Dagmar F. Hernandez-Suarez

Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics

Background: Clopidogrel is by far the most prescribed platelet adenosine diphosphate (ADP) antagonist in Puerto Rico despite the advent of newer agents (prasugrel and ticagrelor). Given the paucity of data on clopidogrel responsiveness in Hispanics, we sought to determine the association between clinical characteristics and platelet reactivity in Puerto Rican patients on clopidogrel therapy. Study population: A total of 100 Puerto Rican patients on clopidogrel therapy were enrolled and allocated into two groups: Group I, without high on-treatment platelet reactivity (HTPR); and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay. Results: The cohort was comprised of Hispanic patients with coronary artery disease (57%), peripheral artery disease (32%), carotid artery stenosis (7%), cerebral artery aneurysm (2%), and stroke (2%). Mean platelet reactivity was 200 ± 61 P2Y12 reaction units (PRUs) (range: 8–324), and 35% of patients had HTPR (PRUs ⩾ 230). Multivariable logistic regression analysis determined that diabetes mellitus (DM) [odds ratio (OR) = 3.27; 95% confidence interval (CI): 1.20–8.96], use of proton-pump inhibitors (PPIs) (OR = 3.60; 95% CI: 1.09–11.82), and calcium channel blockers (CCBs) (OR = 3.10; 95% CI: 1.09–8.83) were independent predictors of HTPR (p < 0.05) after adjusting for other clinical variables. Conclusions: In a sample of 100 Puerto Rican Hispanic patients on clopidogrel, 35% had HTPR. Furthermore, DM, PPIs and CCBs predicted HTPR. Clinical outcome data are needed to identify appropriate PRU thresholds for risk prediction in the Puerto Rican population.

Potential Usefulness of Clopidogrel Pharmacogenetics in Ce rebral Endovascular Procedures and Carotid Artery Stenting

BACKGROUND Previous reports have shown inadequate response to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in 5-30% of patients undergoing percutaneous coronary interventions (PCI), due mostly to clopidogrel resistance. This prevalence increases up to 66% in patients undergoing neurointerventional procedures. However, clinical significance of CYP2C19 genotypes in neurointerventional procedures or carotid artery stenting (CAS) is unknown. OBJECTIVE The purpose of this review is to update our current knowledge and understanding of the pharmacogenetic basis for poor clopidogrel responsiveness in patients undergoing CAS and endovascular interventions as well as to explore usefulness of genotyping to reduce the rate of procedure-related thrombosis that results in ischemic complications. METHOD A literature search for pharmacogenetic studies in cerebral endovascular interventions and CAS was conducted on three databases using a list of the most relevant pharmacogenetic biomarkers. RESULTS The review included 7 papers involving 3 genetic polymorphisms on CYP2C19 and 442 subjects. Patients harboring at least one loss-of-function CYP2C19 polymorphism (e.g., CYP2C19*2 and *3) are at an increased risk of thromboembolic complications such as stent thrombosis following neurointerventional procedures. Notably, patients who carry the gain-of-function CYP2C19*17 allele may have increased risk of ischemic events following endovascular treatment, independent of clopidogrel responsiveness. CONCLUSION Studies assessing the influence of CYP2C19 polymorphisms on high on-treatment platelet reactivity in CAS and cerebrovascular disease patients are still limited and need further validation in large multicenter studies. This review covers an important topic in the field of antiplatelet therapy for cerebral endovascular procedures and CAS.

Effect of cilostazol on platelet reactivity among patients with peripheral artery disease on clopidogrel therapy

Abstract Background: Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel. Methods: We performed a cross-sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measured ex vivo using the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19, ABCB1, PON1 and P2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute). Results: Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207±53 (range, 78–325) with higher P2Y12 reaction units in the non-cilostazol group, 224±45 vs. 191±55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity. Conclusions: In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR.

Pharmacogenetic association study on clopidogrel response in Puerto Rican Hispanics with cardiovascular disease: a novel characterization of a Caribbean population

Introduction High on-treatment platelet reactivity (HTPR) to clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease. Methods We performed a retrospective study of 111 patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU) ≥230. Genotyping testing was performed using Taqman® Genotyping Assays. Results The mean PRU across the cohort was 203±61 PRU (range 8–324), and 42 (38%) patients had HTPR. Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (odds ratio [OR]=1.15; 95% CI: 1.03–1.27), diabetes mellitus (OR=3.46; 95% CI: 1.05–11.43), hematocrit (OR=0.75; 95% CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; 95% CI: 1.21–16.20) were the only independent predictors of HTPR. Conclusion Moreover, we propose a predictive model to determine PRU values as measured by VerifyNow P2Y12 assay for the Puerto Rican Hispanic population. This model has the potential to identify Hispanic patients at higher risk for adverse events on clopidogrel.

Clinical Relevant Polymorphisms Affecting Clopidogrel Pharmacokinetics and Pharmacodynamics: Insights from the Puerto Rico Newborn Screening Program

Background: Variations in several clopidogrel-pharmacogenes have been linked to clopidogrel response variability and clinical outcomes. We aimed to determine the frequency distribution of major polymorphisms on CYP2C19, PON1, ABCB1 and P2RY12 pharmacogenes in Puerto Ricans. Methods: This was a cross-sectional, population-based study of 200 unrelated “Guthrie” cards specimens from newborns registered in the Puerto Rican newborn screening program (PRNSP) between 2004 and 2014. Taqman® SNP assay techniques were used for genotyping. Results: Minor allele frequencies (MAF) were 46% for PON1 (rs662), 41% for ABCB1 (rs1045642), 14% for CYP2C19*17, 13% for CYP2C19*2, 12% for P2RY12-H2 and 0.3% for CYP2C19*4. No carriers of the CYP2C19*3 variants were detected. All alleles and genotype proportions were found to be in Hardy–Weinberg equilibrium (HWE). Overall, there were no significant differences between MAFs of these variants in Puerto Ricans and the general population (n = 453) of the 1000 Genome project, except when comparisons to each individual parental group were performed (i.e., Africans, Europeans and East-Asians; p < 0.05). As expected, the prevalence of these markers in Puerto Ricans most resembled those in the 181 subjects from reference populations of the Americas. Conclusions: These prevalence data provide a necessary groundwork for future clinical studies of clopidogrel pharmacogenetics in Caribbean Hispanics.

Nonbacterial Thrombotic Endocarditis of the Tricuspid Valve in a Male Patient with Antiphospholipid Syndrome

Valve vegetations in nonbacterial thrombotic endocarditis consist of fibrin and platelet aggregates and can be related to circulating immune complexes, such as in the case of antiphospholipid syndrome. In patients with primary antiphospholipid syndrome, echocardiographic studies have disclosed heart valve abnormalities in about a third of patients. Unusual associations between antiphospholipid syndrome and nonbacterial thrombotic endocarditis include presentation as an intracardiac mass compatible with a myxoma on imaging studies, as well as isolated involvement of the tricuspid valve. Both of these scenarios have been previously reported in female patients. This article presents the case of a 53-year-old Hispanic male with antiphospholipid syndrome who presented to the hospital with symptoms of heart failure and persistent right calf pain. An intracardiac mass attached to the anterior leaflet of the tricuspid valve was found through transthoracic echocardiography. Further imaging studies suggested the mass to be a myxoma and the patient underwent mass excision with tricuspid valve replacement. Pathology report of the surgical specimen was consistent with a diagnosis of nonbacterial thrombotic endocarditis. This case highlights the importance of considering nonbacterial thrombotic endocarditis as a key differential diagnosis in patients with concomitant antiphospholipid syndrome and intracardiac masses, as well as challenges encountered in diagnosis and management.

A Reminder From the Devastation Hurricane Maria Left Behind

On September 20, 2017, Hurricane Maria hit Puerto Rico, causing an unprecedented humanitarian crisis on a level that none of us have experienced before. The following editorial intends to show a physicians perspective of the impact of this storm on healthcare, particularly in triggering cardiovascular events.

Potential usefulness of diastolic parameters measured by strain imaging echocardiography in the early prediction of chemotherapy-induced cardiotoxicity

Over the past decades, chemotherapy has significantly increased the overall prognosis and survival of several patients diagnosed with cancer. However, the usefulness of some chemotherapeutic agents has been hindered by a collateral dose-dependent cardiotoxicity. To date, although extensive efforts have been directed to the early detection of subclinical toxicity in patients treated with these drugs, it remains unclear which approach would be best in order to prevent chemotherapy-induced cardiotoxicity (CIC). For many years, conventional echocardiography has been among preferred noninvasive imaging modality to monitor left ventricular ejection fraction (LVEF) in patients undergoing chemotherapy. Unfortunately, a significant reduction in LVEF is not recognized early on after chemotherapy-induced myocardial damage. Moreover, delayed recognition has been associated with poor recovery potential and poor clinical outcome. Thus, there is a critical need to identify early, reliable parameters of subclinical injury. Myocardial deformation imaging, also known as strain imaging echocardiography (SIE), is becoming readily available for advanced routine echocardiography and has shown value in detecting subclinical ventricular dysfunction in several clinical scenarios. Abnormalities in systolic deformation parameters have been identified as early manifestation but left ventricular diastolic properties remain less well defined. We hypothesize that onset as well as progression of cardiotoxicity not only should disturb deformation curves of myocardial contraction, but also relaxation. Hence, SIE may detect subtle myocardial changes in diastole that could be of potential benefit in the early prediction of CIC. If this premise is proven correct, the use of a standardized advanced echocardiographic imaging protocol using both, systolic and diastolic strain imaging, will prove to be a powerful noninvasive tool as baseline and follow-up of these patients. Furthermore, it will foster the developing of more effective screening strategies in at risk cancer survivor populations, or identify the best time to start cardioprotective therapy to prevent CIC. Also, this experience might be extrapolated to other non-oncologic patient population in need of a surveillance tool to early recognize cardiac injury secondary to the use of cardiotoxic medications.

Maximal systolic excursion of the tricuspid annulus is independent of right atrial size and function in chronic pulmonary hypertension

Even though the tricuspid annulus (TA) is anatomically and functionally related to right atrioventricular dependence and tricuspid annular plane systolic excursion (TAPSE) is a well‐known measure of right ventricular (RV) systolic function, there is paucity of data regarding the potential impact that right atrial (RA) size and function have on TAPSE. Hence, we sought to determine whether RA volumetric and longitudinal measures affect TAPSE in patients with chronic pulmonary hypertension (cPH).

Strain Imaging Echocardiography: What Imaging Cardiologists Should Know.

Despite recent advances in clinical imaging, echocardiography remains as the most accessi-ble and reliable noninvasive. Since knowledge of left ventricular systolic function remains so critically important in determining prognosis; every effort should be made to prevent subjective estimations. The advent of strain imaging echocardiography now offers a readily available and portable imaging tool that not only offers an objective characterization of myocardial dynamics; but also allows for early detection of subclinical left ventricular dysfunction. This review outlines the basic concepts of strain imaging to better understand the mechanism of myocardial function as well their applicability in the least common cardiac diagnosis among current clinical practice.