Lerman, Amir

Introduction: The endothelium controls coronary blood flow (CBF) by regulating microvascular tone, which is an important index of microcirculatory health. The difference in vasomotor response of the microvasculature between males and females is not well described. Hypothesis: Males and females react differently to different doses of intracoronary (IC) acetylcholine (Ach) injections. Methods: Patients with angina and non-obstructive coronary artery disease (<50% stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental IC Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF (mL/min) was then calculated from CAD and doppler-derived flow velocity. Comparisons between the 2 sexes were performed. Results: A total of 1927 patients (mean age 51±13 years, 67% females) were included. Males were significantly younger (49±13 vs 53±12, P<0.0001) than females and had a higher smoking exposure rate (56% vs 41%, P<0.0001). Baseline (B) CBF was significantly lower in males (27.7 [19.2; 40.8] vs 30.2 [20.6; 43.4], P=0.04). The gap between females and males widened the first 2 doses, but then diminished after the highest dose (41.2 [24.5; 67.8] vs 44.5 [25.9; 72.0], P=0.09) (Fig 1A) . On multivariable analyses, female sex was an independent predictor of higher CBF at all doses (Estimate±StdError) (B= 1.14±0.53; 10 -6 : 1.59±0.61; 10 -5 : 2.54±0.82; 10 -4 : 2.70±1.2; P<0.05 for all). When calculating the %ΔCBF, females had a significantly larger augmentation of flow after the first 2 doses of IC Ach (10 -6 : 3 [-14; 24] vs. -2 [-16; 19], P=0.02; 10 -5 : 21 [-7;68] vs. 12 [-10; 50], P=0.003). However, with the highest Ach dose, there was an equalization of overall augmentation (10 -4 : 49 [-1; 109] vs. 46 [-5; 106], P=0.46) (Fig 1B). Conclusions: Females had higher CBF regardless of given Ach concentration. Females have a higher sensitivity to Ach at smaller doses, while males exhibit a greater vasodilatory reaction at higher doses.

Introduction: Coronary microvascular dysfunction (CMD) is associated with increased morbidity and mortality. Anemia is an important predictor of outcomes in several cardiovascular diseases, such as heart failure and coronary artery disease (CAD), however its significance in patients with non-obstructive CAD is not fully elucidated. Hypothesis: We hypothesized that anemia would be associated with CMD and future adverse outcomes. Methods: We enrolled 1334 patients with signs and/or symptoms of ischemia and with non-obstructive CAD (<50% angiographic stenosis) who underwent invasive CMD evaluation and had follow-up data. CMD was defined as coronary flow reserve (CFR) (hyperemic flow/baseline flow as measured by the doppler wire) of ≤2 in response to intracoronary adenosine injection. Anemia was defined as a Hgb < 13.0 g/L in males and <12.0 g/L in females. MACE was defined as any incidence of myocardial infarction, cardiac revascularization (PCI, CABG) and all-cause mortality. Results: Overall mean age was 51.3±12.4 years, 66% were female. Patients with anemia were more likely to be female and have diabetes mellitus. Anemics were more likely to be diagnosed with CMD (Odds Ratio 2.01, 95% Confidence Interval [1.14-3.54]; P = 0.02). This relationship remained significant even after adjusting for cardiovascular risk factors like age, sex, hypertension, diabetes mellitus and dyslipidemia (OR 1.84, 95% CI [1.03-3.29], P = 0.04). Furthermore, patients with anemia were more likely to experience MACE (OR 1.86, 95% CI [1.30-2.66], P = 0.001), independent of possible confounders (OR 1.84, 95% CI [1.27-2.69], P = 0.002). Conclusions: Anemia is an independent predictor of CMD and future adverse cardiovascular events in patients with NOCAD. Moreover, it was associated with an increased risk of future adverse events. Further studies are needed to elucidate whether treatment of anemia in this population translates into outcomes.

Introduction: Changes in coronary artery diameter (CAD) and coronary blood flow (CBF) in reaction to acetylcholine are important surrogates of endothelial health, and abnormalities in these parameters might represent early atherosclerosis. Menopause is associated with an increased risk of coronary artery disease, yet the role of menopause on the endothelium is not well described. Hypothesis: The vasodilatory response of the endothelium to acetylcholine (Ach) decreases after menopause. Methods: A total of 1271 (42% pre-menopausal) females with angina and non-obstructive coronary artery disease (<50% angiographic stenosis) that underwent coronary reactivity study were enrolled. A doppler wire was positioned and incremental Ach doses were injected (10 -6 , 10 -5 , and 10 -4 mol/L). CBF was then calculated from CAD and doppler-derived flow velocity. Comparisons between the pre-and post-menopause groups were performed. Results: Mean age of the pre-menopausal group was 44±10 years, while that of the post-menopausal 59±9 years. Pre-menopausal females had higher baseline CAD as compared to post-menopausal females (2.22 [1.90; 2.65] vs. 2.20 [1.85; 2.55] mm, P=0.03). However, this difference was nullified with subsequent doses of Ach (Figure 1A&B ). Pre-menopausal females had a higher baseline CBF than post-menopausal females (32.1 [21.7; 44.9] vs. 29.2 [19.8; 42.0] mL/min; P=0.01). This difference progressively increased with successive doses of Ach (10 -4 :49.5 [30.3; 77.0] vs. 41.7 [24.4; 69.0] mL/min; P=0.0002), revealing a greater microvascular vasodilatory response in pre-menopausal females (Cumulative %ΔCBF after highest dose= 60 [2.6; 122] vs 45 [-4; 98], P=0.002) ( Figure 1C&D ). Conclusions: Premenopausal females have greater sensitivity of the microvascular endothelium to Ach compared to post-menopausal, suggesting a possible role for estrogen in mediating the effect of stress on the microvasculature through the endothelium.

Introduction: Diabetes mellitus and insulin resistance are associated with accelerated vascular injury and progression of coronary atherosclerosis. CD34 + progenitor cells are mobilized and recruited to repair the endothelial and vascular damage. Hypothesis: We hypothesized that the interaction of insulin levels and retention of CD34+ progenitors in the coronary arteries will be different between patients with and without insulin resistance. Methods: In patients with no obstructive coronary artery disease (NOCAD: <40% angiographic stenosis), blood samples were collected concurrently from the proximal aorta and the coronary sinus, and CD34+ cells counted using flow cytometry. CD34+ cells gradient was calculated by subtracting aortic from coronary sinus cell counts, with a higher gradient reflecting lower retention. Patients on antidiabetic medications were excluded. Insulin resistance (IR) was estimated as HOMA-IR index ([insulin]*[glucose]/405)) ≥2. Results: Of 128 patients (mean age 51±11 years, 77% females), 60 (47%) had IR (mean age 51±10 years, 73% females) and 68 (53%) did not (mean age 50±13 years, 79% females). The groups did not differ in age, sex or LDL cholesterol. The IR group had higher BMI and triglyceride levels and lower HDL cholesterol. CD34 + cell gradient correlated directly significantly with insulin levels in patients without IR (r=0.25, p=0.04) (Fig1A) , but inversely in those with IR (r=-0.39, p=0.01) (Fig1B) . Both associations remained significant after adjustment for age, sex, and BMI (IR: r=-0.39, p=0.02; no IR: r=29, p=0.04). Conclusions: In NOCAD patients with IR, higher levels of serum insulin were associated with increased retention of CD34 + cells in the coronary arteries. The current study supports a potential role for CD34 + cells for vascular repair in patients with IR.

Introduction: Survivorship needs to be comprehensively evaluated amongst older adults. We examined follow-up mortality in patients referred to cardiac catheterization laboratory by prospectively examining frailty. Methods: Frailty in 923 patients ≥55 years was determined using Rockwood’s deficit index. The frailty deficit was based on symptoms, signs, disabilities, diseases, and laboratory measurements. The number of deficits was expressed as a proportion of the total measured deficits. Frailty index was grouped into <0.10 (control), 0.10-<0.20, 0.20-<0.30, 0.30+ and age- and gender-adjusted follow-up mortality was determined using a Cox proportional hazards model. Results: There were 180 (20%) with frailty index <0.10, 348 (38%) in 0.10-<0.20, 215 (23%) in 0.20-<0.30 and 177 (19%) with an index of 0.30 or higher. Patients with a frailty index of 0.30+ were significantly older than those with an index <0.10 (75 ± 10 vs 67 ± 8 years; p<0.001) and more likely to be women (50% vs 20%; p<0.001). Patients with frailty index ≥0.20 and ≥0.30 had a significantly higher mortality risk (HR 3.95, 95% CI 1.51-10.3 and HR: 10.3, 95% CI 4.11-25.7, respectively) on follow-up which remained significant following adjustment for age and gender (HR 3.20, 95% CI 1.21-8.45 and HR: 7.99, 95% CI 3.13-20.4). Conclusions: Among older adults refereed to catheterization laboratory, frailty deficit index predicts follow-up mortality.

Background: Treatment options for refractory angina not amenable to revascularization are limited. Extracorporeal shockwave myocardial revascularization (ESMR) is a novel non-invasive application of low intensity shock waves that stimulates angiogenesis to improve ischemia. We aimed to determine the safety and efficacy of ESMR in patients with refractory angina. Methods: A single-arm multicenter U.S. prospective trial was implemented to assess safety and efficacy of ESMR therapy in patients with Class III/Class IV refractory angina. Each patient received 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy was assessed at baseline and 4 months after treatment by maximal treadmill exercise time and ischemic burden on pharmacological single photon emission computed tomography (SPECT). Safety was assessed by incidence of adverse events, electrocardiography, echocardiography, laboratory markers, and pain questionnaires. Results: Fifteen patients with medically refractory angina were enrolled. Exercise treadmill time from baseline to last follow-up after ESMR increased significantly (38%) by 122.3±156.9 seconds (319.8±157.2 vs. 422.1±183.3 seconds, p=0.016) (Figure 1). There was no difference in the mean summed stress score (SSS) on pharmacological-SPECT 4 months after treatment vs. baseline (17.8±14.9 vs. 21.2±15.3, p=0.233). However, SPECT SSS revealed that untreated areas had greater progression in ischemic burden vs. treated areas (3.69±6.2 vs. 0.31±4.5, p=0.038). There was no significant change in the mean summed echo score from baseline to post treatment (0.4±5.1, p=0.79).There were no changes in electrocardiography, echocardiographic parameters, or laboratory markers. No serious adverse events or complications occurred, and pain with ESMR was minimal (score of 0.5±1.2 to 1.1±1.2 out of 10). Conclusions: We find that ESMR is a safe and efficacious treatment which may be clinically feasible for patients with refractory angina pectoris.

Objective: To evaluate outcomes of acute spontaneous coronary artery dissection (SCAD) managed with percutaneous coronary intervention (PCI) or conservative therapy. Background: SCAD is a non-atherosclerotic acute coronary syndrome that typically affects young otherwise healthy females. Whether SCAD with normal vessel flow at presentation should be managed with PCI or conservative therapy remains unknown. Methods: We performed a retrospective study of patients after a first SCAD episode (n=142). We excluded those treated with fibrinolysis (n=12) or coronary artery bypass grafting (CABG, n=8). We evaluated in-hospital and late outcomes in three SCAD groups: Vessel occlusion at presentation treated with PCI (Occ-PCI, n=30); normal vessel flow treated with PCI (NF-PCI, n=34) and those managed conservatively (CON, n=58). Results: Overall mean age was 42+9 years, 91% were female and 41% presented with STEMI. Outcomes are shown in the table below. In Occ-PCI, technical failure occurred in 8/30 (27%), of whom 5 required emergency CABG with one in-hospital death. Comparing NF-PCI with CON, there were no differences in clinical characteristics. Technical failure occurred in 16/34 (47%) of NF-PCI due to failure to cross with wire/device (8/34) or final loss of flow (8/34). Emergency CABG was required in 5 (15%). In CON, 54/58 had an uneventful in-hospital course. Four (7%) exhibited early dissection progression of whom two received PCI and one CABG. Long-term rates of target vessel revascularization, but not recurrent SCAD, were higher in NF-PCI vs CON (26% vs 9%, p=0.02; 24% vs 14%, p=0.23). Conclusions: PCI for acute SCAD is associated with high rates of technical failure and adverse clinical outcomes. In SCAD with normal vessel flow, conservative management may be preferable, with close early observation due to a hazard of progression of dissection. These findings underscore the importance of tailoring therapy to etiology of coronary obstruction.

Objectives: CABG and PCI are used for revascularization of multivessel coronary artery disease (MVCAD). However, limited information is available comparing the rates of in-hospital and 30-day major adverse cardiac and cerebrovascular event (early MACCE), including early death, stroke, myocardial infarction (MI), and repeat revascularization, among patients with multiple arterial CABG (MultArt) vs PCI. Methods: We reviewed 12,615 MVCAD patients with isolated primary CABG or PCI from 1993 through 2009. CABG patients (n=6,667) were grouped by number of arterial grafts into left internal mammary artery/saphenous vein (LIMA/SV) (n=5,712) or MultArt (n=955); PCI patients (n=5,948) into balloon angioplasty (BA) (n=1,020), bare metal stent (BMS) (n=3,242), and drug-eluting stent (DES) (n=1,686). Results: Early MACCE rate was significantly greater for PCI than CABG (8.5% vs 4.1% [P<.001]) and lower for MultArt than LIMA/SV or PCI (1.5% vs 4.5% and 8.5%, respectively [P<.001]). Stroke and early death rates were higher in CABG vs PCI (2.2% vs 0.4% [P<.001], and 1.5% vs 1.0% [P=0.01], respectively), whereas MI and repeat revascularization were lower (0.5% vs 6.0% and 0.3% vs 2.2%, respectively [P<.001]). Stroke and early death were similar in MultArt and PCI and lower vs LIMA/SV (0.6% and 0.4% vs 2.6%, and 0.5% and 1.0% vs 1.7%, respectively [P<.001]); MI and repeat revascularization rates were similar in MultArt and LIMA/SV and lower vs PCI (0.4% and 0.6% vs 6.0%, and 0.3% and 0.3% vs 2.3%, respectively [P<.001]). In propensity score-matched analysis, CABG had significantly improved early MACCE rate compared with BA (4.7% vs 13.2% [P<.001]), BMS (4.3% vs 8.3% [P<.001]), and DES (2.9% vs 5.5% [P=.008]), and MultArt compared with PCI (1.8% vs 7.8% [P<.001]) fig. Conclusions: In MVCAD patients undergoing isolated primary revascularization, CABG conferred lower early MACCE rate vs PCI. Early MACCE rate was markedly decreased after MultArt compared with LIMA/SV, BA, BMS, and DES.

Introduction: We compared outcome of repeat CABG (RCABG) and PCI in patients with previous CABG. Hypothesis: RCABG may improve survival versus PCI. Methods: From 1993 through 2009, 3,058 patients underwent revascularization after previous CABG. RCABG patients (n=530) were grouped by the use of arterial grafts (n=396), or saphenous vein grafts (SVG; n=134). At previous CABG, 37% of RCABG patients received IMA graft. PCI patients (n=2,528) were grouped into balloon angioplasty (BA; n=491), bare metal stent (BMS; n=1,267), and drug-eluting stent (DES; n=769). PCI patients were further stratified by the treated target into native coronary artery (n=1,637), bypass grafts (n=674), or both (n=216). Propensity score analysis matched 287 patients. Results: RCABG had increased 30-day mortality compared with PCI (HR=3.92; 95% CI, 2.25-6.84; P <.001) in multivariable analysis, while in propensity matched analysis it did not ( P =.09). Overall survival, however, was greater for RCABG compared with PCI in multivariable analysis (HR=0.70; 95% CI, 0.59-0.83; P <.001), as well as in propensity matched analysis (10-year survival rates were 52% vs 37%, respectively [ P =.005]). Compared with RCABG, PCI involving bypass grafts had increased mortality (HR, 1.39; 95% CI, 1.09-1.78; P =.008), whereas PCI targeting only the native coronaries did not (HR, 1.12; 95% CI, 0.85-1.47; P =.43); BMS patients had increased mortality (HR, 1.34; 95% CI, 1.06-1.68; P =.013), but DES did not (HR, 1.28; 95% CI, 0.77-2.12; P =.35). At RCABG, 318 patients (60%) received an IMA graft and late survival was similar to those receiving SVG; The use of IMA in previous CABG was associated with improved survival (HR=0.82; 95% CI, 0.72-0.92; P <.001]. Conclusions: Long-term survival after previous CABG is improved with RCABG compared to PCI, especially when PCI involves bypass grafts. There is no difference in long-term survival between RCABG using arterial grafts vs SVG only if IMA is used in either previous or RCABG.