The effect of pegylated granulocyte colony-stimulating factor on collateral function and myocardial ischaemia in chronic coronary artery disease: A randomized controlled trial.

OBJECTIVE: To test the effect of long-term pegfilgrastim on collateral function and myocardial ischaemia in patients with chronic stable coronary artery disease (CAD). METHODS: This was a prospective clinical trial with randomized 2:1 allocation to pegfilgrastim or placebo for 6 months. The primary study endpoint was collateral flow index (CFI) as obtained during a 1-minute ostial coronary artery balloon occlusion. CFI is the ratio of mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure (mm Hg/mm Hg). Secondary endpoints were signs of myocardial ischaemia determined during the same coronary occlusion, that is quantitative intracoronary (i.c.) ECG ST-segment shift (mV) and the occurrence of angina pectoris. Endpoints were obtained at baseline before and at follow-up after three subcutaneous study drug injections. RESULTS: Collateral flow index in the pegfilgrastim group changed from 0.096 ± 0.076 at baseline to 0.126 ± 0.070 at follow-up (P = 0.0039), while in the placebo group CFI changed from 0.157 ± 0.146 to 0.122 ± 0.043, respectively (P = 0.29); the CFI increment at follow-up was +0.030 ± 0.075 in the pegfilgrastim group and -0.034 ± 0.148 in the placebo group (P = 0.0172). In the pegfilgrastim group, i.c. ECG ST-segment shift changed from +1.23 ± 1.01 mV at baseline to +0.93 ± 0.97 mV at follow-up (P = 0.0049), and in the placebo group, it changed from +0.98 ± 1.02 mV to +1.43 ± 1.09 mV, respectively (P = 0.05). At follow-up, the fraction of patients free from angina pectoris during coronary occlusion had increased in the pegfilgrastim but not in the placebo group. CONCLUSION: Pegfilgrastim given over the course of 6 months improves collateral function in chronic stable CAD, which is reflected by reduced myocardial ischaemia during a controlled coronary occlusion.

Direct quantitative assessment of the peripheral artery collateral circulation in patients undergoing angiography.

BACKGROUND: Despite the fact that numerous studies have pursued the strategy of improving collateral function in patients with peripheral artery disease, there is currently no method available to quantify collateral arterial function of the lower limb. METHODS AND RESULTS: Pressure-derived collateral flow index (CFIp, calculated as (occlusive pressure-central venous pressure)/(aortic pressure-central venous pressure); pressure values in mm Hg) of the left superficial femoral artery was obtained in patients undergoing elective coronary angiography using a combined pressure/Doppler wire (n=30). Distal occlusive pressure and toe oxygen saturation (Sao2) were measured for 5 minutes under resting conditions, followed by an exercise protocol (repetitive plantar-flexion movements in supine position; n=28). In all patients, balloon occlusion of the superficial femoral artery over 5 minutes was painless under resting conditions. CFIp increased during the first 3 minutes from 0.451±0.168 to 0.551±0.172 (P=0.0003), whereas Sao2 decreased from 98±2% to 93±7% (P=0.004). Maximal changes of Sao2 were inversely related to maximal CFIp (r(2)=0.33, P=0.003). During exercise, CFIp declined within 1 minute from 0.560±0.178 to 0.393±0.168 (P<0.0001) and reached its minimum after 2 minutes of exercise (0.347±0.176), whereas Sao2 declined to a minimum of 86±6% (P=0.002). Twenty-five patients (89%) experienced pain or cramps/tired muscles, whereas 3 (11%) remained symptom-free for an occlusion time of 10 minutes. CFIp values were positively related to the pain-free time span (r(2)=0.50, P=0.002). CONCLUSIONS: Quantitatively assessed collateral arterial function at rest determined in the nonstenotic superficial femoral artery is sufficient to prevent ischemic symptoms during a total occlusion of 5 minutes. During exercise, there is a decline in CFIp that indicates a supply-demand mismatch via collaterals or, alternatively, a steal phenomenon. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01742455.

Effects of Thoratec pulsatile ventricular assist device timing on the abdominal aortic wave intensity pattern.

Arterial waves are seen as possible independent mediators of cardiovascular risks, and the wave intensity analysis (WIA) has therefore been proposed as a method for patient selection for ventricular assist device (VAD) implantation. Interpreting measured wave intensity (WI) is challenging, and complexity is increased by the implantation of a VAD. The waves generated by the VAD interact with the waves generated by the native heart, and this interaction varies with changing VAD settings. Eight sheep were implanted with a pulsatile VAD (PVAD) through ventriculoaortic cannulation. The start of PVAD ejection was synchronized to the native R wave and delayed between 0 and 90% of the cardiac cycle in 10% steps or phase shifts (PS). Pressure and velocity signals were registered, with the use of a combined Doppler and pressure wire positioned in the abdominal aorta, and used to calculate the WI. Depending on the PS, different wave interference phenomena occurred. Maximum unloading of the left ventricle (LV) coincided with constructive interference and maximum blood flow pulsatility, and maximum loading of the LV coincided with destructive interference and minimum blood flow pulsatility. We believe that noninvasive WIA could potentially be used clinically to assess the mechanical load of the LV and to monitor the peripheral hemodynamics such as blood flow pulsatility and risk of intestinal bleeding.

Electrocardiographic ST-segment monitoring during controlled occlusion of coronary arteries.

BACKGROUND: Ischemia monitoring cannot always be performed by 12-lead ECG. Hence, the individual performance of the ECG leads is crucial. No experimental data on the ECG's specificity for transient ischemia exist. METHODS: In 45 patients a 19-lead ECG was registered during a 1-minute balloon occlusion of a coronary artery (left anterior descending artery [LAD], right coronary artery [RCA] or left circumflex artery [LCX]). ST-segment shifts and sensitivity/specificity of the leads were measured. RESULTS: During LAD occlusion, V3 showed maximal ST-segment elevation (0.26mV [IQR 0.16-0.33mV], p=0.001) and sensitivity/specificity (88% and 80%). During RCA occlusion, III showed maximal ST-elevation (0.2mV [IQR 0.09-0.26mV], p=0.004), aVF had the best sensitivity/specificity (85% and 68%). During LCX occlusion, V6 showed maximal ST-segment elevation (0.04mV [IQR 0.02-0.14mV], p=0.005), and sensitivity/specificity was (31%/92%) but could be improved (63%/72%) using an optimized cut-off for ischemia. CONCLUSION: V3, aVF and V6 show the best performance to detect transient ischemia.

Coronary collaterals and risk for restenosis after percutaneous coronary interventions: a meta-analysis.

BACKGROUND: The benefit of the coronary collateral circulation (natural bypass network) on survival is well established. However, data derived from smaller studies indicates that coronary collaterals may increase the risk for restenosis after percutaneous coronary interventions. The purpose of this systematic review and meta-analysis of observational studies was to explore the impact of the collateral circulation on the risk for restenosis. METHODS: We searched the MEDLINE, EMBASE and ISI Web of Science databases (2001 to 15 July 2011). Random effects models were used to calculate summary risk ratios (RR) for restenosis. The primary endpoint was angiographic restenosis > 50%. RESULTS: A total of 7 studies enrolling 1,425 subjects were integrated in this analysis. On average across studies, the presence of a good collateralization was predictive for restenosis (risk ratio (RR) 1.40 (95% CI 1.09 to 1.80); P = 0.009). This risk ratio was consistent in the subgroup analyses where collateralization was assessed with intracoronary pressure measurements (RR 1.37 (95% CI 1.03 to 1.83); P = 0.038) versus visual assessment (RR 1.41 (95% CI 1.00 to 1.99); P = 0.049). For the subgroup of patients with stable coronary artery disease (CAD), the RR for restenosis with 'good collaterals' was 1.64 (95% CI 1.14 to 2.35) compared to 'poor collaterals' (P = 0.008). For patients with acute myocardial infarction, however, the RR for restenosis with 'good collateralization' was only 1.23 (95% CI 0.89 to 1.69); P = 0.212. CONCLUSIONS: The risk of restenosis after percutaneous coronary intervention (PCI) is increased in patients with good coronary collateralization. Assessment of the coronary collateral circulation before PCI may be useful for risk stratification and for the choice of antiproliferative measures (drug-eluting stent instead bare-metal stent, cilostazol).

Gender is an independent risk factor for distribution pattern and lesion morphology in chronic critical limb ischemia.

BACKGROUND: The aim of this study was to determine gender differences in atherosclerotic lesion morphology and distribution pattern of patients with critical limb ischemia (CLI). METHODS: In this prospective cohort study, 233 patients, including 134 men (58%) and 99 women (43%) presenting with critically ischemic limbs were consecutively enrolled. Lesions of the entire lower limb arterial tree were evaluated and grouped into iliac, femoropopliteal, and below-the-knee (BTK) arterial disease. To elucidate whether gender is an independent risk factor for distribution pattern, we performed multivariable logistic regression models adjusted for cardiovascular risk factors. RESULTS: At time of diagnosis, women with CLI presented with higher mean age (78 ±10 vs 74 ±10, P = .01), suffered more often from hypertension (83% vs 71%, P = .04), and fewer were current or former smokers (25% vs 70%, P < .001). After multivariate analysis, women with CLI showed a 2.5-fold higher risk for femoropopliteal lesions (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.05-6.11, P = .04), with a threefold higher risk for occlusions compared with men (OR, 3.81; 95% CI, 1.45-10.0; P = .01). Moreover, in women a higher risk for multilevel disease was observed (OR, 3.81; 95% CI, 1.45-10.0; P = .01). In contrast, men presented more often with isolated BTK lesions compared with women (OR, 0.15; 95% CI, 0.05-0.70; P = .03). CONCLUSIONS: The finding that female gender may be an independent predictor for pronounced femoropopliteal involvement and more severe and diffuse atherosclerotic disease in CLI may be of particular relevance for early detection and for choosing distinct treatment strategies in women compared with men. Further studies are warranted, especially on confounding risk factors that might be different in men and women and their possible association with lesion morphology in patients with critical limb ischemia.

Survival benefits of revascularization in patients with critical limb ischemia and renal insufficiency.

BACKGROUND: Evidence for the best treatment strategy for patients with critical limb ischemia (CLI) at different stages of renal insufficiency (RI) is rare. Therefore, we determined the benefit of revascularization vs medical therapy (MT) only in CLI patients with different levels of RI. METHODS: This intention-to-treat cohort study with follow-up at 2, 6, and 12 months was conducted in a consecutive series of 351 patients with CLI. Revascularization by surgical (78 patients) or endovascular techniques (191 patients) was performed in 269 patients. MT as first-line therapy was administered in 82 patients. Patients were grouped according to glomerular filtration rate (GFR), estimated with the Modification of Diet in Renal Disease equation, into absent/mild RI (estimated GFR [eGFR], ≥ 60 mL/min/1.73 m(2)), moderate RI (eGFR, 30-59 mL/min/1.73 m(2)), and severe RI (eGFR, <30 mL/min/1.73 m(2) or dialysis). Primary outcome measures were overall and amputation-free survival. Cox regression models adjusted for baseline characteristics after Kaplan-Meier survival estimates were performed. RESULTS: The mean age differed significantly between groups (P < .001), and patients with absent/mild RI were more often men (P < .001) or smokers (P < .001) and less often hypertensive (P < .001). Risk factor adjustment showed that revascularized CLI patients with absent/mild RI had a longer amputation-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.26-0.82; P = .008), higher limb salvage (HR, 0.29; 95% CI, 0.17-0.91; P < .029), and better clinical success than MT patients (HR, 0.33; 95% CI, 0.17-0.65; P = .001). The moderate RI group benefited from revascularization in overall survival (HR, 0.51; 95% CI, 0.26-0.99; P = .049), amputation-free survival (HR, 0.51; 95% CI, 0.29-0.90; P = .020), and clinical success (HR, 0.42; 95% CI, 0.22-0.80; P = .008). A beneficial effect on overall survival was found even in patients with severe RI when revascularized (HR, 0.33; 95% CI, 0.12-0.91; P = .032 vs MT). CONCLUSIONS: Patients with CLI may benefit from revascularization compared with MT alone at all levels of renal impairment. Thus, revascularization should not be withheld in CLI patients at any level of RI.

Benefit of immediate revascularization in women with critical limb ischemia in an intention-to-treat analysis.

BACKGROUND: Evidence for the best treatment strategy in women with critical limb ischemia (CLI) is limited and controversial with studies contradicting each other. Therefore, we determined the benefit of immediate revascularization compared to medical therapy (MT) with optional delayed revascularization in men and women with CLI. METHODS: This cohort study with follow-up at 2, 6, and 12 months was conducted in a consecutive series of 356 patients (41% women) presenting with 394 critically ischemic limbs. In this intention-to-treat study, 292 limbs were assigned to immediate revascularization by either surgical (81 limbs) or endovascular techniques (211 limbs) at the time of first presentation with CLI, whereas MT as first-line therapy was administered in 102 limbs with CLI. Primary outcome measures were overall and amputation-free survival. Cox-regression models adjusted for 10 baseline characteristics following Kaplan-Meier Survival estimates were performed. RESULTS: Women with CLI were significantly older than men (P < .001), had higher systolic blood pressure (P = .03) and cholesterol levels (P = .04), but less women presented with renal failure (P = .03) and less were smokers (P < .001). In women, but not in men, immediate revascularization was associated with a prolonged overall survival (hazard ratio [HR], 2.37; 95% confidence interval [CI], 1.29-4.34; P = .01) and amputation-free survival compared to MT (HR, 2.11; 95% CI, 1.30-3.43; P = .01), irrespective of whether surgery or percutaneous transluminal angioplasty (PTA) was performed (not significant). Except for overall survival (HR, 2.14; 95% CI, 0.95-4.82; P = .07), outcomes were not significantly changed after Cox regression analysis. CONCLUSION: Women presenting with CLI profit from immediate revascularization therapy, irrespective of revascularization technique used and despite advanced age and differences in other cardiovascular risk factors. Thus, our data suggest aggressive and early limb salvage efforts in women with CLI.

Determinants of preformed collateral vessels in the human heart without coronary artery disease.

BACKGROUND: Coronary collaterals protect myocardium jeopardized by coronary artery disease (CAD). Promotion of collateral circulation is desirable before myocardial damage occurs. Therefore, determinants of collateral preformation in patients without CAD should be elucidated. METHODS: In 106 patients undergoing coronary angiography who were free of coronary stenoses, a total of 39 clinical test variables were collected. The coronary collateral flow index (CFI) was measured. Stepwise multiple linear regression analysis was performed after choosing a restricted number of candidates emerging from univariate testing. Separate multiple regression analyses were performed in patients with and without beta-blocker therapy. RESULTS: Nine parameters were found to be possible determinants of CFI by univariate analysis: arterial hypertension (aHT), dyslipidemia, statins, diuretics, age, height, heart rate (HR), pulse pressure amplitude, and left ventricular end-diastolic pressure (LVEDP). After multiple regression analysis, a low HR, absence of aHT, and elevated LVEDP were significantly related to CFI (F = 5.31, p = 0.002, adjusted r(2) = 0.12). In patients without beta-blockers, a low HR and absence of aHT were independent predictors of CFI (F = 8.03, p < 0.001, n = 50, adjusted r(2) = 0.30). CONCLUSIONS: A low HR and absence of aHT are both related to collateral preformation in humans. We suppose that bradycardia favors fluid shear stress in coronary arteries, thus triggering collateral growth.

Instantaneous coronary collateral function during supine bicycle exercise.

AIMS: The instantaneous response of the collateral circulation to isometric physical exercise in patients with non-occlusive coronary artery disease (CAD) is not known. METHODS AND RESULTS: Thirty patients (age 59 +/- 9 years) undergoing percutaneous coronary intervention because of stable CAD were included in the study. Collateral function was determined before and during the last minute of a 6 min protocol of supine bicycle exercise during radial artery access coronary angiography. Collateral flow index (CFI, no unit) was determined as the ratio of mean distal coronary occlusive to mean aortic pressure both subtracted by central venous pressure. To avoid confounding due to recruitment of coronary collaterals by repetitive balloon occlusions, patients were randomly assigned to a group 'rest first' with CFI measurement during rest followed by CFI during exercise, and to a group 'exercise first' with antecedent CFI measurement during exercise before CFI at rest. Simultaneously, coronary collateral conductance (occlusive myocardial blood flow per aorto-coronary pressure drop) was determined by myocardial contrast echocardiography in the last 10 consecutive patients. Overall, CFI increased from 0.168 +/- 0.118 at rest to 0.262 +/- 0.166 during exercise (P = 0.0002). The exercise-induced change in CFI did not differ statistically in the two study groups. Exercise-induced CFI reserve (CFI during exercise divided by CFI at rest) was 2.2 +/- 1.8. Overall, rest to peak bicycle exercise change of coronary collateral conductance was from 0.010 +/- 0.010 to 1.109 +/- 0.139 mL/min/100 mmHg (P < 0.0001); the respective change was similar in both groups. CONCLUSION: In patients with non-occlusive CAD, collateral flow instantaneously doubles during supine bicycle exercise as compared with the resting state. ClinicalTrials.gov Identifier: NCT00947050.

Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial.

BACKGROUND: The efficacy of granulocyte colony-stimulating factor (G-CSF) for coronary collateral growth promotion and thus impending myocardial salvage has not been studied so far, to our best knowledge. METHODS AND RESULTS: In 52 patients with chronic stable coronary artery disease, age 62+/-11 years, the effect on a marker of myocardial infarct size (ECG ST segment elevation) and on quantitative collateral function during a 1-minute coronary balloon occlusion was tested in a randomized, placebo-controlled, double-blind fashion. The study protocol before coronary intervention consisted of occlusive surface and intracoronary lead ECG recording as well as collateral flow index (CFI, no unit) measurement in a stenotic and a > or =1 normal coronary artery before and after a 2-week period with subcutaneous G-CSF (10 microg/kg; n=26) or placebo (n=26). The CFI was determined by simultaneous measurement of mean aortic, distal coronary occlusive, and central venous pressure. The ECG ST segment elevation >0.1 mV disappeared significantly more often in response to G-CSF (11/53 vessels; 21%) than to placebo (0/55 vessels; P=0.0005), and simultaneously, CFI changed from 0.121+/-0.087 at baseline to 0.166+/-0.086 at follow-up in the G-CSF group, and from 0.152+/-0.082 to 0.131+/-0.071 in the placebo group (P<0.0001 for interaction of treatment and time). The absolute change in CFI from baseline to follow-up amounted to +0.049+/-0.062 in the G-CSF group and to -0.010+/-0.060 in the placebo group (P<0.0001). CONCLUSIONS: Subcutaneous G-CSF is efficacious during a short-term protocol in improving signs of myocardial salvage by coronary collateral growth promotion.

Coronary wave intensity patterns in stable coronary artery disease: influence of stenosis severity and collateral circulation.

Objective: Wave intensity analysis is a method that allows separating pulse waves into components generated proximally and in the periphery of arterial trees, as well as characterising them as accelerating or decelerating. The early diastolic suction wave (eaDSW) is one of the most prominent wave events in the coronaries. The aim of this study was to determine whether (1) microvascular dilatation directly influences its energy, (2) stenosis severity can be assessed proximal to stenoses, (3) distal pulse wave entrapment exists in the presence of stenoses and (4) coronary collaterals influence wave entrapment. Methods: In 43 coronary artery disease patients, Doppler flow velocity and pressure measurements were performed in a proximal coronary segment at rest, in a distal segment at rest, during adenosine-induced hyperaemia and during balloon occlusion. Wave energies were calculated as the area under the wave intensity curves. Results: The eaDSW energy showed a significant increase during hyperaemia, but did not differ between proximal and distal segments. There was no significant correlation between eaDSW energy and coronary stenosis severity. Pulse wave entrapment could not be observed consistently in the distal segments. Consequently, the effect of coronary collaterals on pulse wave entrapment could not be studied. Conclusions: Microvascular dilation in the coronary circulation increases distal eaDSW energy. However, it does not show any diagnostically useful variation between measurement sites, various stenosis degrees and amount of collateral flow. The assessment eaDSW and its reflections were not useful for the quantification of coronary stenosis severity or the collateral circulation in clinical practice.

Time-Dependent Myocardial Necrosis in Patients With ST-Segment-Elevation Myocardial Infarction Without Angiographic Collateral Flow Visualized by Cardiac Magnetic Resonance Imaging: Results From the Multicenter STEMI-SCAR Project.

Background Acute complete occlusion of a coronary artery results in progressive ischemia, moving from the endocardium to the epicardium (ie, wavefront). Dependent on time to reperfusion and collateral flow, myocardial infarction ( MI ) will manifest, with transmural MI portending poor prognosis. Late gadolinium enhancement cardiac magnetic resonance imaging can detect MI with  high diagnostic accuracy. Primary percutaneous coronary intervention is the preferred reperfusion strategy in patients with ST -segment-elevation MI with <12 hours of symptom onset. We sought to visualize time-dependent necrosis in a population with ST -segment-elevation MI by using late gadolinium enhancement cardiac magnetic resonance imaging (STEMI-SCAR project). Methods and Results ST -segment-elevation MI patients with single-vessel disease, complete occlusion with TIMI (Thrombolysis in Myocardial Infarction) score 0, absence of collateral flow (Rentrop score 0), and symptom onset <12 hours were consecutively enrolled. Using late gadolinium enhancement cardiac magnetic resonance imaging, the area at risk and infarct size, myocardial salvage index, transmurality index, and transmurality grade (0-50%, 51-75%, 76-100%) were determined. In total, 164 patients (aged 54±11 years, 80% male) were included. A receiver operating characteristic curve (area under the curve: 0.81) indicating transmural necrosis revealed the best diagnostic cutoff for a symptom-to-balloon time of 121 minutes: patients with >121 minutes demonstrated increased infarct size, transmurality index, and transmurality grade (all P<0.01) and decreased myocardial salvage index ( P<0.001) versus patients with symptom-to-balloon times ≤121 minutes. Conclusions In MI with no residual antegrade and no collateral flow, immediate reperfusion is vital. A symptom-to-balloon time of >121 minutes causes a high grade of transmural necrosis. In this pure ST -segment-elevation MI population, time to reperfusion to salvage myocardium was less than suggested by current guidelines.

Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide.

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.

Selective Heart Rate Reduction With Ivabradine Increases Central Blood Pressure in Stable Coronary Artery Disease.

Heart rate (HR) lowering by ß-blockade was shown to be beneficial after myocardial infarction. In contrast, HR lowering with ivabradine was found to confer no benefits in 2 prospective randomized trials in patients with coronary artery disease. We hypothesized that this inefficacy could be in part related to ivabradine's effect on central (aortic) pressure. Our study included 46 patients with chronic stable coronary artery disease who were randomly allocated to placebo (n=23) or ivabradine (n=23) in a single-blinded fashion for 6 months. Concomitant baseline medication was continued unchanged throughout the study except for ß-blockers, which were stopped during the study period. Central blood pressure and stroke volume were measured directly by left heart catheterization at baseline and after 6 months. For the determination of resting HR at baseline and at follow-up, 24-hour ECG monitoring was performed. Patients on ivabradine showed an increase of 11 mm Hg in central systolic pressure from 129±22 mm Hg to 140±26 mm Hg (P=0.02) and in stroke volume by 86±21.8 to 107.2±30.0 mL (P=0.002). In the placebo group, central systolic pressure and stroke volume remained unchanged. Estimates of myocardial oxygen consumption (HR×systolic pressure and time-tension index) remained unchanged with ivabradine.The decrease in HR from baseline to follow-up correlated with the concomitant increase in central systolic pressure (r=-0.41, P=0.009) and in stroke volume (r=-0.61, P<0.001). In conclusion, the decrease in HR with ivabradine was associated with an increase in central systolic pressure, which may have antagonized possible benefits of HR lowering in coronary artery disease patients. CLINICAL TRIALSURL: http://www.clinicaltrials.gov. Unique identifier NCT01039389.

Obesity-associated activation of angiotensin and endothelin in the cardiovascular system.

The renin-angiotensin system (RAS) and the endothelin system have been implicated in the pathogenesis of human cardiovascular and renal diseases, and inhibition of the RAS markedly improves morbidity and survival. Obesity in humans is associated with an increased risk for the development of hypertension, atherosclerosis and focal-segmental glomerulosclerosis, however the exact mechanisms underlying these pathologies in obese individuals are not known. This article discusses the clinical importance of obesity and the current evidence for local activation of the renin-angiotensin system and its interactions with the endothelin system in obesity and the cardiovascular pathologies associated with it.

Obesity increases prostanoid-mediated vasoconstriction and vascular thromboxane receptor gene expression.

OBJECTIVES: Vasoconstrictor prostanoids have been implicated in abnormal vasomotion in atherosclerosis and hypertension. METHOD: Using lean and diet-induced obese mice, we investigated whether obesity affects vascular function or expression of genes involved in prostanoid action. RESULTS: In lean C57BL/6J mice, at high concentrations acetylcholine caused endothelium-dependent contractions in the carotid artery but not in the aorta. Endothelium-dependent contractions to acetylcholine were blocked by the non-selective cyclooxygenase (COX) inhibitors indomethacin and meclofenamate, or a prostaglandin H2/thromboxane A2 receptor antagonist, but not by inhibitors of COX-2, thromboxane synthase or cytochrome P450 monooxygenase. Obesity increased endothelium-dependent contractions to acetylcholine in the carotid artery, and prostanoid-mediated vasoconstriction was now present in the aorta. Similarly, contractions to endothelin-1 were largely blocked by meclofenamate and were increased in the aorta of obese mice. Real-time quantitative polymerase chain reaction analysis of the thromboxane receptor gene in the carotid artery revealed a robust upregulation in obese animals (18-fold, 0.05); in comparison, obesity had a less pronounced effect on thromboxane synthase (2.1-fold increase, 0.05), or preproendothelin-1 gene expression (4.2-fold increase, 0.05). CONCLUSIONS: These data demonstrate that obesity augments prostanoid-dependent vasoconstriction and markedly increases vascular thromboxane receptor gene expression. These changes are likely to promote the development of vascular disease, hypertension and thrombosis associated with obesity.

Oral contraceptives and the risk of thrombosis and atherosclerosis.

Oral contraceptives containing synthetic oestrogens have been used successfully as birth control for > 40 years and are currently prescribed to > 100 million women worldwide. Several new progestins have been introduced and the third generation of progestins has now been available for two decades. Oral contraceptives are prescribed over a prolonged period of time and therefore substantially impact on hormonal, metabolic and plasmatic functions. Oral contraceptives increase the risk for venous thrombosis and pulmonary embolism, particularly if associated with confounding factors, such as genetic predisposition, smoking, hypertension or obesity. The risk of developing coronary artery disease is also increased in users with cardiovascular risk factors. This article discusses mechanistic and clinical issues and reviews the need for novel approaches targeting the considerable side effects in order to reduce cardiovascular morbidity in women using oral contraceptives.