Management of coronary artery disease in patients with aortic stenosis.

Aortic stenosis (AS) is the most common valvular heart disorder in the elderly population. As a result of the shared pathophysiological processes, AS frequently coexists with coronary artery disease (CAD). These patients have traditionally been managed through surgical aortic valve replacement (SAVR) and coronary artery bypass grafting. However, increasing body of evidence supports transcatheter aortic valve implantation (TAVI) as an alternative treatment for severe AS across the spectrum of operative risk. This has created the potential for treating AS and concurrent CAD completely percutaneously. In this review we consider the evidence guiding the optimal management of patients with severe AS and CAD. While invasive coronary angiography plays a central role in detecting CAD in patients with AS undergoing surgery or TAVI, the benefits of complementary functional assessment of coronary stenosis in the context of AS have not been fully established. Although the indications for revascularisation of significant proximal CAD in SAVR patients have not recently changed, routine revascularisation of all significant CAD before TAVI in patients with minimal angina is not supported by the latest evidence. Several ongoing trials will provide new insights into physiology-guided revascularisation in TAVI recipients. The role of the heart team remains essential in this complex patient group, and if revascularisation is being considered careful evaluation of clinical, anatomical and procedural factors is essential for individualised decision-making.

The Impact of a Dedicated Chronic Total Occlusion PCI Program on Heart Team Decision Making.

BACKGROUND: Guidelines endorse a heart team (HT) approach to standardize the decision-making process for patients with complex coronary artery disease (CAD). With percutaneous treatment options for complex CAD increasing, we hypothesized that practice had changed over the past decade-and that more individuals, previously deemed too high risk for intervention, would now be referred for either surgical or percutaneous revascularization. METHODS: This observational study was conducted at St Thomas' Hospital (London, United Kingdom). All patients discussed at HT meetings were recorded and treatment recommendations audited. A subset of historic cases was selected for blinded, repeat discussion. RESULTS: From April 2018 to 2019, a total of 52 HT meetings discussing 375 cases were held. Patients tended to be male, with a majority demonstrating multivessel CAD in the context of preserved left ventricular function. SYNTAX scores were balanced across the tertiles. Thirty-five percent of patients had at least 1 chronic total occlusion (mean J-CTO, 3 [interquartile range, 2-3]), affecting the right coronary artery in 60%. Fifteen historic patients with isolated CTOs were re-presented an average of 8 years later; only 3 patients received the same outcome, with 80% now receiving a recommendation for revascularization over medical therapy. CONCLUSIONS: A dedicated program supporting complex coronary intervention is associated with a change in treatment recommendations issued by the local HT. In line with international guidelines, this might indicate that any complex or multivessel CAD should be discussed at HT meetings with, ideally, the presence of CTO operators.

Transcatheter Replacement of Transcatheter Versus Surgically Implanted Aortic Valve Bioprostheses.

BACKGROUND: Surgical aortic valve replacement and transcatheter aortic valve replacement (TAVR) are now both used to treat aortic stenosis in patients in whom life expectancy may exceed valve durability. The choice of initial bioprosthesis should therefore consider the relative safety and efficacy of potential subsequent interventions. OBJECTIVES: The aim of this study was to compare TAVR in failed transcatheter aortic valves (TAVs) versus surgical aortic valves (SAVs). METHODS: Data were collected on 434 TAV-in-TAV and 624 TAV-in-SAV consecutive procedures performed at centers participating in the Redo-TAVR international registry. Propensity score matching was applied, and 330 matched (165:165) patients were analyzed. Principal endpoints were procedural success, procedural safety, and mortality at 30 days and 1 year. RESULTS: For TAV-in-TAV versus TAV-in-SAV, procedural success was observed in 120 (72.7%) versus 103 (62.4%) patients (p = 0.045), driven by a numerically lower frequency of residual high valve gradient (p = 0.095), ectopic valve deployment (p = 0.081), coronary obstruction (p = 0.091), and conversion to open heart surgery (p = 0.082). Procedural safety was achieved in 116 (70.3%) versus 119 (72.1%) patients (p = 0.715). Mortality at 30 days was 5 (3%) after TAV-in-TAV and 7 (4.4%) after TAV-in-SAV (p = 0.570). At 1 year, mortality was 12 (11.9%) and 10 (10.2%), respectively (p = 0.633). Aortic valve area was larger (1.55 ± 0.5 cm2 vs. 1.37 ± 0.5 cm2; p = 0.040), and the mean residual gradient was lower (12.6 ± 5.2 mm Hg vs. 14.9 ± 5.2 mm Hg; p = 0.011) after TAV-in-TAV. The rate of moderate or greater residual aortic regurgitation was similar, but mild aortic regurgitation was more frequent after TAV-in-TAV (p = 0.003). CONCLUSIONS: In propensity score-matched cohorts of TAV-in-TAV versus TAV-in-SAV patients, TAV-in-TAV was associated with higher procedural success and similar procedural safety or mortality.

Repeat Transcatheter Aortic Valve Replacement for Transcatheter Prosthesis Dysfunction.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) use is increasing in patients with longer life expectancy, yet robust data on the durability of transcatheter heart valves (THVs) are limited. Redo-TAVR may play a key strategy in treating patients in whom THVs fail. OBJECTIVES: The authors sought to examine outcomes following redo-TAVR. METHODS: The Redo-TAVR registry collected data on consecutive patients who underwent redo-TAVR at 37 centers. Patients were classified as probable TAVR failure or probable THV failure if they presented within or beyond 1 year of their index TAVR, respectively. RESULTS: Among 63,876 TAVR procedures, 212 consecutive redo-TAVR procedures were identified (0.33%): 74 within and 138 beyond 1 year of the initial procedure. For these 2 groups, TAVR-to-redo-TAVR time was 68 (38 to 154) days and 5 (3 to 6) years. The indication for redo-TAVR was THV stenosis in 12 (16.2%) and 51 (37.0%) (p = 0.002) and regurgitation or combined stenosis-regurgitation in 62 (83.8%) and 86 (62.3%) (p = 0.028), respectively. Device success using VARC-2 criteria was achieved in 180 patients (85.1%); most failures were attributable to high residual gradients (14.1%) or regurgitation (8.9%). At 30-day and 1-year follow-up, residual gradients were 12.6 ± 7.5 mm Hg and 12.9 ± 9.0 mm Hg; valve area 1.63 ± 0.61 cm2 and 1.51 ± 0.57 cm2; and regurgitation ≤mild in 91% and 91%, respectively. Peri-procedural complication rates were low (3 stroke [1.4%], 7 valve malposition [3.3%], 2 coronary obstruction [0.9%], 20 new permanent pacemaker [9.6%], no mortality), and symptomatic improvement was substantial. Survival at 30 days was 94.6% and 98.5% (p = 0.101) and 83.6% and 88.3% (p = 0.335) at 1 year for patients presenting with early and late valve dysfunction, respectively. CONCLUSIONS: Redo-TAVR is a relatively safe and effective option for selected patients with valve dysfunction after TAVR. These results are important for applicability of TAVR in patients with long life expectancy in whom THV durability may be a concern.

Infective endocarditis complicating transcatheter aortic valve implantation.

Infective endocarditis complicating transcatheter aortic valve implantation (TAVI-IE) is a relatively rare condition with an incidence of 0.2%-3.1% at 1 year post implant. It is frequently caused by Enterococci, Staphylococcus aureus and coagulase negative staphylococci While the incidence currently appears to be falling, the absolute number of cases is likely to rise substantially as TAVI expands into low risk populations following the publication of the PARTNER 3 and Evolut Low Risk trials. Important risk factors for the development of TAVI-IE include a younger age at implant and significant residual aortic regurgitation. The echocardiographic diagnosis of TAVI-IE can be challenging, and the role of supplementary imaging techniques including multislice computed tomography (MSCT) and positron emission tomography (18FDG PET) is still emerging. Treatment largely parallels that of conventional prosthetic valve endocarditis (PVE), with prolonged intravenous antibiotic therapy and consideration of surgical intervention forming the cornerstones of management. The precise role and timing of cardiac surgery in TAVI-IE is yet to be defined, with a lack of clear evidence to help identify which patients should be offered surgical intervention. Minimising unnecessary healthcare interventions (both during and after TAVI) and utilising appropriate antibiotic prophylaxis may have a role in preventing TAVI-IE, but robust evidence for specific preventative strategies is lacking. Further research is required to better select patients for advanced hybrid imaging, to guide surgical management and to inform prevention in this challenging patient cohort.

Simultaneous Transcatheter Double Valve Treatment of Mediastinal Radiation-Induced Severe Calcific Aortic and Mitral Stenosis.

Mediastinal radiation-induced severe calcific valve disease carries increased operative mortality. Transcatheter therapies are also challenging and potentially hazardous. We used a unique constellation of imaging and planning technologies to successfully plan, simulate, and perform novel combined transcatheter aortic valve replacement and valve in mitral annular calcification in a high-risk patient. (Level of Difficulty: Advanced.).

Long-Term Outcomes Following Heart Team Revascularization Recommendations in Complex Coronary Artery Disease.

Background The Heart Team ( HT ) comprises integrated interdisciplinary decision making. Current guidelines assign a Class Ic recommendation for an HT approach to complex coronary artery disease ( CAD ). However, there remains a paucity of data in regard to hard clinical end points. The aim was to determine characteristics and outcomes in patients with complex CAD following HT discussion. Methods and Results This observational study was conducted at St Thomas' Hospital (London, UK). Case mixture included unprotected left main, 2-vessel (including proximal left anterior descending artery) CAD , 3-vessel CAD , or anatomical and/or clinical equipoise. HT strategy was defined as optimal medical therapy ( OMT ) alone, OMT +percutaneous coronary intervention ( PCI ), or OMT +coronary artery bypass grafting. From April 2012 to 2013, 51 HT meetings were held and 398 cases were discussed. Patients tended to have multivessel CAD (74.1%), high SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) scores (median, 30; interquartile range, 23-39), and average age 69±11 years. Multinomial logistic regression analysis performed to determine variables associated with HT strategy demonstrated decreased likelihood of undergoing PCI compared with OMT in older patients with chronic kidney disease and peripheral vascular disease. The odds of undergoing coronary artery bypass grafting compared with OMT decreased in the presence of cardiogenic shock and left ventricular dysfunction and increased in younger patients with 3-vessel CAD . Three-year survival was 60.8% (84 of 137) in the OMT cohort, 84.3% (107 of 127) in the OMT + PCI cohort, and 90.2% in the OMT +coronary artery bypass grafting cohort (92 of 102). Conclusions In our experience, the HT approach involved a careful selection process resulting in appropriate patient-specific decision making and good long-term outcomes in patients with complex CAD .

Transcatheter heart valve interventions: where are we? Where are we going?

Transcatheter heart valve interventions have transformed the outcomes of patients with valvular heart disease (VHD) who are unfavourable candidates for surgery. Technological advances have allowed extension of these interventions to younger or lower risk patients and those with other forms of VHD and may in the future permit earlier treatment of VHD in less symptomatic patients or those with moderate disease. The balance of risks and benefits is likely to differ between lower and higher risk patients, and more evidence is needed to evaluate the net benefit of transcatheter technology in these groups. As academic researchers, clinicians, industry, and patient stakeholders collaborate to research these broader indications for transcatheter valve interventions, it is essential to address (i) device durability and deliverability, (ii) specific anatomical needs (e.g. bicuspid aortic valves, aortic regurgitation, mitral and tricuspid valve disease), (iii) operator training, and (iv) the reinforced importance of the multidisciplinary Heart Team.

CXCR2 Inhibition - a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial.

BACKGROUND: There is emerging evidence of the central role of neutrophils in both atherosclerotic plaque formation and rupture. Patients with lower neutrophil counts following acute coronary syndromes tend to have a greater coronary flow reserve, which is a strong predictor of long-term cardiovascular health. But so far, no data are available regarding the impact of neutrophil inhibition on cardiovascular clinical or surrogate endpoints. Therefore, the aim of this study is to investigate the effects of AZD5069, a cysteine-X-cysteine chemokine receptor 2 (CXCR2) inhibitor, on coronary flow reserve and coronary structure and function in patients with coronary artery disease. METHODS/DESIGN: Ninety subjects with coronary artery disease undergoing percutaneous coronary intervention will be included in this investigator-driven, randomised, placebo-controlled, double-blind, phase IIa, single-centre study. Participants will be randomised to receive either AZD5069 (40 mg) administered orally twice daily or placebo for 24 weeks. Change in coronary flow reserve as determined by 13N-ammonia positron emission tomography-computed tomography will be the primary outcome. Change in the inflammatory component of coronary plaque structure and the backward expansion wave, an invasive coronary physiological measure of diastolic function, will be assessed as secondary outcomes. DISCUSSION: Cardiovascular surrogate parameters, such as coronary flow reserve, may provide insights into the potential mechanisms of the cardiovascular effects of CXCR2 inhibitors. Currently, ongoing trials do not specifically focus on neutrophil function as a target of intervention, and we therefore believe that our study will contribute to a better understanding of the role of neutrophil-mediated inflammation in coronary artery disease. TRIAL REGISTRATION: EudraCT, 2016-000775-24 . Registered on 22 July 2016. International Standard Randomised Controlled Trial Number, ISRCTN48328178 . Registered on 25 February 2016.

Implementation and consistency of Heart Team decision-making in complex coronary revascularisation.

BACKGROUND: A multidisciplinary team (MDT) approach for decision-making in patients with complex coronary artery disease (CAD) is now a class IC recommendation in the European and American guidelines for myocardial revascularisation. The aim of this study was to evaluate the implementation and consistency of Heart Team HT decision-making in complex coronary revascularisation. METHODS: We prospectively evaluated the data of 399 patients derived from 51 consecutive MDT meetings held in a tertiary cardiac centre. A subset of cases was randomly selected and re-presented with the same clinical data to a panel blinded to the initial outcome, at least 6 months after the initial discussion, in order to evaluate the reproducibility of decision-making. RESULTS: The most common decisions included continued medical management (30%), coronary artery bypass grafting (CABG) (26%) and percutaneous coronary intervention (PCI) (17%). Other decisions, such as further assessment of symptoms or evaluation with further invasive or non-invasive tests were made in 25% of the cases. Decisions were implemented in 93% of the cases. On re-discussion of the same data (n=40) within a median period of 9 months 80% of the initial HT recommendations were successfully reproduced. CONCLUSIONS: The Heart Team is a robust process in the management of patient with complex CAD and decisions are largely reproducible. Although outcomes are successfully implemented in the majority of the cases, it is important that all clinical information is available during discussion and patient preference is taken into account.

Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury.

Cardiac troponins are released and cleared slowly after myocardial injury, complicating the diagnosis of early, and recurrent, acute myocardial infarction. Cardiac myosin-binding protein C (cMyC) is a similarly cardiac-restricted protein that may have different release/clearance kinetics. Using novel antibodies raised against the cardiac-specific N-terminus of cMyC, we used confocal microscopy, immunoblotting and immunoassay to document its location and release. In rodents, we demonstrate rapid release of cMyC using in vitro and in vivo models of acute myocardial infarction. In patients, with ST elevation myocardial infarction (STEMI, n = 20), undergoing therapeutic ablation of septal hypertrophy (TASH, n = 20) or having coronary artery bypass surgery (CABG, n = 20), serum was collected prospectively and frequently. cMyC appears in the serum as full-length and fragmented protein. Compared to cTnT measured using a contemporary high-sensitivity commercial assay, cMyC peaks earlier (STEMI, 9.3 ± 3.1 vs 11.8 ± 3.4 h, P < 0.007; TASH, 9.7 ± 1.4 vs 21.6 ± 1.4 h, P < 0.0001), accumulates more rapidly (during first 4 h after TASH, 25.8 ± 1.9 vs 4.0 ± 0.4 ng/L/min, P < 0.0001) and disappears more rapidly (post-CABG, decay half-time 5.5 ± 0.8 vs 22 ± 5 h, P < 0.0001). Our results demonstrate that following defined myocardial injury, the rise and fall in the serum of cMyC is more rapid than that of cTnT. We speculate that these characteristics could enable earlier diagnosis of myocardial infarction and reinfarction in suspected non-STEMI, a population not included in this early translational study.

Direct TAVI using a balloon-expandable system: a novel technique to eliminate pre-deployment balloon aortic valvuloplasty.

AIMS: Transcatheter aortic valve implantation (TAVI) is now the therapy of choice for those patients with severe symptomatic aortic stenosis who are considered to be at too high risk for conventional surgery. Balloon aortic valvuloplasty (BAV) is routinely performed to allow placement of the balloon-expandable valve during the procedure. Instrumentation of the valve has been linked to procedural stroke risk, with the associated runs of rapid pacing risking haemodynamic compromise. We outline a novel technique to eliminate BAV prior to transcatheter valve placement. METHODS AND RESULTS: We illustrate a clinical case that outlines the problems encountered in transcatheter valve placement despite a prior BAV. The solution used in this case involved the partial inflation of the distal section of the balloon allowing easy passage of the SAPIEN XT valve from the transaortic route. After bench testing, we report a series of patients who have undergone this "direct TAVI" procedure from both the transaortic and the transfemoral routes. CONCLUSIONS: In a limited series within a single centre, "direct TAVI" has been shown to be effective in allowing accurate placement of a balloon-expandable device without the need for prior BAV.

Coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final five-year follow-up of the SYNTAX trial.

AIMS: Coronary artery bypass grafting (CABG) has been considered the standard of care for patients with three-vessel disease (3VD), but long-term comparative results from randomized trials of CABG vs. percutaneous coronary intervention (PCI) using drug-eluting stents (DES) remain limited. METHODS AND RESULTS: Patients with de novo 3VD or left main disease were randomly assigned to PCI with the paclitaxel-eluting first-generation stent or CABG in the SYNTAX trial. This pre-specified analysis presents the 5-year outcomes of patients with 3VD (n = 1095). The rate of major adverse cardiac and cerebrovascular events (MACCE) was significantly higher in patients with PCI compared with CABG (37.5 vs. 24.2%, respectively; P < 0.001). Percutaneous coronary intervention as opposed to CABG resulted in significantly higher rates of the composite of death/stroke/myocardial infarction (MI) (22.0 vs. 14.0%, respectively; P < 0.001), all-cause death (14.6 vs. 9.2%, respectively; P = 0.006), MI (9.2 vs. 4.0%, respectively; P = 0.001), and repeat revascularization (25.4 vs. 12.6%, respectively; P < 0.001); however, stroke was similar between groups at 5 years (3.0 vs. 3.5%, respectively; P = 0.66). Results were dependent on lesion complexity (P for interaction = 0.12); in patients with a low (0-22) SYNTAX score, PCI vs. CABG resulted in similar rates of MACCE (33.3% vs. 26.8%, respectively; P = 0.21) but significantly more repeat revascularization (25.4% vs. 12.6%, respectively; P = 0.038), while in intermediate (23-32) or high (≥ 33) SYNTAX score terciles, CABG demonstrated clear superiority in terms of MACCE, death, MI, and repeat revascularization. Differences in MACCE between PCI and CABG were larger in diabetics [hazard ratio (HR) = 2.30] than non-diabetics (HR = 1.51), although the P for interaction failed to reach significance for MACCE (P for interaction = 0.095) or any of the other endpoints. CONCLUSION: Five-year results of patients with 3VD treated with CABG or PCI using the first-generation paclitaxel-eluting DES suggest that CABG should remain the standard of care as it resulted in significantly lower rates of death, MI, and repeat revascularization, while stroke rates were similar. For patients with low SYNTAX scores, PCI is an acceptable revascularization strategy, although at a price of significantly higher rates of repeat revascularization. CLINICAL TRIAL REGISTRATION: NCT00114972.

What is the optimum adjunctive reperfusion strategy for primary percutaneous coronary intervention?

Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event. As understanding of its pathophysiology has improved, the central role of platelets in initiation and orchestration of this process has become clear. Key components of STEMI include formation of occlusive thrombus, mediation and ultimately amplification of the local vascular inflammatory response resulting in increased vasoreactivity, oedema formation, and microvascular obstruction. Activation, degranulation, and aggregation of platelets are the platforms from which these components develop. Therefore, prompt, potent, and predictable antithrombotic therapy is needed to optimise clinical outcomes after primary percutaneous coronary intervention. We review present pharmacological and mechanical adjunctive therapies for reperfusion and ask what is the optimum combination when primary percutaneous coronary intervention is used as the mode of revascularisation in patients with STEMI.

Assessment of coronary artery stenosis severity and location: quantitative analysis of transmural perfusion gradients by high-resolution MRI versus FFR.

OBJECTIVES: This study sought to test the hypothesis that transmural perfusion gradients (TPG) on adenosine stress myocardial perfusion cardiac magnetic resonance (CMR) predict hemodynamically significant coronary artery disease (CAD) as defined by fractional flow reserve (FFR). BACKGROUND: Myocardial ischemia affects the subendocardial layers of the left ventricular myocardium earlier and more severely than the outer layers, and the identification of TPG should be sensitive and specific for the diagnosis of CAD. Previous studies have shown that high spatial resolution myocardial perfusion CMR allows quantitation of TPG between the subendocardium and the subepicardium. METHODS: Sixty-seven patients (53 men, age 61 ± 9 years) underwent coronary angiography and high-resolution (1.2 × 1.2-mm in-plane) adenosine stress perfusion CMR at 3.0-T. TPG was calculated for 3 coronary territories. Visual analysis was performed to identify myocardial ischemia. FFR was measured in all vessels with ≥50% severity stenosis. FFR <0.8 was considered hemodynamically significant. In a training group of 30 patients, the optimal threshold of TPG to detect significant CAD was determined (Group 1). This threshold was then tested prospectively in the remaining 37 patients (Group 2). RESULTS: In Group 1, a 20% TPG provided the best diagnostic threshold on both per-segment and per-patient analysis. Applied to Group 2, this threshold yielded a sensitivity of 0.78, specificity of 0.94, and area under the curve of 0.86 for the detection of CAD in a per-segment analysis and of 0.89, 0.83, and 0.86 in a per-patient analysis, respectively. TPG had a similar diagnostic accuracy to visual assessment. Linear regression analysis showed a relationship between TPG and FFR values, with r = 0.63 (p < 0.001). CONCLUSIONS: The quantitative analysis of transmural perfusion gradients on high-resolution myocardial perfusion CMR accurately predicts hemodynamically significant CAD as defined by FFR. A TPG diagnostic threshold of 20% is as accurate as visual assessment.

Coronary collaterals remain recruitable after percutaneous intervention.

BACKGROUND: Rapid loss of collateral support has been reported after percutaneous coronary intervention (PCI), leaving the myocardium susceptible to subsequent infarction. However, well-developed collaterals have been found in normal hearts, suggesting that collaterals exist even in the absence of an ischemic stimulus. We assessed the plasticity and determinants of collateral supply after PCI. METHODS AND RESULTS: Collateral flow index (CFI) was calculated in 60 patients as (P(w)-P(v))/(P(a)-P(v)) by measurement of aortic (P(a)), central venous (P(v)), and coronary wedge (P(w)) pressures. CFI was reassessed during transient balloon occlusion 5 minutes and 24 hours after PCI in the first 29 patients and at 6 months in the subsequent 25 patients. We also evaluated the relationship between collateral supply, lesion characteristics, and circulating hemopoietic cells numbers before and after successful PCI. CFI at baseline was 0.23+/-0.10, with no change 5 minutes and 1 day later (0.21+/-0.12, P=0.62; and 0.22+/-0.11, P=0.96, respectively). At 6 months, CFI was 0.14+/-0.07 or 63+/-27% of the baseline value (P<0.001). CFI was proportional to severity of the coronary lesion at baseline (r=0.63, P<0.0001) but not 6 months after PCI (r=-0.04, P=0.87). The number of circulating CD133+ and CD34+ cells was associated with CFI 6 months after PCI (CD133, r=0.59, P=0.035; CD34, r=0.63, P=0.037). CONCLUSIONS: Coronary collateral flow remains undiminished for at least 24 hours after successful PCI. Functional collateral support subsequently declines but does not regress completely.

Circulating humoral factors and endothelial progenitor cells in patients with differing coronary collateral support.

BACKGROUND: The mechanisms underlying the variation in collateral formation between patients, even with similar patterns of coronary artery disease, remain unclear. This study investigates whether circulating humoral or cellular factors can provide an insight into this variation. METHODS AND RESULTS: Thirty patients with isolated left anterior descending coronary artery disease underwent percutaneous coronary intervention with collateral flow index (CFI) determined using a pressure wire. Patients with inadequate (CFI <0.25) compared with those with adequate (CFI > or =0.25) collateral support had, or tended to have, lower concentrations of coronary sinus growth factors and plasma exerting a weaker effect on endothelial cell migration and angiogenesis in vitro. However, there was an inverse correlation between serum mitogenicity and CFI (r=-0.61, P<0.01). No significant differences were detected between the 2 groups in plasma levels of total vascular endothelial growth factor, vascular endothelial growth factor165, or placental growth factor. There was a strong positive correlation between numbers of CD34/CD133-positive circulating hemopoietic precursor cells and CFI (r=0.75, P<0.001). In patients with inadequate, compared with those with adequate, CFI, the numbers of differentiated endothelial progenitor cells (EPCs) appearing in the circulation and in culture were significantly reduced by 75% (P<0.05) and 70% (P<0.05), respectively. CONCLUSIONS: In this study, inadequate coronary collateral development is associated with reduced numbers of circulating EPCs and impaired chemotactic and proangiogenic but not mitogenic activity. These findings are consistent with current efforts to enhance collateral formation by augmentation of circulating EPCs.