kinase-1 (JNK1) and in tyrosine phosphorylation of focal adhesion kinase (FAK). Alphavbeta3-integrin antagonists partially inhibited increases in JNK1 activity but had no effect on FAK phosphorylation. In SMC isolated from beta3-integrin-deficient mice, focal adhesion formation was impaired in response to thrombin but not sphingosine-1-phosphate, a potent activator of Rho. In summary, alphavbeta3-integrins play an important role in alpha-thrombin-induced proliferation and focal adhesion formation in RASMC.

MTHFR 677 C-->T mutation: a predictor of early-onset coronary artery disease risk.

The atherosclerotic potential of the methyenetetrahydrofolate reductase (MTHFR) gene mutation 677 C --> T substitution remains controversial. In this study, we describe the association of this mutation in a Southern Texan patient population of multiracial ethnic background with risk and extent of coronary artery disease (CAD) as measured by luminal narrowing. Sixty nine patients who were 50 years or younger composed our population. Chi-square analysis was used to analyze the data and found a significant association between CAD and this mutation (P value=0.03). In addition, in the small number of patients in this study who had diabetes, those who had mutation have more severe disease than those without the mutation. This study highlights the potential cardiovascular prognostic significance of the MTHFR 677 C --> T in the studied population.

Vascular expression of integrin-associated protein and thrombospondin increase after mechanical injury.

BACKGROUND: Integrin-associated protein (IAP) is a thrombospondin (TSP)-binding, Gi protein-coupled cell surface receptor. The vascular function of IAP has not been defined, and it is not known whether TSP and IAP are expressed at the same time in injured arteries. METHODS: Left brachial arteries of baboons were injured using balloon withdrawal technique. Arteries were harvested 1 week after injury, and immunohistochemistry and in situ hybridization were performed using standard techniques. Uninjured right brachial arteries served as a control. Proliferation studies were performed using cultured human aortic smooth muscle cells (SMC). RESULTS: We found significant IAP expression in the media and neointima 7 days after injury using BRIC-126, an immunoglobulin (Ig) G2b monoclonal antibody that recognizes IAP with high specificity. In contrast, IAP staining in the uninjured vessel was only observed in the endothelium. Concurrent with IAP expression, TSP mRNA and protein expression in the neointima and media was enhanced 1 week after injury. In cultured SMC, activation of IAP was sufficient to elicit a proliferative response. TSP-induced proliferation was inhibited by antibodies that block TSP binding to IAP and mimicked by 4N1K, a 10-amino acid peptide derived from the IAP binding site within the carboxyl terminus of TSP. CONCLUSIONS: Vascular expression of IAP and TSP increased after mechanical injury and activation of IAP elicited a proliferative response in cultured SMC. These findings support the hypothesis that IAP participates in vascular healing responses.

Eptifibatide and 7E3, but not tirofiban, inhibit alpha(v)beta(3) integrin-mediated binding of smooth muscle cells to thrombospondin and prothrombin.

BACKGROUND: Our objective was to determine whether abciximab, eptifibatide, or tirofiban inhibited ligand binding to alpha(v)beta(3) integrins on human aortic smooth muscle cells (HASMCs) or human umbilical vein endothelial cells (HUVECs). Abciximab binds alpha(IIb)beta(3) on platelets and alpha(v)beta(3) on HUVECs with similar affinity, whereas eptifibatide and tirofiban are thought to be highly specific for alpha(IIb)beta(3). The conclusion that eptifibatide does not bind vascular alpha(v)beta(3) integrins may be premature, however, because recent studies have demonstrated that the affinity of alpha(v)beta(3) for various ligands, including antagonists, is subject to modulation. METHODS AND RESULTS: Abciximab and 7E3, the anti-beta(3) integrin monoclonal antibody from which abciximab was derived, bound alpha(v)beta(3) on HASMCs in a specific and saturable manner and with an affinity similar to binding to alpha(IIb)beta(3) on platelets. 7E3 and eptifibatide inhibited alpha(v)beta(3)-mediated attachment of HASMCs to thrombospondin (TSP) and prothrombin but had no effect on alpha(v)beta(5)- or beta(1)-mediated HASMC attachment to vitronectin-, collagen-, or fibronectin-coated or noncoated tissue culture plates. The inhibitory effect of eptifibatide was similar in magnitude and not additive to that of 7E3. Eptifibatide and 7E3 inhibited alpha(v)beta(3)-mediated attachment of HUVECs. Tirofiban had only nonspecific effects on HASMC attachment to extracellular matrix proteins. In cell proliferation assays, eptifibatide inhibited alpha(v)beta(3)-mediated responses to soluble TSP by HASMCs and beta(3) integrin-expressing HEK cells. CONCLUSIONS: Eptifibatide and 7E3, but not tirofiban, specifically inhibit alpha(v)beta(3)-mediated binding of human smooth muscle and endothelial cells.