Citations

Background Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles ( EV s), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EV s released by senescent nephron cells can be identified in urine of patients with hypertension. Methods and Results We recruited patients with essential hypertension ( EH ) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine‐level measurements. EV s isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin‐2 (distal tubules). Overall percentage of urinary p16+ EV s was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16 + /urate transporter 1 + were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16 + /prominin‐2 + levels were elevated only in EH versus healthy volunteers and p16 + /uromodulin + in renovascular hypertension versus EH . Conclusions Levels of p16 + EV s are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH , EV s originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary EV s levels may be useful to identify intrarenal sites of cellular senescence.

Background: Reducing door-to-balloon time may not reduce mortality, but reducing the time from symptom onset to first medical contact (FMC) may alone improve patient outcomes. The purpose of this study was to focus on analyzing sex differences in FMC call delay and its trend over the decades in patients with suspected acute coronary syndrome (ACS). Methods: Large private telemedicine data in patients with suspected ACS were used to investigate time delay in contacting a telemedicine call center. We identified 24,592 calls to a primary call center of patients with anginal symptoms and first electrocardiogram (ECG), using mobile 12-lead ECG devices. For the purpose of the current analysis, we included the first call of 14,420 patients for whom demographic, clinical ECG data were available. Results: First mobile ECG changes included suspected S-T Segment (ST) elevation in 2,220 (16%) cases, ST depression in 3,143 (22%) cases, or both in 685 (5%) patients. There were 6,721 (47%) calls to the center within less than 1 h of symptom onset. Chest pain, dyspnea, heart rate, male sex, absence of diabetes mellitus, early time period of the study, and ischemic ST segment changes on the first ECG were all independently associated with the increased likelihood of contacting the center within less than 1 h of symptom onset to FMC ( p < 0.01 for all). Conclusions: Both chest pain and ischemic ECG changes were sex dependent for early medical contact, as such factors were significant among men ( p = 0.001 and p = 0.024, respectively), but not among women ( p = 0.024). The later time period of the study was associated with a shorter time delay among women more than that of men ( p = 0.014). Women with prehospital chest pain or ischemic ST segment changes tend to seek medical help later than men. Temporal trends show attenuation of this sex disparity, with more women presenting earlier in the last decade.

Background Women with non‐obstructive coronary artery disease have increased cardiovascular morbidity. The role of risk factors in this population has yet to be established. We aimed to study the predictive effect of triglycerides and the triglyceride/high‐density lipoprotein ratio on major adverse cardiovascular events (MACE) in patients with non‐obstructive coronary artery disease, and to explore the role of lipid lowering therapy in modifying this risk. Methods and Results This is a prospective cohort study enrolling patients with anginal symptoms referred to the cardiac catheterization laboratory for suspected ischemia, who were subsequently diagnosed with non‐obstructive coronary artery disease, defined as no stenosis >20% on angiography. All patients had baseline laboratory testing and were followed for 7.8±4.3 years for the development of major adverse cardiovascular events. We performed Cox proportional hazard testing to determine the effect of triglycerides on risk of major adverse cardiovascular events among men and women by baseline statin use. A total of 462 patients were included. Median age was 53 (Q1, Q3: 45, 62) years. In a Cox proportional hazard model stratified by statin use adjusting for confounders, among those not on baseline statins, triglycerides were independently predictive of major adverse cardiovascular events in women (per 50 mg/dL risk ratio: hazard ratio 1.25 [95% CI : 1.06, 1.47]; P =0.01). This was not true among men. The interaction between triglycerides and sex, and triglycerides and statin was statistically significant. Conclusions Triglyceride levels may play a key role in predicting cardiovascular‐specific risk in women, and statin use may be protective. Further investigation is necessary to better delineate the role of statin use in preventing cardiovascular risk.

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

Commercially available heart valves have many limitations, such as a lack of remodeling, risk of calcification, and thromboembolic problems. Many state-of-the-art tissue-engineered heart valves (TEHV) rely on recellularization to allow remodeling and transition to mechanical behavior of native tissues. Current in vitro testing is insufficient in characterizing a soon-to-be living valve due to this change in mechanical response; thus, it is imperative to understand the performance of an in situ valve. However, due to the complex in vivo environment, this is difficult to accomplish. Finite element (FE) analysis has become a standard tool for modeling mechanical behavior of heart valves; yet, research to date has mostly focused on commercial valves. The purpose of this study has been to evaluate the mechanical behavior of a TEHV material before and after 6 months of implantation in a rat subdermis model. This model allows the recellularization and remodeling potential of the material to be assessed via a simple and inexpensive means prior to more complex ovine orthotropic studies. Biaxial testing was utilized to evaluate the mechanical properties, and subsequently, constitutive model parameters were fit to the data to allow mechanical performance to be evaluated via FE analysis of a full cardiac cycle. Maximum principal stresses and strains from the leaflets and commissures were then analyzed. The results of this study demonstrate that the explanted tissues had reduced mechanical strength compared to the implants but were similar to the native tissues. For the FE models, this trend was continued with similar mechanical behavior in explant and native tissue groups and less compliant behavior in implant tissues. Histology demonstrated recellularization and remodeling although remodeled collagen had no clear directionality. In conclusion, we observed successful recellularization and remodeling of the tissue giving confidence to our TEHV material; however, the mechanical response indicates the additional remodeling would likely occur in the aortic/pulmonary position.

Background: Serum uric acid may serve as a marker of cardiovascular events and outcomes in men, but further studies are required to determine its role in women. We aimed to determine differences in procedural characteristics and outcomes in women undergoing percutaneous coronary intervention(PCI). Methods: We retrospectively analyzed the Mayo Clinic Cardiovascular Catheterization Laboratory database, and included patients undergoing PCI from 1/1/2000 to 12/31/2007. There were 495 women who underwent PCI in this time period. Patients were divided into normal uric acid (n=240) and high uric acid (n=255) groups, and high uric acid was defined as >6.0 mg/dL. Patients were followed for adverse outcomes for a median of 47.1 (IQR 23.8, 62.8) months. Results: Mean age was 66.6 + 12.7 years in the normal group vs. 70.5 + 11.2 years in the elevated uric acid group(p=0.01). Hypertension and diabetes were more prevalent in the elevated uric acid group (p<0.01). BMI was significantly higher in the elevated uric acid group (p=0.001). There was a higher prevalence of calcified lesions among women with elevated uric acid when compared to those with normal uric acid levels (47% vs. 30% p<0.001). There was significantly lower TIMI=3 flow postprocedurally in those with elevated uric acid levels when compared to those with normal uric acid levels (91 % vs. 97%, p=0.003). After adjusting for potential confounders including age, hyperlipidemia, hypertension, BMI, diabetes, and chronic kidney disease, elevated uric acid was associated with increased likelihood of death (HR 1.8, p=0.01) and the composite endpoint of death or subsequent myocardial infarction (HR 1.5, p=0.03). Discussion: Uric acid may be an independent determinant of procedural characteristics and a predictor of outcomes after percutaneous intervention. Further studies are required to better understand the effect of uric acid on cardiovascular events in women.

Background: Serum uric acid is a marker of oxidative stress, and may serve as a marker of adverse cardiovascular events and outcomes including cardiovascular death, hospitalization and myocardial infarction. We aimed to determine whether uric acid predicts cardiovascular events and death in patients undergoing carotid endarterectomy (CEA). Methods: We enrolled 327 patients undergoing CEA between February 2002 and June 2017 who had complete laboratory work up at baseline. Patients were followed through the electronic chart as well as via regular nursing follow-up for a median of 10.9 years (IQR 7.3, 13.4). There were a total of 67 adverse cardiovascular events during follow-up. Results: Baseline serum uric acid levels were significantly higher in patients who developed cardiovascular events during the follow-up period vs. those that did not [6.87 + 2.29 vs. 6.39 + 1.61); p=0.047). Baseline serum uric was independently associated with cardiovascular events when adjusting for age, creatinine, diabetes mellitus, and hyperlipidemia (L-R 4.0, p=0.04)(Figure 1). Sex stratified analysis showed that serum uric acid was also an independent predictor of both cardiovascular events and death in men, not women undergoing after adjustment for confounders including age, cholesterol, systolic blood pressure and glucose (LR 4.97; p=0.03). Discussion: Higher uric acid levels are associated with cardiovascular events and death after CEA. Further investigation is necessary to determine the role of uric acid as a modifiable risk factor in these patients.

Background: Uric acid is a known risk factor for atherosclerosis. We aimed to determine whether baseline uric acid levels predict plaque stability on presentation and future cerebrovascular events (CVA) in patients undergoing carotid endarterectomy (CEA). Methods: We analyzed 317 patients who underwent CEA between 2/2002 and 6/2017. Patients were stratified according to plaque stability as unstable or stable --those who presented with a history of > 1 neurologic event were “unstable” and those with no history of CVA were classified as stable. All patients underwent comprehensive baseline laboratory testing at baseline prior to CEA and then were followed by a nurse coordinator and through the medical record for the development of cerebrovascular events including stroke and transient ischemic attack for a median of 10.9 years (IQR 7.3, 13.4). Results: Baseline uric acid was significantly higher in patients presenting with unstable plaque vs. stable plaque(6.5 (IQR 5.6, 7.9) vs. 5.8(IQR 4.8,6.6); p<0.001), and was an independent predictor of plaque stability when adjusting for potential confounders including glucose, BMI, hsCRP, cholesterol, and systolic blood pressure (L-R 6.9, p=0.0096). There were a total of 58 CVA during follow-up, and baseline uric acid was higher among patients who developed CVA vs those without CVA [(6.9 + 2.1) mg/dL vs. (6.4 + 1.7) mg/dL; p=0.037]. After adjusting for diabetes, cholesterol, systolic blood pressure, smoking , age, aspirin, and creatinine, uric acid and cholesterol were both independent predictors of stroke in this population [uric acid: (LR 4.84, p=0.03); cholesterol: (L-R 11.8, p=0.0006)]. Discussion: While cholesterol has been associated with poor outcomes in patients with vascular disease, our data suggest that uric acid may be a novel risk factor for stroke in patients undergoing CEA. Further investigation is necessary to understand the therapeutic potential of reducing uric acid levels in these patients and the potential benefit of reducing overall cerebrovascular risk.