Biomedical subjects

Larisa H Cavallari

Publications and source records attributed to Larisa H Cavallari.

9 recordsLinked to original sources

PubMed2026

Persistent tic disorders are associated with 17q12 duplications.

Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.

Journal Article↗

PubMed2026

2025 Acute Coronary Syndrome Guideline: Missing the Boat on CYP2C19 Genotyping.

The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss-of-function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss-of-function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss-of-function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19-guided P2Y12 inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.

Humans↗

PubMed2026

Genotype-Guided Antidepressant Prescribing for Patients With Depression: A Randomized Clinical Trial.

IMPORTANCE: The effectiveness of pharmacogenetics to guide prescribing of selective serotonin reuptake inhibitors (SSRIs) for depression remains unclear, despite the well-established association between SSRI pharmacokinetics and genetic variation. OBJECTIVE: To determine whether pharmacogenetic-guided prescribing of SSRIs improves treatment response in patients with depression. DESIGN, SETTING, AND PARTICIPANTS: The ADOPT PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) Depression pragmatic randomized clinical trial was conducted from August 10, 2021, through April 27, 2024, at primary care, psychiatry, or family medicine clinics at enrolling sites throughout the US. Patients were aged 8 years or older and had experienced depression for 3 months or longer. INTERVENTION: Patients were randomized to genotype-guided SSRI prescribing (intervention group) or usual care (control group). Actionable drug metabolism phenotypes were defined as those for which pharmacogenetic clinical guidelines recommend alternative medication selection or dose adjustment. MAIN OUTCOMES AND MEASURES: The primary outcome was change in Patient-Reported Outcomes Measurement Information System (PROMIS) depression T scores at 3 months among patients with the actionable phenotype. Secondary end points included adverse effect severity of SSRIs at 3 months and depression remission (measured with PROMIS depression scores and Patient Health Questionnaire-8 [PHQ-8] scores) at 6 months. RESULTS: This study of 1460 patients included 1239 adults (84.9%) (mean [SD] age, 40.6 [16.7] years) and 221 children (15.1%) (mean [SD] age, 14.6 [1.8] years). Most patients were female (1096 [75.1%]). A total of 692 patients (47.4%) had an actionable phenotype; 351 (50.7%) were assigned to the intervention, and 341 (49.3%) were assigned to usual care. At baseline, 463 of the 692 patients (66.9%) reported having depressive symptoms for more than 2 years, 603 (87.1%) were receiving pharmacologic treatment, and 354 (51.2%) were receiving nonpharmacologic treatment. At 3 months, no significant differences were observed between the intervention and usual care groups in change in PROMIS depression T scores (mean [SD] change, -4.3 [8.4] vs -4.0 [8.1]; P = .68), medication adverse effect burden (mean [SD] change, 8.2 [4.3] vs 7.8 [4.5]; P = .37), or Patient Health Questionnaire-8 score change (mean [SD] change, -3.3 [5.2] vs -2.7 [4.8]; P  = .13). However, at 6 months, the PROMIS depression T-score remission rate (score ≤16) was higher in the intervention group compared with the usual care group (153 of 317 patients [48.3%] vs 122 of 310 patients [39.4%]; P = .02). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, genotype-guided prescribing of SSRIs did not improve control of depression symptoms at 3 months compared with usual care but was associated with higher depression remission rates at 6 months. These findings suggest a possible longer-term clinical benefit and indicate that future studies should focus on the durability and long-term impact of genotype-guided prescribing in the management of depressive symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT04445792 (Master Protocol Research Program platform trial) and NCT05966155 (ADOPT PGx Depression trial).

Humans↗

PubMed2025

Impact of Race on Profiles of Platelet Reactivity and Clinical Outcomes in Clopidogrel-Treated Participants.

Black individuals undergoing percutaneous coronary intervention (PCI) experience higher rates of major adverse cardiovascular events (MACE) than non-Black individuals. This study assessed the racial differences in platelet reactivity and clinical outcomes among clopidogrel-treated participants. Two cohorts were analyzed. The pharmacodynamic (PD) cohort involved patients with atherosclerotic cardiovascular disease on maintenance clopidogrel therapy undergoing platelet function testing. The primary outcome was high platelet reactivity (HPR, i.e., P2Y12 reaction unit [PRU] > 208). The PCI cohort included participants undergoing PCI on clopidogrel-based dual antiplatelet therapy. The primary outcome was 1-year MACE, defined as the composite of cardiovascular death, myocardial infarction (MI), ischemic stroke, or stent thrombosis. Data on clinically significant bleeding and CYP2C19 genotyping alleles were collected. The PD and PCI cohorts included 728 (32.1% Black) and 2,770 (20.5% Black) participants, respectively. Black participants had higher PRU levels (184 [IQR 128-234] vs. 144 [IQR 88-195]; P < 0.001) and higher prevalence of HPR (39.3% vs. 20.6%; P < 0.001). Independent predictors of HPR included Black race, hemoglobin levels, and presence of CYP2C19 loss-of-function allele. In the PCI cohort, Black participants had a higher risk of MACE (HR 1.47; 95% CI 1.02-2.11; P = 0.037), primarily driven by MI (HR 1.71; 95% CI 1.09-2.67; P = 0.019), with no significant difference in clinically significant bleeding (HR 1.08; 95% CI 0.65-1.80; P = 0.768). Black participants on clopidogrel exhibit higher platelet reactivity, increased rates of HPR, and an elevated risk of MACE within 1 year after PCI, without significant differences in bleeding compared to non-Black participants.

Aged↗

PubMed2006

Sex difference in the antiplatelet effect of aspirin in patients with stroke.

BACKGROUND: There is substantial interpatient variability in response to aspirin after an ischemic stroke or transient ischemic attack (TIA), as assessed by ex vivo effects of aspirin on platelet aggregation. The factors contributing to this variability are not well defined. OBJECTIVE: To determine whether demographic, social, or clinical characteristics are associated with ex vivo response to aspirin in patients with a history of stroke or TIA. METHODS: Eighty-one patients who were taking aspirin for secondary stroke prevention and underwent ex vivo platelet aggregation studies were identified. The medical records of eligible patients were reviewed by clinicians who specialize in the management of stroke patients. Characteristics were compared between 45 patients who had a complete response to aspirin and 36 patients who exhibited an incomplete (partial) response to aspirin based on the results of platelet aggregation testing. RESULTS: The median (range) aspirin dose was similar in complete (325; 81-1950 mg/day) and partial (325; 81-1300 mg/day) responders. There was no association between aspirin response and age, race, body mass index, medical history, smoking status, or use of statin or hormone replacement therapy. However, sex was significantly associated with response to aspirin, with more women in the partial versus complete responder group (75% vs 49%; p = 0.02). CONCLUSIONS: Our data suggest that aspirin may be less effective at inhibiting platelet aggregation in women compared with men who have a history of ischemic stroke or TIA.

Adult↗

PubMed2005

Cardiovascular pharmacogenomics.

There is large interpatient variability in the response to drugs, including cardiovascular drugs. Thus, while some patients achieve the desired therapeutic response from their drug therapy, others do not. There is also a subset of patients who will experience adverse effects, which can range from bothersome to life threatening. Research in recent years has provided compelling evidence that in many cases, genetics contributes importantly to this variable drug response. Thus, pharmacogenomics is a field focused on unravelling the genetic determinants of variable drug response. Examples from the literature of genetic associations with drug efficacy and toxicity are described to provide insight into the field, including the roles of genetic variability in drug-metabolizing enzymes and drug targets. There is also a detailed discussion of the experimental approaches used in cardiovascular pharmacogenomics. Current research is largely focused on a limited candidate gene approach, which allows for description of significant genetic associations with variable response, but often does not explain the genetic basis of variable drug response enough to be useful clinically. As such, there is a move towards genome-wide approaches, and the various technologies available to obtain genomic data are discussed. Cardiovascular pharmacogenomics has the potential for leading to improvements in the use of cardiovascular drug therapy, through selection of the most appropriate drug therapy in an individual based on their genetic information. It will probably be a decade or more before genetic information is widely used in drug therapy decisions, but it seems clear that important findings in the area will continue to expand and the experimental approaches will continue to evolve.

Animals↗

PubMed2004

Racial differences in patients' potassium concentrations during spironolactone therapy for heart failure.

STUDY OBJECTIVE: To determine whether the effects of spironolactone on potassium homeostasis vary by race by comparing serum potassium concentrations and potassium supplement use in African-American and Caucasian patients receiving spironolactone for heart failure. DESIGN: Retrospective medical record review. SETTING: Two heart failure centers. PATIENTS: Fifty African-American and 67 Caucasian patients with heart failure who were receiving a stable dosage of spironolactone in addition to standard heart failure therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. MEASUREMENTS AND MAIN RESULTS: Medical records of eligible patients were reviewed by pharmacists and physicians who specialize in heart failure management. No significant differences were observed in diuretic therapy or renal function between racial groups; however, African-Americans were receiving higher doses of ACE inhibitors. African-Americans had lower serum potassium concentrations (4.2 +/- 0.4 vs 4.5 +/- 0.5 mEq/L, p<0.01) and a higher prevalence of potassium supplementation (48% vs 15%, p<0.01). In a subset of patients, spironolactone therapy was associated with a 2-fold greater increase in serum potassium concentration and a 3-fold greater reduction in potassium supplement use among Caucasians than African-Americans. CONCLUSION: Our findings suggest that a large percentage of patients with heart failure, particularly African-Americans, still require potassium supplementation despite treatment with spironolactone and standard vasodilator therapy.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

New treatment option for heart failure patients: eplerenone.

Aldosterone plays an important role in the harmful cardiac remodeling process and pathophysiology of heart failure after a myocardial infarction. Until recently, spironolactone (Aldactone) was the only pharmacologic agent available to directly block the deleterious effects of aldosterone. The use of spironolactone is complicated by its antiprogesterone and antiandrogen side effects, such as gynecomastia and menstrual irregularities. Eplerenone (Inspra), a member of a new class of drugs called selective aldosterone receptor antagonists, was recently approved for the treatment of both hypertension and post-myocardial infarction heart failure and appears to be devoid of the antiprogesterone and antiandrogen effects. In a trial in patients with heart failure following a myocardial infarction, eplerenone treatment significantly reduced mortality and morbidity compared to placebo. Eplerenone may be considered as part of the therapeutic plan in patients who have suffered a myocardial infarction and demonstrate evidence of heart failure.

Aldosterone↗

PubMedDate not supplied

Racial differences in potassium response to spironolactone in heart failure.

Evidence of racial differences in aldosterone concentrations and K+ disposition suggests that response to aldosterone antagonism might vary by race. The authors sought to determine whether K+ response to spironolactone differs between African Americans and Caucasians with heart failure. Heart failure patients of African-American (n = 34) or Caucasian (n = 17) race were started on spironolactone 12.5 mg/d, with up-titration as tolerated. Laboratory values and drug therapy were similar between racial groups at baseline. Spironolactone was titrated to a median dose of 25 mg/d in both groups. Neither concomitant medications nor serum creatinine changed significantly in either group during spironolactone dose titration. Median serum K+ concentrations increased by 0.5 mEq/L (range, -0.7 to 1.6 mEq/L) in Caucasians, but only 0.1 mEq/L (range, -0.8 to 0.9 mEq/L) in African Americans; p < 0.01. These data suggest that African Americans with heart failure may be less responsive to the renal effects of spironolactone.

Adult↗