Pharmacogenomic Approach to Selecting Antiplatelet Therapy in Patients With Acute Coronary Syndromes: The PHARMCLO Trial.

BACKGROUND: Although clopidogrel is still frequently used in patients with acute coronary syndromes (ACS), its efficacy is hampered by interpatient response variability caused by genetic polymorphisms associated with clopidogrel's metabolism. OBJECTIVES: The goal of this study was to evaluate whether selecting antiplatelet therapy (clopidogrel, prasugrel, or ticagrelor) on the basis of a patient's genetic and clinical characteristics leads to better clinical outcomes compared with the standard of care, which bases the selection on clinical characteristics alone. METHODS: Patients hospitalized for ACS were randomly assigned to standard of care or the pharmacogenomic arm, which included the genotyping of ABCB1, CYP2C19*2, and CYP2C19*17 using an ST Q3 system that provides data within 70 min at each patient's bedside. The patients were followed up for 12 ± 1 month for the primary composite endpoint of cardiovascular death and the first occurrence of nonfatal myocardial infarction, nonfatal stroke, and major bleeding defined according to Bleeding Academic Research Consortium type 3 to 5 criteria. RESULTS: After enrolling 888 patients, the study was prematurely stopped. Clopidogrel was used more frequently in the standard-of-care arm (50.7% vs. 43.3%), ticagrelor in the pharmacogenomic arm (42.6% vs. 32.7%; p = 0.02), and prasugrel was equally used in both arms. The primary endpoint occurred in 71 patients (15.9%) in the pharmacogenomic arm and in 114 (25.9%) in the standard-of-care arm (hazard ratio: 0.58; 95% confidence interval: 0.43 to 0.78; p < 0.001). CONCLUSIONS: A personalized approach to selecting antiplatelet therapy for patients with ACS may reduce ischemic and bleeding events. (Pharmacogenetics of Clopidogrel in Patients With Acute Coronary Syndromes [PHARMCLO]; NCT03347435).

Pro-inflammatory genetic profile and familiarity of acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a multifactorial disease with a complex pathogenesis where lifestyle, individual genetic background and environmental risk factors are involved. Altered inflammatory responses are implicated in the pathogenesis of atherosclerosis and a premature AMI of parents is associated with an increased risk of the disease in their offspring (Offs). However, the genetic background of familiarity for AMI is still largely unknown. To understand which genes may predispose to increased risk of cardiovascular disease gene polymorphism of immune regulatory genes, and clinical events from the Offs of parents with an early AMI were investigated. Genetics data from Offs were compared with those obtained from healthy subjects and an independent cohort of patients with clinical sporadic AMI. Rates of clinical events during a 24 years follow up from Offs and from an independent Italian population survey were also evaluated. RESULTS: This study showed that a genetic signature consisting of the concomitant presence of the CC genotype of VEGF, the A allele of IL-10 and the A allele of IFN-γ was indeed present in the Offs population. In fact, the above genetic markers were more frequent in unaffected Offs (46.4%) and patients with sporadic AMI (31.8%) than in the CTR (17.3%) and the differences were highly statistically significant (Offs vs CTR: p = 0.0001, OR = 4.129; AMI vs CTR: p = 0.0001, OR = 2.224). During the 24-year follow-up, Offs with a positive familiarity in spite of a relatively young age showed an increased prevalence of diabetes, ischemic heart disease and stroke. These findings reinforce the notion that subjects with a familial history of AMI are at risk of an accelerated aging of cardiovascular system resulting in cardiovascular events. CONCLUSION: Our data suggest that selected genes with immune regulatory functions are part of the complex genetic background contributing to familiarity for cardiovascular diseases. This inflammatory genetic profile, along with classical cardiovascular risk factors, may be used for better defining individual risk of AMI in unaffected subjects.

Usefulness of myocardial performance index in multiple sclerosis mitoxantrone-induced cardiotoxicity.

AIMS: The authors sought to investigate the ability of the Doppler-derived myocardial performance index (MPI) to predict cardiotoxicity in multiple sclerosis (MS) patients under mitoxantrone therapy. METHODS AND RESULTS: The aauthors prospectively evaluated 28 MS patients (mean age 41±9 years, 12 males and 16 females) treated with low-dose mitoxantrone (basal mean cumulative dose 30±14 mg/m(2), end of follow-up mean dose 41±17 mg/m(2)). All patients underwent two-dimensional and Doppler-echocardiography at baseline and after a mean follow-up of 22±8 months. MPI was estimated using mitral inflow and left ventricular (LV) outflow pattern. Comparing data at baseline and at the end of follow-up, significant decrease in ejection fraction (EF) was observed (60±5 vs 56±4, p<0.03). The MPI was 0.52±0.1 at baseline and 0.60±0.1 at the end of follow-up (p<0.04). Such difference was mainly due to a isovolumic relaxation time prolongation (80±12 at baseline and 98±30 at the end of follow-up, p<0.05). The area under the receiver operating characteristic curve, analysed for an MPI cut-point value of 0.57, in identifying a significant reduction of LVEF ≤50% was of 0.94±0.065 with sensitivity and specificity of 97.5% and 90%, respectively. CONCLUSION: In conclusion, it can be speculated that a higher basal value of MPI could represent a subclinical LV cardiotoxicity, identifying a future decrease of EF and a progression to congestive heart failure in MS patients under mitoxantrone therapy.

Assessment of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis: a tissue Doppler echocardiographic analysis.

AIM: Tissue Doppler echocardiography was investigated for its applicability in detecting subtle myocardial involvement in multiple sclerosis patients receiving a low dose of mitoxantrone. METHODS AND RESULTS: Twenty Caucasian patients with multiple sclerosis (mean age 43.9+/-9.3 years, 12 males and 8 females) treated with mitoxantrone (mean cumulative dose 35.4+/-21.6 mg/m(2)), were compared to 20 healthy subjects (mean age 45.4+/-15.3 years, 11 males and 9 females) matched for age and gender. All subjects underwent conventional and Tissue Doppler echocardiography. Patients with heart failure, life-threatening arrhythmias, and other prominent manifestations of heart disease were excluded. No differences were observed in blood pressure, heart rate, and conventional systolic and diastolic echocardiographic parameters. At Tissue Doppler echocardiography, patients with multiple sclerosis showed differences of the systolic mechanic expressed by a significant lower S-wave peak velocity at the lateral site of mitral annulus (11.4+/-2.5 cm/sec vs. 15.0+/-4.1 cm/sec, P < 0.02). Such S-wave peak velocity significantly correlated with a cumulative dose of mitoxantrone (r =-0.37, P < 0.05). CONCLUSION: Tissue Doppler echocardiography suggests an early involvement of the systolic myocardial function at the low dose of mitoxantrone. Therefore, Tissue Doppler echocardiography may be used as a noninvasive method for monitoring subclinical cardiotoxicity in multiple sclerosis patients receiving mitoxantrone.

Evaluation of the myocardial performance index for early detection of mitoxantrone-induced cardiotoxicity in patients with multiple sclerosis.

AIMS: Multiple sclerosis is the most common cause of neurological disability in young adults. Mitoxantrone is a synthetic anthracenedione, recently approved for the treatment of worsening multiple sclerosis, which is known to induce cardiotoxicity. This study was designed to evaluate the early alterations in left ventricular function in patients with multiple sclerosis receiving mitoxantrone, by the use of the myocardial performance index, a new parameter of global (systolic and diastolic) ventricular function. METHODS AND RESULTS: The study included 29 Caucasian patients with multiple sclerosis (mean age 41.8+/-9.3 years, 12 males and 17 females) treated with mitoxantrone (mean cumulative dose 30.8+/-18.2 mg/m(2)) who were compared with 28 healthy subjects (mean age 37.8+/-11.8 years, 13 males and 15 females). Both groups underwent a complete two-dimensional and Doppler echocardiography including assessment of the mitral inflow and left ventricular outflow patterns for estimation of the Doppler-derived myocardial performance index. This parameter is defined as the sum of isovolumic contraction time and isovolumic relaxation time, divided by ventricular ejection time. No differences were observed in blood pressure, heart rate, left ventricular diameters, mass and ejection fraction in multiple sclerosis patients compared to the controls. The mitral flow pattern showed a significant decrease of E wave calculated as peak velocity (E(pv)) (63.3+/-13.4 vs. 77.2+/-17.2, P<0.002) and time velocity integral (E(tvi)) (8.8+/-1.9 vs. 10.3+/-2.4, P<0.02), with a significant decrease of E(pv)/A(pv) ratio and a non-significant decrease of E(tvi)/A(tvi) ratio in the patients. In addition, E-wave deceleration time was significantly increased in multiple sclerosis patients compared to controls (178.2+/-30.2 vs. 137.9+/-14.7, P<0.0001). The mean value of myocardial performance index was 0.55+/-0.1 in patients compared to 0.37+/-0.06 in the controls (P<0.0001). A significant correlation between the given cumulative dose of mitoxantrone and myocardial performance index (r=0.67, P<0.001) and E-wave deceleration time (r=0.45, P<0.001) respectively were demonstrated. CONCLUSION: The myocardial performance index represents a parameter of combined systolic and diastolic myocardial performance strongly correlated with the given cumulative dose of mitoxantrone. The myocardial performance index may be an adjunctive parameter to conventional echocardiography for detecting sub-clinical cardiotoxicity of mitoxantrone in the clinical management of the multiple sclerosis patients.

Circadian distribution of acute myocardial infarction by anatomic location and coronary artery involvement.

PURPOSE: Acute myocardial infarction follows a circadian pattern, with a morning peak ascribed to sympathetic activation. However, about 20% of myocardial infarctions occur between midnight and 6 AM; these events may have different characteristics. METHODS: We studied 1571 patients with acute myocardial infarction (866 anterior and 705 inferior myocardial infarctions) who were admitted to our coronary care units from January 1997 to February 2001. We noted the time of the infarction, its anatomic location, and the involved coronary arteries. RESULTS: Inferior myocardial infarctions were more frequent during the night (midnight to 6 AM) than during other periods of the day (n = 238, 34% of all inferior infarctions, P <0.01). When coronary angiography was performed (795 patients), 92% (127/138) of inferior infarctions were due to right coronary artery occlusion, whereas only 54% (130/242) of the remaining inferior infarctions involved that artery. CONCLUSION: Inferior myocardial infarctions occur disproportionately at night, usually due to right coronary artery occlusion. This suggests that a protective role for sleep may be limited to left coronary artery-related events.