Biventricular Pulsus Alternans

Pulsus alternans is a rare hemodynamic condition characterized by beat-to-beat variability in systolic pressure. It is attributed to variations in stroke volume with alternate cardiac cycles and is typically seen in patients with advanced myopathic conditions. Left ventricular pulsus alternans is rare, and right ventricular pulsus alternans is even less common. There are only a few reports of biventricular pulsus alternans. We report the case of a 62-year-old female with a recent anterior wall myocardial infarction who had biventricular pulsus alternans at the time of cardiac catheterization

Eptifibatide and abciximab inhibit insulin-induced focal adhesion formation and proliferative responses in human aortic smooth muscle cells

<p>Abstract</p> <p>Background</p> <p>The use of abciximab (c7E3 Fab) or eptifibatide improves clinical outcomes in diabetics undergoing percutaneous coronary intervention. These β₃integrin inhibitors antagonize fibrinogen binding to α_IIbβ₃integrins on platelets and ligand binding to α_vβ₃integrins on vascular cells. α_vβ₃integrins influence responses to insulin in various cell types but effects in human aortic smooth muscle cells (HASMC) are unknown.</p> <p>Results and discussion</p> <p>Insulin elicited a dose-dependent proliferative response in HASMC. Pretreatment with m7E3 (an anti-β₃integrin monoclonal antibody from which abciximab is derived), c7E3 or LM609 inhibited proliferative responses to insulin by 81%, 59% and 28%, respectively. Eptifibatide or cyclic RGD peptides completely abolished insulin-induced proliferation whereas tirofiban, which binds α_IIbβ₃but not α_vβ₃, had no effect. Insulin-induced increases in c-Jun NH₂-terminal kinase-1 (JNK1) activity were partially inhibited by m7E3 and eptifibatide whereas antagonism of α_vβ₃integrins had no effect on insulin-induced increases in extracellular signal-regulated kinase (ERK) activity. Insulin stimulated a rapid increase in the number of vinculin-containing focal adhesions per cell and treatment with m7E3, c7E3 or eptifibatide inhibited insulin-induced increases in focal adhesions by 100%, 74% and 73%, respectively.</p> <p>Conclusion</p> <p>These results demonstrate that α_vβ₃antagonists inhibit signaling, focal adhesion formation and proliferation of insulin-treated HASMC.</p

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

Association of CYP2C19*17 Allele and Choice of P2Y12 Inhibitor on Cardiovascular Outcomes Following Percutaneous Coronary Intervention

Introduction: The CYP2C19*17 allele variant is a gain-of-function polymorphism which increases levels of the active metabolite of clopidogrel. Objective: *17 is associated with increased bleeding risk during clopidogrel therapy, but it is unclear whether alternative P2Y12 inhibitors, prasugrel and ticagrelor, produce better clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). Methods: A single-center observational study was conducted in 928 PCI patients who received CYP2C19 testing and dual anti-platelet therapy (DAPT). Risk of major adverse cardiovascular or cerebrovascular events (MACCE) and clinically significant bleeding over 12 months were compared across genotype and DAPT groups by proportional hazards regression. Results: 584 patients were treated with clopidogrel while 344 patients had alternative therapy. In the clopidogrel group, 173 patients were hetero- or homozygous for *17 and 91 patients were hetero- or homozygous for a loss of function allele (LOF; *2 or *3). Patients treated with clopidogrel were older, more commonly female, and more likely to have hypertension, diabetes, and an acute coronary syndrome (ACS) than patients on alternative therapy. There were no differences in MACCE or clinically significant bleeding events in *17 patients treated with clopidogrel compared to alternative therapy in either the total population (p=0.54) or in ACS patients (p=0.98). Patients with LOF alleles were 3.4 times more likely in the total population (p \u3c0.0001) and 6.7 times more likely among ACS patients (p \u3c0.0001) to have MACCE if prescribed clopidogrel compared with alternative therapy. Discussion: *17 patients had equivalent clinical outcomes when treated with clopidogrel or alternative P2Y12 inhibitors

Implementation of inpatient models of pharmacogenetics programs

The operational elements essential for establishing an inpatient pharmacogenetic service are reviewed, and the role of the pharmacist in the provision of genotype-guided drug therapy in pharmacogenetics programs at three institutions is highlighted

Evaluation of race and ethnicity disparities in outcome studies of CYP2C19 genotype-guided antiplatelet therapy

Dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin remains the standard of care for all patients undergoing percutaneous coronary intervention (PCI). It is well-established that patients carrying CYP2C19 no function alleles have impaired capacity to convert clopidogrel into its active metabolite and thus, are at higher risk of major adverse cardiovascular events (MACE). The metabolism and clinical effectiveness of prasugrel and ticagrelor are not affected by CYP2C19 genotype, and accumulating evidence from multiple randomized and observational studies demonstrates that CYP2C19 genotype-guided antiplatelet therapy following PCI improves clinical outcomes. However, most antiplatelet pharmacogenomic outcome studies to date have lacked racial and ethnic diversity. In this review, we will (1) summarize current guideline recommendations and clinical outcome evidence related to CYP2C19 genotype-guided antiplatelet therapy, (2) evaluate the presence of potential racial and ethnic disparities in the major outcome studies supporting current genotype-guided antiplatelet therapy recommendations, and (3) identify remaining knowledge gaps and future research directions necessary to advance implementation of this precision medicine strategy for dual antiplatelet therapy in diverse, real-world clinical settings

Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding

We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure–associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42’s role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9–mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies

Stable Patterns of Gene Expression Regulating Carbohydrate Metabolism Determined by Geographic Ancestry

Background: Individuals of African descent in the United States suffer disproportionately from diseases with a metabolic etiology (obesity, metabolic syndrome, and diabetes), and from the pathological consequences of these disorders (hypertension and cardiovascular disease). Methodology/Principal Findings: Using a combination of genetic/genomic and bioinformatics approaches, we identified a large number of genes that were both differentially expressed between American subjects self-identified to be of either African or European ancestry and that also contained single nucleotide polymorphisms that distinguish distantly related ancestral populations. Several of these genes control the metabolism of simple carbohydrates and are direct targets for the SREBP1, a metabolic transcription factor also differentially expressed between our study populations. Conclusions/Significance: These data support the concept of stable patterns of gene transcription unique to a geographic ancestral lineage. Differences in expression of several carbohydrate metabolism genes suggest both genetic and transcriptional mechanisms contribute to these patterns and may play a role in exacerbating the disproportionate levels o