Viviany R. Taqueti

A brief history of the development of mannequin simulators for clinical education and training

Simulation for medical and healthcare applications, although still in a relatively nascent stage of development, already has a history that can inform the process of further research and dissemination. The development of mannequin simulators used for education, training, and research is reviewed, tracing the motivations, evolution to commercial availability, and efforts toward assessment of efficacy of those for teaching cardiopulmonary resuscitation, cardiology skills, anaesthesia clinical skills, and crisis management. A brief overview of procedural simulators and part-task trainers is also presented, contrasting the two domains and suggesting that a thorough history of the 20+ types of simulator technologies would provide a useful overview and perspective. There has been relatively little cross fertilisation of ideas and methods between the two simulator domains. Enhanced interaction between investigators and integration of simulation technologies would be beneficial for the dissemination of the concepts and their applications.

Effects of Sex on Coronary Microvascular Dysfunction and Cardiac Outcomes

Background— Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease. The relative extent to which CMD affects both sexes is largely unknown. Methods and Results— We investigated 405 men and 813 women who were referred for evaluation of suspected coronary artery disease with no previous history of coronary artery disease and no visual evidence of coronary artery disease on rest/stress positron emission tomography myocardial perfusion imaging. Coronary flow reserve was quantified, and coronary flow reserve <2.0 was used to define the presence of CMD. Major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, late revascularization, and hospitalization for heart failure, were assessed in a blinded fashion over a median follow-up of 1.3 years (interquartile range, 0.5–2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; Fisher exact test =0.39; equivalence P=0.0002). Regardless of sex, coronary flow reserve was a powerful incremental predictor of major adverse cardiac events (hazard ratio, 0.80 [95% confidence interval, 0.75–086] per 10% increase in coronary flow reserve; P<0.0001) and resulted in favorable net reclassification improvement (0.280 [95% confidence interval, 0.049–0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (n=404; 307 women/97 men) without evidence of coronary artery calcification on gated computed tomography imaging, CMD was common in both sexes, despite normal stress perfusion imaging and no coronary artery calcification (44% of men versus 48% of women; Fisher exact test P=0.56; equivalence P=0.041). Conclusions— CMD is highly prevalent among at-risk individuals and is associated with adverse outcomes regardless of sex. The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions.

Global Coronary Flow Reserve Is Associated With Adverse Cardiovascular Events Independently of Luminal Angiographic Severity and Modifies the Effect of Early Revascularization

Background— Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease (CAD), identifies patients at risk for cardiac death. We sought to determine the association between CFR, angiographic CAD, and cardiovascular outcomes. Methods and Results— Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease were estimated with the use of the CAD prognostic index, and CFR was measured noninvasively by positron emission tomography. A modest inverse correlation was seen between CFR and CAD prognostic index (r=−0.26; P<0.0001). After adjustment for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CAD prognostic index were independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% confidence interval, 1.20–3.40; P=0.008; hazard ratio for 10-U increase in CAD prognostic index, 1.17; 95% confidence interval, 1.01–1.34; P=0.032). Subjects with low CFR experienced rates of events similar to those of subjects with high angiographic scores, and those with low CFR or high CAD prognostic index showed the highest risk of events (P=0.001). There was a significant interaction (P=0.039) between CFR and early revascularization by coronary artery bypass grafting, such that patients with low CFR who underwent coronary artery bypass grafting, but not percutaneous coronary intervention, experienced event rates comparable to those with preserved CFR, independently of revascularization. Conclusions— CFR was associated with outcomes independently of angiographic CAD and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact the outcomes of revascularization.

Preserved Coronary Flow Reserve Effectively Excludes High-Risk Coronary Artery Disease on Angiography

Myocardial perfusion imaging has limited sensitivity for the detection of high-risk coronary artery disease (CAD). We tested the hypothesis that a normal coronary flow reserve (CFR) would be helpful for excluding the presence of high-risk CAD on angiography. Methods: We studied 290 consecutive patients undergoing 82Rb PET within 180 d of invasive coronary angiography. High-risk CAD on angiography was defined as 2-vessel disease (≥70% stenosis), including the proximal left anterior descending artery; 3-vessel disease; or left main CAD (≥50% stenosis). Patients with prior Q wave myocardial infarction, elevated troponin levels between studies, prior coronary artery bypass grafting, a left ventricular ejection fraction of less than 40%, or severe valvular heart disease were excluded. Results: Fifty-five patients (19%) had high-risk CAD on angiography. As expected, the trade-off between the sensitivity and the specificity of the CFR for identifying high-risk CAD varied substantially depending on the cutoff selected. In multivariable analysis, a binary CFR of less than or equal to 1.93 provided incremental diagnostic information for the identification of high-risk CAD beyond the model with the Duke clinical risk score (>25%), percentage of left ventricular ischemia (>10%), transient ischemic dilation index (>1.07), and change in the left ventricular ejection fraction during stress (<2) (P = 0.0009). In patients with normal or slightly to moderately abnormal results on perfusion scans (<10% of left ventricular mass) during stress (n = 136), a preserved CFR (>1.93) excluded high-risk CAD with a high sensitivity (86%) and a high negative predictive value (97%). Conclusion: A normal CFR has a high negative predictive value for excluding high-risk CAD on angiography. Although an abnormal CFR increases the probability of significant obstructive CAD, it cannot reliably distinguish significant epicardial stenosis from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.

Interaction of Impaired Coronary Flow Reserve and Cardiomyocyte Injury on Adverse Cardiovascular Outcomes in Patients Without Overt Coronary Artery Disease

Background— Minimally elevated serum cardiac troponin reflects myocardial injury and is associated with increased mortality, even absent coronary artery disease (CAD). We sought to investigate the relationship between low-level troponin elevation and impaired coronary flow reserve (CFR), an integrated measure of coronary vasomotor function, and to assess their contributions to adverse outcomes in patients without overt CAD. Methods and Results— Consecutive patients (n=761) undergoing evaluation for suspected CAD with troponin before stress myocardial perfusion positron emission tomography were followed up (median, 2.8 years) for major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, or late revascularization. Patients with flow-limiting CAD, left ventricular ejection fraction <40%, or revascularization within 60 days of imaging were excluded. CFR was quantified from stress/rest myocardial blood flow with the use of positron emission tomography. Compared with patients with negative troponin, those with at least 1 positive troponin (n=97) had higher pretest clinical scores, more renal dysfunction, and lower left ventricular ejection fraction and CFR. In adjusted analysis, impaired CFR remained independently associated with positive troponin (odds ratio, 2.18; 95% confidence interval, 1.37–3.47; P=0.001), and both impaired CFR and positive troponin were independently associated with major adverse cardiovascular events (hazard ratio, 2.25; 95% confidence interval, 1.31–3.86; P=0.003; and hazard ratio, 2.42; 95% confidence interval, 1.34–4.40; P=0.004, respectively). Impaired CFR and positive troponin identified patients at highest risk of major adverse cardiovascular events (log-rank P<0.0001), with a significant interaction (P<0.007) seen between CFR and troponin. Conclusions— In patients without overt CAD, impaired CFR was independently associated with minimally elevated troponin and major adverse cardiovascular events. Impaired CFR, here reflecting microvascular dysfunction, modified the effect of a positive troponin on adverse outcomes.

Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated with Severely Impaired Coronary Flow Reserve, Not Obstructive Disease

Background: Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. Methods: Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction >40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. Results: Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD (P<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05–4.02; P=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (P<0.0001, P for interaction=0.04). Conclusions: Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.

A small-molecule antagonist of LFA-1 blocks a conformational change important for LFA-1 function

Lymphocyte function‐associated antigen(LFA)‐1/intercellular adhesion molecule (ICAM)‐1interactions mediate several important steps in the evolution of animmune response. LFA‐1 is normally expressed in a quiescent state onthe surface of leukocytes and interacts weakly with its ligands ICAM‐1,‐2, and ‐3. LFA‐1 activity may be regulated by receptor clustering andby increasing the affinity of LFA‐1 for its ligands. Affinitymodulation of LFA‐1 has been shown to occur via a conformational changein the LFA‐1 heterodimer that can be detected by using monoclonalantibody 24 (mAb24). We have recently described a small‐moleculeantagonist of LFA‐1, BIRT 377, that demonstrates selective in vitro andin vivo inhibition of LFA‐1/ICAM‐1‐mediated binding events. We nowdemonstrate that BIRT 377 blocks the induction of the mAb24 reporterepitope on LFA‐1 on the surface of SKW‐3 cells treated with variousagonists known to induce high‐affinity LFA‐1. These data imply thatBIRT 377 exerts its inhibitory effects by preventing up‐regulation ofLFA‐1 to its high‐affinity conformation.

T-bet Controls Pathogenicity of CTLs in the Heart by Separable Effects on Migration and Effector Activity

CD8+ CTL contribute to the pathogenesis of myocarditis and cardiac allograft rejection. Using a transgenic model of myocarditis, we examined the role of the transcription factor T-bet in the differentiation of pathogenic cardiac Ag-specific CTL. We demonstrate that T-bet-deficient CTL are significantly impaired in their ability to cause disease, despite intact proliferation and activation phenotypes. In the absence of T-bet, there is markedly reduced expression of the chemokine receptor CXCR3, and CXCR3-gene knockout CTL are significantly less pathogenic than control CTL. Retroviral-mediated CXCR3 expression in T-bet-deficient CD8+ T cells reconstitutes their ability to infiltrate but not to damage the heart, establishing that CD8+ T cell pathogenicity is related to T-bet-dependent CXCR3 expression, reduced cytotoxicity, and enhanced regulation. These findings highlight the potential therapeutic benefit of targeting T-bet-regulated gene expression and CXCR3-dependent migration in immune-mediated heart disease.

Increased Microvascularization and Vessel Permeability Associate with Active Inflammation in Human Atheromata

Background—Studies have shown the feasibility of imaging plaques with 2-deoxy-2-[18F]fluoroglucose (FDG) positron emission tomography and dynamic contrast–enhanced magnetic resonance imaging with inconsistent results. We sought to investigate the relationship between markers of inflammatory activation, plaque microvascularization, and vessel wall permeability in subjects with carotid plaques using a multimodality approach combining FDG positron emission tomography, dynamic contrast–enhanced magnetic resonance imaging, and histopathology. Methods and Results—Thirty-two subjects with carotid stenoses underwent noninvasive imaging with FDG positron emission tomography and dynamic contrast–enhanced magnetic resonance imaging, 46.9% (n=15) before carotid endarterectomy. We measured FDG uptake (target:background ratio [TBR]) by positron emission tomography and Ktrans (reflecting microvascular permeability and perfusion) by magnetic resonance imaging and correlated imaging with immunohistochemical markers of macrophage content (CD68), activated inflammatory cells (major histocompatibility complex class II), and microvessels (CD31) in plaque and control regions. TBR and Ktrans correlated significantly with tertiles of CD68+ (P=0.009 and P=0.008, respectively), major histocompatibility complex class II+ (P=0.003 and P<0.001, respectively), and CD31+ (P=0.004 and P=0.008, respectively). Regions of plaques were associated with increased CD68+ (P=0.002), major histocompatibility complex class II+ (P=0.002), CD31+ (P=0.02), TBR (P<0.0001), and Ktrans (P<0.0001), as compared with those without plaques. Microvascularization correlated with macrophage content (rs=0.52; P=0.007) and inflammatory activity (rs=0.68; P=0.0001) and TBR correlated with Ktrans (rs=0.53; P<0.0001). In multivariable mixed linear regression modeling, TBR remained independently associated with Ktrans (&bgr;[SE], 2.68[0.47]; P<0.0001). Conclusions—Plaque regions with active inflammation, as determined by macrophage content and major histocompatibility complex class II expression, showed increased FDG uptake, which correlated with increased Ktrans and microvascularization. The correlation between Ktrans and TBR was moderate, direct, highly significant, and independent of clinical symptoms and plaque luminal severity.

Correlates of carotid stenosis in patients undergoing coronary artery bypass grafting--a case control study.

Abstract Carotid duplex ultrasonography (DUS) is routinely performed prior to coronary artery bypass graft surgery (CABG) on all patients > 65 years old because of the reported associated risk of finding concomitant carotid artery stenosis. Identifying risk factors that correlate with severe carotid stenosis may result in more cost-effective screening for patients with asymptomatic carotid artery disease prior to CABG. We performed a retrospective study to identify risk factors for significant carotid artery disease in patients scheduled to undergo CABG between March 2005 and March 2008 at the Massachusetts General Hospital. Patients with carotid stenosis ≥ 70% identified by DUS (n = 50) were matched by age and sex to control patients who had < 50% stenosis (n = 50). Data were analyzed using the chi-squared test or analysis of variance as appropriate. Logistic regression was used to examine multivariate correlates of carotid stenosis. A total of 643 patients were screened to arrive at the patient cohorts described below. This produced a prevalence of 7.7% for significant (> 70%) carotid disease. The patient cohorts were predominantly male with no significant difference in the incidence of diabetes, hypertension, extent of coronary artery disease (CAD) (i.e. left main coronary artery disease (LMCA) and one, two-, or three-vessel CAD) or lipid abnormalities in the two groups. Univariate analysis identified the presence of peripheral arterial disease (PAD, p = 0.001), a cervical bruit (p < 0.0001), a prior neurological event (p = 0.020), and the presence of an abdominal aortic aneurysm (AAA; p = 0.046) as significant predictors of ≥ 70% internal carotid artery stenosis. Logistic regression analysis revealed that the presence of a carotid bruit (p = 0.0068) and PAD (p = 0.0194) were associated with an increased risk of significant carotid artery disease. In conclusion, the presence of a carotid bruit or PAD predicts an increased likelihood of significant carotid artery disease in patients undergoing CABG. Unlike previous studies, LMCA or extent of CAD did not correlate with significant carotid artery disease. Using these predictive models, a prospective outcomes trial is required to validate these criteria.