Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry - Informing optimal antiplatelet strategies.

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no-function allele carriers. However, the influence of patient-specific demographic, clinical, and other genetic factors on outcomes with genotype-guided DAPT has not been defined. In addition, the impact of genotype-guided de-escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no-function allele has not been investigated in a diverse, real-world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient-specific factors on clinical outcomes with CYP2C19-guided DAPT, evaluate the safety and effectiveness of CYP2C19-guided DAPT de-escalation following PCI in a real-world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real-world population.

Risk Factors, Use of Revascularization, and Outcomes in Young Adults With ST-Elevation Myocardial Infarction.

The incidence of acute myocardial infarction is increasing in younger age groups, with differences in treatment and outcomes based on gender. ST-elevation myocardial infarction (STEMI) in young adults, however, is incompletely understood as most of the current studies were performed in homogenous populations, did not focus on STEMI, and lack direct comparisons with older adults. We performed a retrospective observational study using the Statewide Planning And Research Cooperative System for all admissions in New York State with a principal diagnosis of STEMI from 2011 to 2018. There were 58,083 STEMIs with the majority being male (68.2%) and non-Hispanic White (64.8%), with an average age of 63.9 ± 13.9 years. Of these, 8,494 (14.6%) occurred in patients aged <50 years. The proportion of STEMIs in women increased with age, from 19.2% in the <50-year-old age group to 48.9% in the ≥70-year-old age group. Young adults with STEMI had greater prevalence of obesity, current tobacco use, other substance use, and major psychiatric disorders, were more likely to receive revascularization, and had lower 1-year mortality than older age groups. Revascularization was associated with at least a 3 times lower odds ratio of 1-year mortality in all age groups. In conclusion, young adults with STEMI had a unique set of risk factors and co-morbidities and were more likely to undergo revascularization than older age groups. In all age groups, female gender was associated with a higher burden of co-morbidities, decreased use of revascularization, and increased 1-year mortality.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

Pharmacogenomic prescribing opportunities in percutaneous coronary intervention and bone marrow transplant patients.

Aim: To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Patients & methods: Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. Results: In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. Conclusion: A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.

Patients with Left Ventricular Thrombus Despite Normal Systolic Function.

The formation of a thrombus in the left ventricle (LV) in patients with normal systolic function is very rare. We report a case and identified 31 other adult patients who had an LV thrombus with normal LV systolic function. The median (IQR) age of these patients was 43 [37,59] years with a slight male predominance (59%). The vast majority of patients presented with embolic complications (28; 88%) with 3 of the other patients presenting with a febrile illness. Most of the cases occurred in the setting of an identifiable medical condition that carries an increased risk of thrombosis including inflammatory diseases, malignancies or hypereosinophilia. Treatment generally included anticoagulation with or without surgical removal or systemic thrombolysis. Recurrence of LV thrombus and/or embolic events have been reported in patients with LV thrombus and normal LV systolic function suggesting that long term anticoagulation may be needed.

Expression of Cyr61 in ApoE-/- mice with chronic unilateral renal artery ligation.

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE-/- mice were randomized to surgically induced RAS, RAS + treatment with either irbesartan, aliskiren or amlodipine or sham-surgery. RAS resulted in increased plasma angiotensin II levels, a mild, sustained increase in systolic blood pressure and increased aortic lipid deposition compared to sham-surgery. Surgically induced RAS led to the formation of atheroma in the infrarenal aorta and there was consistent and intense staining for Cyr61 within the atheroma. Treatment with irbesartan, aliskiren and amlodipine were associated with decreased aortic lipid deposition and decreased staining for Cyr61 in aortic atheroma. Serum levels of Cyr61 were not increased in mice or humans with RAS. In summary, Cyr61 expression in aortic atheroma but not serum is increased by RAS in ApoE-/- mice and is reduced by agents that lower blood pressure.

Ability of a novel shock index that incorporates invasive hemodynamics to predict mortality in patients with ST-elevation myocardial infarction.

OBJECTIVE: To determine whether the use of invasively measured hemodynamics improves the prognostic ability of a shock index (SI). BACKGROUND: SI such as Admission-SI, Age-SI, Modified SI (MSI), and Age-MSI predict short-term mortality in ST-elevation myocardial infarction (STEMI). METHODS: Single-center study of 510 patients who underwent primary percutaneous coronary intervention. STEMI SI was defined as age × heart rate (HR) divided by coronary perfusion pressure (CPP). RESULTS: The mean age was 62 ± 14 years, 66% were males with hypertension (69%), tobacco use (38%), diabetes (28%) and chronic kidney disease (6%). The mean HR, systolic blood pressure (SBP), and CPP were 81 ± 18 bpm, 124 ± 28 mmHg, and 52.8 ± 16.3 mmHg, respectively. Patients with STEMI SI ≥182 (n = 51) were more likely to experience a cardiac arrest in the catheterization laboratory (9.8% vs. 2.0%; p = .001), require mechanical circulatory support (47.1% vs. 8.5%; p < .0001) and be treated with vasopressors (56.9% vs. 10.7%; p < .0001) compared to STEMI SI < 182 (n = 459). After multivariate adjustment, patients with STEMI SI ≥182 were 10, 10.1 and 4.8 times more likely to die during hospitalization, at 30 days and at 5 years, respectively. The C statistic of STEMI SI was 0.870, similar to GRACE score (AUC = 0.902; p = .29) and TIMI STEMI score (AUC = 0.895; p = .36). CONCLUSION: STEMI SI is an easy to calculate risk score that identifies STEMI patients at high risk of in-hospital death.

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.

Targeted repair of heart injury by stem cells fused with platelet nanovesicles.

Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.

Projected impact of a multigene pharmacogenetic test to optimize medication prescribing in cardiovascular patients.

AIM: To determine the projected impact of a multigene pharmacogenetic (PGx) test on medication prescribing. MATERIALS & METHODS: A retrospective analysis was conducted with 122 cardiac catheterization laboratory patients undergoing angiography for eligibility of potential PGx-guided interventions that could have occurred if multigene PGx information was pre-emptively available at the time of the procedure. Medication data and presence of actionable at-risk genotypes were used to determine eligibility of a PGx intervention. RESULTS: 20% of the study population (n = 24) would have qualified for at least one PGx-based medication intervention per US FDA or Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines within 6 months of their cardiac catheterization procedure. Commonly encountered gene-drug pairs for these interventions included: CYP2C19 for clopidogrel and antidepressants, CYP2D6 for antidepressants and codeine, SLCO1B1 for simvastatin, and VKORC1/CYP2C9 for warfarin. CONCLUSION: Pre-emptive use of a multigene PGx test in the cardiac catheterization laboratory offers potential to reduce adverse medication outcomes.

Clinical Evidence Supports a Protective Role for CXCL5 in Coronary Artery Disease.

Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both DNA genotyping and mRNA expression levels in peripheral blood mononuclear cells were quantified via microarray gene chips. We observed a negative association of CXCL5 levels with CAD at an odds ratio (OR) of 0.46 (95% CI, 0.27-0.75). Controlling for covariates, including sex, statin use, hypertension, hyperlipidemia, obesity, self-reported race, smoking, and diabetes, the OR was not significantly affected [OR, 0.54 (95% CI, 0.31-0.96)], consistent with a protective role for CXCL5 in coronary atherosclerosis. We also identified 18 genomic regions with expression quantitative trait loci of genes correlated with both CAD severity and circulating CXCL5 levels. Our clinical findings are consistent with the emerging link between chemokines and atherosclerosis and suggest new therapeutic targets for CAD.

Angiographic severity does not correlate with fractional flow reserve in heavily calcified coronary arteries.

OBJECTIVES: To determine the relationship between severity of stenosis and hemodynamic significance in calcified coronary arteries. BACKGROUND: Severity of stenosis is widely used to determine the need for revascularization but the effect of lesion calcification on hemodynamic significance is not well understood. METHODS: Two hundred consecutive patients undergoing fractional flow reserve (FFR) testing of an intermediate coronary lesion with a pressure wire and intravenous infusion of adenosine were studied. Coronary calcium was quantified based upon radiopacities at the site of the stenosis on cineangiography using the method of Mintz et al. (0 = none or mild calcium, 1 = moderate calcium, 2 = severe calcium). RESULTS: Mean age was 61 ± 11 years, 66% were males, 87.5% had hypertension, 44.5% had diabetes, and 20.5% were current smokers. The mean coronary stenosis by quantitative coronary angiography was 60 ± 12% and the mean FFR was 0.83 ± 0.08. There were 109, 45, and 46 patients classified as Calcium Score of 0, 1, or 2, respectively. Compared to those with no/mild or moderate calcification, patients with severe coronary calcium were older and more likely to have chronic kidney disease and pulmonary disease. The correlation between angiographic severity and FFR decreased as lesion calcification increased [calcium score = 0 (R2 = 0.25, P < 0.005); calcium score = 1 (R2 = 0.11, P < 0.005); calcium score = 2 (R2 = 0.02, P = 0.35)]. CONCLUSIONS: In patients with heavily calcified coronary lesions, there was no association between angiographic stenosis and hemodynamic significance and FFR is needed to determine hemodynamic significance of intermediate lesions. © 2016 Wiley Periodicals, Inc.

Identification of Factors Associated With Improved Survival After Renal Artery Stenting.

Atherosclerotic renal artery stenosis (RAS) is associated with high mortality rates, but large randomized trials have not shown improvement in survival with renal artery stenting. These results suggest that factors other than ongoing renal hypoperfusion are important in determining survival in patients with RAS. Using logistic regression models, we performed a single-center, case-control study that included 188 patients with ≥70% RAS with an average age of 67 ± 10 years, 54% women, 20% black, and 70% smokers; 118 patients (63%) underwent renal artery stenting. A total of 89 patients (47%) died during an average follow-up of 5.1 years. Previous myocardial infarction (MI) (odds ratio 2.6 95% confidence interval [1.4 to 4.7]), left ventricular ejection fraction (LVEF) ≤35% (odds ratio 4.1 95% confidence interval [1.6 to 10.6]), and renal insufficiency were predictors of mortality in this study. The risk associated with LVEF ≤35% and previous MI were additive with mortality of 40%, 54%, and 85%, respectively, with 0, 1, or both these factors. Renal artery stenting was associated with a 43% reduction in mortality in patients with 0 or 1 mortality risk factors (defined as LVEF ≤35%, previous MI, and glomerular filtration rate ≤45 ml/min/1.73 m2) but had no effect on mortality in patients with 2 or 3 mortality risk factors. Systolic blood pressure, diastolic blood pressure, or severity of RAS did not correlate with survival. In conclusion, this retrospective analysis suggests that clinical, in addition to anatomic and physiological, factors should be considered in future studies examining effects of renal artery stenting on survival.

Effects of Restoration of Blood Flow on the Development of Aortic Atherosclerosis in ApoE-/- Mice With Unilateral Renal Artery Stenosis.

BACKGROUND: Chronic unilateral renal artery stenosis (RAS) causes accelerated atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) mice, but effects of restoration of renal blood flow on aortic atherosclerosis are unknown. METHODS AND RESULTS: Male ApoE(-/-) mice underwent sham surgery (n=16) or had partial ligation of the right renal artery (n=41) with the ligature being removed 4 days later (D4LR; n=6), 8 days later (D8LR; n=11), or left in place for 90 days (chronic RAS; n=24). Ligature removal at 4 or 8 days resulted in improved renal blood flow, decreased plasma angiotensin II levels, a return of systolic blood pressure to baseline, and increased plasma levels of neutrophil gelatinase associated lipocalin. Chronic RAS resulted in increased lipid staining in the aortic arch (33.2% [24.4, 47.5] vs 11.6% [6.1, 14.2]; P<0.05) and descending thoracic aorta (10.2% [6.4, 25.9] vs 4.9% [2.8, 7.8]; P<0.05), compared to sham surgery. There was an increased amount of aortic arch lipid staining in the D8LR group (22.7% [22.1, 32.7]), compared to sham-surgery, but less than observed with chronic RAS. Lipid staining in the aortic arch was not increased in the D4LR group, and lipid staining in the descending aorta was not increased in either the D8LR or D4LR groups. There was less macrophage expression in infrarenal aortic atheroma in the D4LR and D8LR groups compared to the chronic RAS group. CONCLUSIONS: Restoration of renal blood flow at either 4 or 8 days after unilateral RAS had a beneficial effect on systolic blood pressure, aortic lipid deposition, and atheroma inflammation.

Review of clopidogrel dose escalation in the current era of potent P2Y12 inhibitors.

Dual anti-platelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for patients with acute coronary syndromes (ACS) and for patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is associated with increased risk of high on-treatment platelet reactivity (HTPR) compared to ticagrelor and prasugrel. Investigators have therefore sought to "escalate" clopidogrel dosing to overcome HTPR to reduce ischemic/thrombotic events. In this review, we will summarize the evidence for dose escalation in the context of genetic determinants of resistance and platelet function data. We will review contemporary clinical trials that have sought to improve delivery of dual antiplatelet therapy to patients with coronary artery disease and discuss the potential of clopidogrel dose escalation in specific populations.

Risk of developing coronary artery disease following a normal coronary angiogram in middle-aged adults.

Atherosclerosis begins in the teenage years and progresses over time in susceptible individuals. It is unknown, however, whether coronary angiography in middle-aged adults showing no evidence of atherosclerosis identifies individuals at low risk for subsequent development of coronary artery disease (CAD). We identified 4068 patients ≥40 years of age who had at least two coronary angiograms between January 1, 1990 and March 31, 2011. Of these, 227 patients (5.8%) had no CAD and 251 patients (6.4%) had mild atherosclerotic disease (stenosis <30%) on the initial angiogram. Patients in the normal-angiogram group were younger, more often female, and less likely to use tobacco than patients in the mild-atherosclerosis group, while rates of diabetes and hypertension were the same. Angiographic evidence of any CAD and obstructive CAD was apparent in 26% and 4.8%, respectively of the normal-angiogram group on subsequent angiography performed 75 ± 46 months later. Myocardial infarction and revascularization occurred in 4.8% and 3.5%, respectively. Progression of CAD (odds ratio = 10.2), development of obstructive CAD (odds ratio = 8.9), myocardial infarction (odds ratio = 2.7), and revascularization (odds ratio = 8.4) were more frequent in the mild-atherosclerosis group. In summary, 26% of middle-aged adults with a normal coronary angiogram who had subsequent angiography for clinical reasons developed CAD, although the annual rates of myocardial infarction or revascularization were very low. Even mild atherosclerosis on the initial angiogram increased the rate of progression of CAD by 10-fold and the rate of revascularization by 8-fold.