Ninian N. Lang

UVA Irradiation of Human Skin Vasodilates Arterial Vasculature and Lowers Blood Pressure Independently of Nitric Oxide Synthase

The incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. The molecular basis for this remains obscure. As nitric oxide (NO) metabolites are abundant in human skin, we hypothesized that exposure to UVA may mobilize NO bioactivity into the circulation to exert beneficial cardiovascular effects independently of vitamin D. In 24 healthy volunteers, irradiation of the skin with two standard erythemal doses of UVA lowered blood pressure (BP), with concomitant decreases in circulating nitrate and rises in nitrite concentrations. Unexpectedly, acute dietary intervention aimed at modulating systemic nitrate availability had no effect on UV-induced hemodynamic changes, indicating that cardiovascular effects were not mediated via direct utilization of circulating nitrate. UVA irradiation of the forearm caused increased blood flow independently of NO synthase (NOS) activity, suggesting involvement of pre-formed cutaneous NO stores. Confocal fluorescence microscopy studies of human skin pre-labeled with the NO-imaging probe diaminofluorescein 2 diacetate revealed that UVA-induced NO release occurs in a NOS-independent, dose-dependent manner, with the majority of the light-sensitive NO pool in the upper epidermis. Collectively, our data provide mechanistic insights into an important function of the skin in modulating systemic NO bioavailability, which may account for the latitudinal and seasonal variations of BP and CVD.

Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience.

Background—Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans. Methods and Results—Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of −0.208 s−1, coefficient of repeatability of 26.96 s−1; intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s−1; P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s−1; P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s−1 (baseline) to 155±45.0 s−1 (P<0.001) and 124±35.0 s−1 (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s−1 (baseline) to 80±14.9 s−1 (P<0.001) and 67.0±15.7 s−1 (P<0.05) at 24 and 48 hours, respectively. Conclusions—Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01323296.

In Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide Feasibility and Safety in Humans

Background— Cell therapy is an emerging and exciting novel treatment option for cardiovascular disease that relies on the delivery of functional cells to their target site. Monitoring and tracking cells to ensure tissue delivery and engraftment is a critical step in establishing clinical and therapeutic efficacy. The study aims were (1) to develop a Good Manufacturing Practice–compliant method of labeling competent peripheral blood mononuclear cells with superparamagnetic particles of iron oxide (SPIO), and (2) to evaluate its potential for magnetic resonance cell tracking in humans. Methods and Results— Peripheral blood mononuclear cells 1–5×109 were labeled with SPIO. SPIO-labeled cells had similar in vitro viability, migratory capacity, and pattern of cytokine release to unlabeled cells. After intramuscular administration, up to 108 SPIO-labeled cells were readily identifiable in vivo for at least 7 days using magnetic resonance imaging scanning. Using a phased-dosing study, we demonstrated that systemic delivery of up to 109 SPIO-labeled cells in humans is safe, and cells accumulating in the reticuloendothelial system were detectable on clinical magnetic resonance imaging. In a healthy volunteer model, a focus of cutaneous inflammation was induced in the thigh by intradermal injection of tuberculin. Intravenously delivered SPIO-labeled cells tracked to the inflamed skin and were detectable on magnetic resonance imaging. Prussian blue staining of skin biopsies confirmed iron-laden cells in the inflamed skin. Conclusions— Human peripheral blood mononuclear cells can be labeled with SPIO without affecting their viability or function. SPIO labeling for magnetic resonance cell tracking is a safe and feasible technique that has major potential for a range of cardiovascular applications including monitoring of cell therapies and tracking of inflammatory cells. Clinical Trial Registration— URL: http://www.clinicaltrials.gov; Unique identifier: NCT00972946, NCT01169935.

Cardiovascular Effects of a Novel SIRT1 Activator, SRT2104, in Otherwise Healthy Cigarette Smokers

Background We examined the effect of the oral SIRT1 activator SRT2104 on cardiovascular function in otherwise healthy cigarette smokers. Methods and Results Twenty‐four otherwise healthy cigarette smokers participated in a randomized double‐blind, placebo‐controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, and markers of platelet and monocyte activation were measured at baseline and at the end of each treatment period together with an assessment of forearm blood flow during intra‐arterial bradykinin, acetylcholine, and sodium nitroprusside infusions. Three hours postdose, mean plasma SRT2104 concentration was 1328±748 ng/mL after 28 days of active treatment. Compared with placebo, serum lipid profile improved during SRT2104 administration, with reductions in serum total cholesterol (−11.6±20 versus 6±21 mg/dL), low‐density lipoprotein cholesterol (−10±17 versus 3±21 mg/dL), and triglyceride (−39.8±77 versus 13.3±57 mg/dL) concentrations (P<0.05 for all). All vasodilators produced a dose‐dependent increase in blood flow (P<0.0001) that was similar during each treatment period (P>0.05 for all). No significant differences in fibrinolytic or blood flow parameters were observed between placebo and SRT2014. Conclusions SRT2104 appears to be safe and well tolerated and associated with an improved lipid profile without demonstrable differences in vascular or platelet function in otherwise healthy cigarette smokers. Clinical Trial Registration http://www.clinicaltrials.gov. Unique identifier: NCT01031108.

Vascular Complications of Cancer Chemotherapy

Development of new anticancer drugs has resulted in improved mortality rates and 5-year survival rates in patients with cancer. However, many of the modern chemotherapies are associated with cardiovascular toxicities that increase cardiovascular risk in cancer patients, including hypertension, thrombosis, heart failure, cardiomyopathy, and arrhythmias. These limitations restrict treatment options and might negatively affect the management of cancer. The cardiotoxic effects of older chemotherapeutic drugs such as alkylating agents, antimetabolites, and anticancer antibiotics have been known for a while. The newer agents, such as the antiangiogenic drugs that inhibit vascular endothelial growth factor signalling are also associated with cardiovascular pathology, especially hypertension, thromboembolism, myocardial infarction, and proteinuria. Exact mechanisms by which vascular endothelial growth factor inhibitors cause these complications are unclear but impaired endothelial function, vascular and renal damage, oxidative stress, and thrombosis might be important. With increasing use of modern chemotherapies and prolonged survival of cancer patients, the incidence of cardiovascular disease in this patient population will continue to increase. Accordingly, careful assessment and management of cardiovascular risk factors in cancer patients by oncologists and cardiologists working together is essential for optimal care so that prolonged cancer survival is not at the expense of increased cardiovascular events.

Dissociation of phenotypic and functional endothelial progenitor cells in patients undergoing percutaneous coronary intervention

Objectives: Endothelial progenitor cells (EPCs) are circulating mononuclear cells with the capacity to mature into endothelial cells and contribute to vascular repair. We assessed the effect of local vascular injury during percutaneous coronary intervention (PCI) on circulating EPCs in patients with coronary artery disease. Design and setting: Prospective case-control study in a university teaching hospital. Patients: 54 patients undergoing elective coronary angiography. Interventions and main outcome measures: EPCs were quantified by flow cytometry (CD34+KDR+ phenotype) complemented by real-time polymerase chain reaction (PCR), and the colony forming unit (CFU-EC) functional assay, before and during the first 24 hours after diagnostic angiography (n = 27) or PCI (n = 27). Results: Coronary intervention, but not diagnostic angiography, resulted in an increase in blood neutrophil count (p<0.001) and C-reactive protein concentrations (p = 0.001) in the absence of significant myocardial necrosis. Twenty-four hours after PCI, CFU-ECs increased threefold (median [IQR], 4.4 [1.3–13.8] vs 16.0 [2.1–35.0], p = 0.01), although circulating CD34+KDR+ cells (0.019% (SEM 0.004%) vs 0.016% (0.003%) of leucocytes, p = 0.62) and leucocyte CD34 mRNA (relative quantity 2.3 (0.5) vs 2.1 (0.4), p = 0.21) did not. There was no correlation between CFU-ECs and CD34+KDR+ cells. Conclusions: Local vascular injury following PCI results in a systemic inflammatory response and increases functional CFU-ECs. This increase was not associated with an early mobilisation of CD34+KDR+ cells, suggesting these cells are not the primary source of EPCs involved in the immediate response to vascular injury.

Urocortins in heart failure

Despite modern advances in the treatment of the causes and consequences of cardiovascular illness, heart disease and heart failure remain a leading cause of death in the western world. Many novel peptides are emerging as biomarkers and potential therapeutic tools for this debilitating condition. Urocortins represent one such group of peptides whose role in normal cardiovascular physiology and disease states is now increasingly being recognized. The cardiovascular effects of the urocortins are mediated via corticotrophin-releasing hormone (CRH) receptors through a variety of intra-cellular signaling pathways. Studies to date have demonstrated a favourable effect of urocortins on hemodynamic and neurohumoral regulation. They cause relaxation of the vasculature as well as having positive inotropic, chronotropic and lusitropic effects on the heart. This makes the urocortins a potentially attractive target in the treatment of heart failure. Indeed, a number of studies have demonstrated increased urocortin activity in experimental and clinical heart failure, with apparent augmented responses in these states. This article provides a review of the role of urocortins in normal cardiovascular physiology and in the pathophysiology of heart failure.

Marked impairment of protease-activated receptor type 1-mediated vasodilation and fibrinolysis in cigarette smokers: smoking, thrombin, and vascular responses in vivo

OBJECTIVES We sought to test the hypothesis that cigarette smoking adversely alters protease-activated receptor type 1 (PAR-1)-mediated vascular effects in vivo in humans. BACKGROUND Distinct from its role in the coagulation cascade, thrombin exerts its major cellular and cardiovascular actions via PAR-1. The activation of PAR-1 causes endothelium-dependent arterial vasodilation and the release of endogenous fibrinolytic factors. METHODS Forearm blood flow was measured with venous occlusion plethysmography in 12 cigarette smokers and 12 age- and gender-matched nonsmokers during intrabrachial infusions of PAR-1-activating-peptide (SFLLRN; 5 to 50 nmol/min), bradykinin (100 to 1,000 pmol/min), and sodium nitroprusside (2 to 8 mug/min). Plasma tissue plasminogen activator (t-PA) and plasminogen-activator inhibitor 1 antigen and activity concentrations were measured throughout the experiment. RESULTS All agonists caused dose-dependent increases in forearm blood flow (p < 0.0001 for all). Although bradykinin and sodium nitroprusside caused similar vasodilation, SFLLRN-induced vasodilation was attenuated in smokers (p = 0.04). Smokers had modest reductions in bradykinin-induced active t-PA release (reduced by 37%, p = 0.03) and had a marked impairment of SFLLRN-induced t-PA antigen (p = 0.02) and activity (p = 0.006) release, with a 96% reduction in overall net t-PA antigen release. The use of SFLLRN also caused similar (p = NS) increases in inactive plasminogen-activator inhibitor 1 in both smokers and nonsmokers (p <or= 0.002 for both). CONCLUSIONS Cigarette smoking causes marked impairment of PAR-1-mediated endothelial vasomotor and fibrinolytic function. Relative arterial stasis and near abolition of t-PA release will strongly promote clot propagation and vessel occlusion. These findings suggest a major contribution of impaired endothelial PAR-1 action to the increased atherothrombotic risk of cigarette smokers.

Effect of PSI-697, a Novel P-Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans

Background Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P‐selectin antagonist PSI‐697 on platelet–monocyte aggregate formation in humans. Methods and Results In a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral PSI‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI‐697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (P>0.05). P‐selectin‐blocking antibody (CLB‐Thromb6), but not PSI‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (P<0.001). Conclusions The novel small‐molecule P‐selectin antagonist PSI‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established. Clinical Trial Registration URL: http://EudraCT.ema.europa.eu Unique identifier: 2007‐005695‐14.

The ease of use and reproducibility of the Alere™ Heart Check System: a comparison of patient and healthcare professional measurement of BNP.

AIMS The aim of the study was to examine the ease of use and the reproducibility of a novel point-of-care BNP measurement system when used by patients and healthcare providers (HCP). PATIENTS & METHODS Patients with symptomatic heart failure were recruited from outpatient clinics at four hospitals. They were provided with brief training and instructional material for the use of the point-of-care BNP measurement system. Finger-prick blood BNP concentration was measured by the HCP and the patient (n = 150). Ease of use and reproducibility of the system were assessed. RESULTS In total, 80% of the 164 patients who completed a questionnaire on the ease of use of the system found it easy to operate. There was excellent correlation of BNP measurement compared between patients and HCP (r = 0.966; p < 0.001). CONCLUSION Patients find the Alere Heart Check BNP measurement system easy to operate. BNP concentration measurements obtained by patients show excellent correlation with those obtained by healthcare providers.