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.

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.

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.

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.

The effect of heart rate reduction by ivabradine on collateral function in patients with chronic stable coronary artery disease.

OBJECTIVE: To evaluate the effect of heart rate reduction by ivabradine on coronary collateral function in patients with chronic stable coronary artery disease (CAD). METHODS: This was a prospective randomised placebo-controlled monocentre trial in a university hospital setting. 46 patients with chronic stable CAD received placebo (n=23) or ivabradine (n=23) for the duration of 6 months. The main outcome measure was collateral flow index (CFI) as obtained during a 1 min coronary artery balloon occlusion at study inclusion (baseline) and at the 6-month follow-up examination. CFI is the ratio between simultaneously recorded mean coronary occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. RESULTS: During follow-up, heart rate changed by +0.2±7.8 beats/min in the placebo group, and by -8.1±11.6 beats/min in the ivabradine group (p=0.0089). In the placebo group, CFI decreased from 0.140±0.097 at baseline to 0.109±0.067 at follow-up (p=0.12); it increased from 0.107±0.077 at baseline to 0.152±0.090 at follow-up in the ivabradine group (p=0.0461). The difference in CFI between the 6-month follow-up and baseline examination amounted to -0.031±0.090 in the placebo group and to +0.040±0.094 in the ivabradine group (p=0.0113). CONCLUSIONS: Heart rate reduction by ivabradine appears to have a positive effect on coronary collateral function in patients with chronic stable CAD. CLINICALTRIALSGOV IDENTIFIER: NCT01039389.

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.

Prognostic relevance of coronary collateral function: confounded or causal relationship?

OBJECTIVE: To expand the limited information on the prognostic impact of quantitatively obtained collateral function in patients with coronary artery disease (CAD) and to estimate causality of such a relation. DESIGN: Prospective cohort study with long-term observation of clinical outcome. SETTING: University Hospital. PATIENTS: One thousand one hundred and eighty-one patients with chronic stable CAD undergoing 1771 quantitative, coronary pressure-derived collateral flow index measurements, as obtained during a 1-min coronary balloon occlusion (CFI is the ratio between mean distal coronary occlusive pressure and mean aortic pressure both subtracted by central venous pressure). Subgroup of 152 patients included in randomised trials on the longitudinal effect of different arteriogenic protocols on CFI. INTERVENTIONS: Collection of long-term follow-up information on clinical outcome. MAIN OUTCOME MEASURES: All-cause mortality and major adverse cardiac events. RESULTS: Cumulative 15-year survival rate was 48% in patients with CFI<0.25 and 65% in the group with CFI≥0.25 (p=0.0057). Cumulative 10-year survival rate was 75% in patients without arteriogenic therapy and 88% (p=0.0482) in the group with arteriogenic therapy and showing a significant increase in CFI at follow-up. By proportional hazard analysis, the following variables predicted increased all-cause mortality: age, low CFI, left ventricular end-diastolic pressure and number of vessels with CAD. CONCLUSIONS: A well-functioning coronary collateral circulation independently predicts lowered mortality in patients with chronic CAD. This relation appears to be causal, because augmented collateral function by arteriogenic therapy is associated with prolonged survival.

Quantitative myocardial contrast echocardiography: a new method for the non-invasive detection of chronic heart transplant rejection.

BACKGROUND: Chronic heart transplant rejection, i.e. cardiac allograft vasculopathy (CAV) is a major adverse prognostic factor after heart transplantation (HTx). This study tested the hypothesis that the relative myocardial blood volume (rBV) as quantified by myocardial contrast echocardiography accurately detects severe CAV as defined by coronary intravascular ultrasound (IVUS). METHODS AND RESULTS: Forty-five HTx patients underwent a total of 50 quantitative IVUS measurements for intima thickness assessment (>1 mm = severe CAV; the reference method). Simultaneously, the two factors constituting myocardial perfusion (mL/min/g) were obtained by transthoracic contrast echocardiography at rest: rBV (the test method), a measure of microvascular density (mL/mL), and its exchange rate ß (1/s; a measure of coronary conductance) after mechanical contrast bubble disruption.Sixty-nine per cent (31 of 45) of the HTx patients showed severe CAV. rBV at rest was equal to 0.17 ± 0.05 in the group without severe CAV, and it was equal to 0.12 ± 0.07 in the group with severe CAV (P = 0.0157). Conversely, ß amounted to 6.4 ± 4.5 in the former and to 10.3 ± 6.2 in the latter group (P = 0.0410), thus, maintaining normal resting myocardial perfusion at 1 mL/min/g. IVUS determined intima thickness correlated significantly and inversely with rBV at rest. An rBV value at rest <0.14 accurately detected severe CAV (intima thickness >1 mm): area under the receiver operating characteristics curve = 0.844, P = 0.004, sensitivity = 0.90, specificity = 0.75. CONCLUSION: Severe CAV can be detected using the non-invasive method of quantitative myocardial contrast echocardiography. rBV at rest amounting to <14% of the surrounding tissue accurately detects coronary intima thickness >1 mm as determined invasively by IVUS. CLINICAL TRIAL NUMBER: NCT00414895.

G-CSF induced arteriogenesis in humans: molecular insights into a randomized controlled trial.

AIMS: Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes. METHODS AND RESULTS: A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10 µg/kg; n=26) or placebo (n=26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34+ endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p < 0.05); for both cell types, the extent of increase correlated with CFI increase (r=0.23 and 0.14, p < 0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p < 0.05). CONCLUSIONS: The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function.

OBJECTIVE: This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN: Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING: University Hospital. PATIENTS: 35 patients with chronic stable coronary artery disease. INTERVENTION: 2-min iCSO. MAIN OUTCOME MEASURES: Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS: I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS: ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.

Cause or effect of arteriogenesis: compositional alterations of microparticles from CAD patients undergoing external counterpulsation therapy.

UNLABELLED: Recently, a clinical study on patients with stable coronary artery disease (CAD) showed that external counterpulsation therapy (ECP) at high (300 mmHg) but not at low inflation pressure (80 mmHg) promoted coronary collateral growth, most likely due to shear stress-induced arteriogenesis. The exact molecular mechanisms behind shear stress-induced arteriogenesis are still obscure. We therefore characterized plasma levels of circulating microparticles (MPs) from these CAD patients because of their ambivalent nature as a known cardiovascular risk factor and as a promoter of neovascularization in the case of platelet-derived MPs. MPs positive for Annexin V and CD31CD41 were increased, albeit statistically significant (P<0.05, vs. baseline) only in patients receiving high inflation pressure ECP as determined by flow cytometry. MPs positive for CD62E, CD146, and CD14 were unaffected. In high, but not in low, inflation pressure treatment, change of CD31CD41 was inversely correlated to the change in collateral flow index (CFI), a measure for collateral growth. MPs from the high inflation pressure group had a more sustained pro-angiogenic effect than the ones from the low inflation pressure group, with the exception of one patient showing also an increased CFI after treatment. A total of 1005 proteins were identified by a label-free proteomics approach from MPs of three patients of each group applying stringent acceptance criteria. Based on semi-quantitative protein abundance measurements, MPs after ECP therapy contained more cellular proteins and increased CD31, corroborating the increase in MPs. Furthermore, we show that MP-associated factors of the innate immune system were decreased, many membrane-associated signaling proteins, and the known arteriogenesis stimulating protein transforming growth factor beta-1 were increased after ECP therapy. In conclusion, our data show that ECP therapy increases platelet-derived MPs in patients with CAD and that the change in protein cargo of MPs is likely in favor of a pro angiogenic/arteriogenic property. TRIAL REGISTRATION: ClinicalTrials.gov NCT00414297.

Determinants of prognostically relevant intracoronary electrocardiogram ST-segment shift during coronary balloon occlusion.

The prognostic relevance of quantitative an intracoronary occlusive electrocardiographic (ECG) ST-segment shift and its determinants have not been investigated in humans. In 765 patients with chronic stable coronary artery disease, the following simultaneous quantitative measurements were obtained during a 1-minute coronary balloon occlusion: intracoronary ECG ST-segment shift (recorded by angioplasty guidewire), mean aortic pressure, mean distal coronary pressure, and mean central venous pressure (CVP). Collateral flow index (CFI) was calculated as follows: (mean distal coronary pressure minus CVP)/(mean aortic pressure minus CVP). During an average follow-up duration of 50 ± 34 months, the cumulative mortality rate from all causes was significantly lower in the group with an ST-segment shift <0.1 mV (n = 89) than in the group with an ST-segment shift ≥0.1 mV (n = 676, p = 0.0211). Factors independently related to intracoronary occlusive ECG ST-segment shift <0.1 mV (r(2) = 0.189, p <0.0001) were high CFI (p <0.0001), intracoronary occlusive RR interval (p = 0.0467), right coronary artery as the ischemic region (p <0.0001), and absence of arterial hypertension (p = 0.0132). "High" CFI according to receiver operating characteristics analysis was ≥0.217 (area under receiver operating characteristics curve 0.647, p <0.0001). In conclusion, absence of ECG ST-segment shift during brief coronary occlusion in patients with chronic coronary artery disease conveys a decreased mortality and is directly influenced by a well-developed collateral supply to the right versus left coronary ischemic region and by the absence of systemic hypertension in a patient's history.

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.

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).

Oversizing and restenosis with self-expanding stents in iliofemoral arteries.

PURPOSE: Uncoated self-expanding nitinol stents (NS) are commonly oversized in peripheral arteries. In current practice, 1-mm oversizing is recommended. Yet, oversizing of NS may be associated with increased restenosis. To provide further evidence, NS were implanted in porcine iliofemoral arteries with a stent-to-artery-ratio between 1.0 and 2.3. Besides conventional uncoated NS, a novel self-expanding NS with an antiproliferative titanium-nitride-oxide (TiNOX) coating was tested for safety and efficacy. METHODS: Ten uncoated NS and six TiNOX-coated NS (5-6 mm) were implanted randomly in the iliofemoral artery of six mini-pigs. After implantation, quantitative angiography (QA) was performed for calculation of artery and minimal luminal diameter. Follow-up was performed by QA and histomorphometry after 5 months. RESULTS: Stent migration, stent fracture, or thrombus formation were not observed. All stents were patent at follow-up. Based on the location of the stent (iliac/femoral) and the stent-to-artery-ratio, stent segments were divided into "normal-sized" (stent-to-artery-ratio < 1.4, n = 12) and "oversized" (stent-to-artery-ratio ≥ 1.4, n = 9). All stent segments expanded to their near nominal diameter during follow-up. Normal-sized stent segments increased their diameter by 6% and oversized segments by 29%. A significant correlation between oversizing and restenosis by both angiography and histomorphometry was observed. Restenosis rates were similar for uncoated NS and TiNOX-coated NS. CONCLUSIONS: TiNOX-coated NS are as safe and effective as uncoated NS in the porcine iliofemoral artery. All stents further expand to near their nominal diameter during follow-up. Oversizing is linearly and positively correlated with neointimal proliferation and restenosis, which may not be reduced by TiNOX-coating.

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.

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.