Genetics of coronary artery disease: should they impact the choice of revascularization?

PURPOSE OF REVIEW: Patients with multivessel coronary artery disease (CAD) may undergo revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). This review will discuss the use of polygenic risk scores for risk-stratification of patients with multivessel CAD in order to guide the choice of revascularization. RECENT FINDINGS: A 57-single nucleotide polymorphism (SNP)-polygenic risk score can accurately risk-stratify patients with CAD and identify those who will receive greater benefit from statin therapy. The most recent genomic studies reveal 243 different SNPs are now significantly associated with CAD. Randomized clinical trials comparing PCI vs. CABG (FREEDOM, SYNTAX, NOBLE, EXCEL) have uncovered factors related to CAD severity (diabetes, SYNTAX score) are critical determinants of outcomes after revascularization. SUMMARY: There is a need to discover predictors of outcomes after PCI vs. CABG to improve clinical decision-making in multivessel CAD. High polygenic risk score is associated with increased CAD severity and better outcomes with statin therapy. Randomized clinical trials indicate CAD severity is associated with better outcomes after CABG compared with PCI. Accordingly, polygenic risk score could also be associated with better outcomes after CABG vs. PCI and used to optimize revascularization for patients with multivessel CAD.

Peptide-mediated disruption of calmodulin-cyclin E interactions inhibits proliferation of vascular smooth muscle cells and neointima formation.

RATIONALE: Cell cycle progression in vascular smooth muscle cells (VSMCs) is a therapeutic target for restenosis. OBJECTIVE: Having discovered that calmodulin (CaM)-dependent cyclin E/CDK2 activity underlies Ca(2+)-sensitive G(1)-to-S phase transitions in VSMCs, we sought to explore the physiological importance of the CaM-cyclin E interaction. METHODS AND RESULTS: A peptide based on the CaM binding sequence (CBS) of cyclin E was designed to interfere with CaM-cyclin E binding. Compared with control peptides, CBS blocked activating Thr160 phosphorylation of CDK2, decreased basal cyclin E/CDK2 activity, and eliminated Ca(2+)-sensitive cyclin E/CDK2 activity in nuclear extracts from mouse VSMCs. Nucleofection with CBS, or treatment with CBS conjugated to the HIV-1 TAT protein transduction domain to improve bioavailability, inhibited G(1)-to-S cell cycle progression in a dose-dependent manner. These effects were not observed with control peptides. TAT-CBS inhibited (3)H-thymidine incorporation in primary human aortic SMCs (HA-SMCs) in vitro, manifested greater transduction into HA-SMCs compared with endothelial cells in vitro, and limited decreased SM22α expression, neointima formation, and medial thickening without affecting collagen deposition or reendothelialization in a mouse model of carotid artery injury in vivo. The antiproliferative effects of CBS remained evident in mouse embryonic fibroblasts derived from wild-type mice but not cyclin E1/E2 double knockout mice. CONCLUSIONS: A synthetic peptide designed to disrupt CaM-cyclin E binding inhibits Ca(2+)/CaM-dependent CDK2 activity, cell cycle progression, and proliferation in VSMCs and limits arterial remodeling following injury. Importantly, this effect appears to be cyclin E-dependent and may form the basis of a potentially novel therapeutic approach for restenosis.

Non-fatal cardiovascular events preceding sudden cardiac death in patients with an acute myocardial infarction complicated by heart failure: insights from the high-risk myocardial infarction database.

AIMS: Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD). METHODS AND RESULTS: The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction (<40%) after AMI. We evaluated the temporal association between SCD with preceding non-fatal CV event [HF hospitalization, recurrent myocardial infarction (MI), or stroke]. Median follow-up was 1.9 years. Mean age was 65.0 ± 11.5 years and 70% were male. The incidence of CV death was 7.9 per 100 patient-years and for SCD was 3.1 per patient-years (40% of CV deaths). The incidence of SCD preceded by HF hospitalization was greater than SCD without preceding HF hospitalization (P < 0.05). However, overall, SCD was less likely to be preceded by a non-fatal CV event compared to other causes of death: 9.6% of SCD events were preceded by an MI (vs. 46.6% for non-sudden CV death); 17.0% of SCD events were preceded with an HF hospitalization (vs. 25.4% for non-sudden CV death); and 2.7% of SCD events were preceded by stroke (vs.12.9% for non-sudden CV death). CONCLUSION: Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.

Quality of life in obstructive hydrocephalus: endoscopic third ventriculostomy compared to cerebrospinal fluid shunt.

PURPOSE: In the current literature, there are essentially no comparisons of quality of life (QOL) outcome after endoscopic third ventriculostomy (ETV) and shunt in childhood hydrocephalus. Our objective was to compare QOL in children with obstructive hydrocephalus, treated with either ETV or shunt. METHODS: A cross-sectional survey was conducted at SickKids, Toronto of children between ages five and 18 years, with obstructive hydrocephalus due to aqueductal obstruction and no other brain abnormalities. Measures of QOL were the Hydrocephalus Outcome Questionnaire and the Health Utilities Index Mark 3. A subset of patients was given the Wechsler Intelligence Scales for Children (WISC-IV). RESULTS: A total of 47 of 59 (80%) eligible patients participated (24 had ETV as primary treatment, 23 had shunt as primary treatment), with a mean age of 12.1 years (standard deviation 3.9) at assessment. The ETV group was older at initial surgery (p < 0.001) and had larger ventricle size at last follow-up (p = 0.047). In all QOL measures, there were no significant differences between the ETV group and shunt group (all p > or = 0.09). Treatment failure, hydrocephalus complications, and the presence of a functioning ETV at assessment were not associated with QOL differences. Among the 11 children (six ETV, five shunt) who were given the WISC-IV, there were no significant differences between the scores of the ETV group and shunt group (all p > or = 0.11). CONCLUSIONS: This is the first study to provide a meaningful comparison of QOL after ETV and shunt in children. These preliminary results suggest that there is no obvious difference in QOL after ETV and shunt.

Genetics, coronary artery disease, and myocardial revascularization: will novel genetic risk scores bring new answers?

Both percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are options for revascularization in multi-vessel coronary artery disease (CAD). However, the best form of revascularization remains controversial. Results from clinical trials (FREEDOM, SYNTAX, NOBLE, EXCEL) have identified factors related to CAD severity such as diabetes and SYNTAX score as indicators that patients may have better outcomes with CABG compared to PCI. Nevertheless, the discovery of other predictors of optimal revascularization therapy is necessary to improve decision-making and personalize the treatment of multi-vessel CAD. Genome-wide association studies have identified numerous previously unknown DNA variants that increase predisposition for CAD. Recently, a composite polygenic risk score has been developed to better assess the relative contribution of multiple SNPs and quantify overall genetic risk for CAD. High polygenic risk score is associated with increased coronary events and greater benefit from statin therapy in large observational studies. This effect is independent from traditional cardiovascular risk factors. At the same time, randomized clinical trials have shown that CAD severity is a determinant of optimal revascularization treatment. It remains unknown whether polygenic risk score is robustly associated with increased CAD severity at presentation, and whether this score can be used to identify patients who will show greater benefit from revascularization with CABG or with PCI.

The aortic root does not dilate over time after replacement of the aortic valve and ascending aorta in patients with bicuspid or tricuspid aortic valves.

OBJECTIVE: Whether the aortopathy associated with bicuspid aortic valve (BAV) disease occurs secondary to genetic or hemodynamic factors remains controversial. In this article we describe the natural history of the aortic root in patients with bicuspid versus tricuspid aortic valves (TAVs) after replacement of the aortic valve and ascending aorta. METHODS: From 1990 to 2010, 406 patients (269 BAV, 137 TAV) underwent aortic valve and ascending aorta replacement at a single institution. Patients with aortic dissection, endocarditis, previous aortic surgery, or Marfan syndrome were excluded. All available follow-up imaging was reviewed. RESULTS: Mean imaging follow-up was 5.5 (±5.3) years. Of all patients, 66.5% had at least 1 aortic root measurement after the index operation. Baseline aortic diameter was comparable between groups. In patients with BAV, aortic root diameter increased at a clinically negligible rate over time (0.654 mm per year; 95% confidence interval, 0.291-1.016; P < .001), similar to patients with TAV (P = .92). Mean clinical follow-up was 8.1 (±5.4) years. During follow-up, 18 patients underwent reoperation, 89% for a degenerated bioprosthetic aortic valve. Only 1 patient underwent reoperation for a primary indication of aortic aneurysmal disease, 22 years after the index operation. There were no differences in cumulative incidence rates of aortic reoperation (P = .14) between patients with BAV and TAV. CONCLUSIONS: Mid-term imaging after aortic valve and ascending aorta replacement indicates that if the aortic root is not dilated at the time of surgery, the risk of enlargement over time is minimal, negating the need for prophylactic root replacement in patients with BAV or TAV.

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes.

Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.

Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries.

We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.

Cardiovascular consequences of drugs used for the treatment of diabetes: potential promise of incretin-based therapies.

Cardiovascular disease is the predominant cause of death in diabetic patients, and yet the cardiovascular benefits of traditional drug treatments for hyperglycemia have been elusive. Two new classes of diabetic drugs targeting the glucagon-like peptide-1 (GLP-1) incretin pathway have emerged. The GLP-1 receptor agonists reduce blood glucose levels by stimulating insulin and inhibiting glucagon secretion and gastric emptying. Dipeptidyl peptidase-4 (DPP-4) inhibitors prolong the half-life of endogenous GLP-1 by inhibiting its proteolytic degradation to the metabolite GLP-1(9-36), thereby increasing insulin and reducing glucagon secretion. Here, we review the biology of GLP-1, including studies of GLP-1 in animal models and humans with heart disease. We also highlight the emerging salutary cardiovascular effects of both GLP-1 and GLP-1(9-36). Unlike the GLP-1R agonist Exendin-4, both GLP-1 and GLP-1(9-36) exert vasodilatory actions on coronary and peripheral mouse vessels. Importantly, the effects of GLP-1 on isolated hearts undergoing experimental ischemia and preconstricted mesenteric arteries were reduced but not abolished by the DPP-4 inhibitor Sitagliptin. We posit that GLP-1-based therapeutics represent novel and promising anti-diabetes drugs, the direct cardiovascular actions of which may translate into demonstrable clinical benefits on cardiovascular outcomes.