Yessica-Haydee Gomez

Statin treatment and new-onset diabetes: A review of proposed mechanisms

New-onset diabetes has been observed in clinical trials and meta-analyses involving statin therapy. To explain this association, three major mechanisms have been proposed and discussed in the literature. First, certain statins affect insulin secretion through direct, indirect or combined effects on calcium channels in pancreatic β-cells. Second, reduced translocation of glucose transporter 4 in response to treatment results in hyperglycemia and hyperinsulinemia. Third, statin therapy decreases other important downstream products, such as coenzyme Q10, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and dolichol; their depletion leads to reduced intracellular signaling. Other possible mechanisms implicated in the effect of statins on new-onset diabetes are: statin interference with intracellular insulin signal transduction pathways via inhibition of necessary phosphorylation events and reduction of small GTPase action; inhibition of adipocyte differentiation leading to decreased peroxisome proliferator activated receptor gamma and CCAAT/enhancer-binding protein which are important pathways for glucose homeostasis; decreased leptin causing inhibition of β-cells proliferation and insulin secretion; and diminished adiponectin levels. Given that the magnitude of the risk of new-onset diabetes following statin use remains to be fully clarified and the well-established beneficial effect of statins in reducing cardiovascular risk, statins remain the first-choice treatment for prevention of CVD. Elucidation of the mechanisms underlying the development of diabetes in association with statin use may help identify novel preventative or therapeutic approaches to this problem and/or help design a new generation statin without such side-effects.

Plasma irisin levels progressively increase in response to increasing exercise workloads in young, healthy, active subjects

BACKGROUND Irisin, a recently discovered myokine, has been shown to induce browning of white adipose tissue, enhancing energy expenditure and mediating some of the beneficial effects of exercise. We aimed to estimate the time frame of changes in irisin levels after acute exercise and the effect of different exercise workloads and intensities on circulating irisin levels immediately post-exercise. METHODS In a pilot study, four healthy subjects (22.5±1.7 years) underwent maximal workload exercise (maximal oxygen consumption, VO2 max) and blood was drawn at prespecified intervals to define the time frame of pre- and post-exercise irisin changes over a 24-h period. In the main study, 35 healthy, non-smoking (23.0±3.3 years) men and women (n=20/15) underwent three exercise protocols ≥48-h apart, in random order: i) maximal workload (VO2 max); ii) relative workload (70% of VO2 max/10 min); and iii) absolute workload (75 W/10 min). Blood was drawn immediately pre-exercise and 3 min post-exercise. RESULTS In the pilot study, irisin levels increased by 35% 3 min post-exercise, then dropped and remained relatively constant. In the main study, irisin levels post-exercise were significantly higher than those of pre-exercise after all workloads (all, P<0.001). Post-to-pre-exercise differences in irisin levels were significantly different between workloads (P=0.001), with the greatest increase by 34% following maximal workload (P=0.004 vs relative and absolute). CONCLUSIONS Circulating irisin levels were acutely elevated in response to exercise, with a greater increase after maximal workload. These findings suggest that irisin release could be a function of muscle energy demand. Future studies need to determine the underlying mechanisms of irisin release and explore irisins therapeutic potential.

Statin Treatment Non-adherence and Discontinuation: Clinical Implications and Potential Solutions

Statins are the most powerful lipid lowering drugs in clinical practice. However, the efficacy of statin therapy, as seen in randomized control trials, is undermined by the documented non-adherence observed in clinical practice. Understanding the clinical consequences of statin non-adherence is an important step in implementing successful interventions aimed at improving adherence. Our previous systematic review included a literature search up to January 2010 on the effects of statin non-adherence or discontinuation on cardiovascular (CV) and cerebrovascular outcomes. We provide an update to this publication and a review of promising interventions that have reported a demonstrated improvement in statin adherence. Through a systematic literature search of PubMed, Ovid Medline, Ovid Embase, CINAHL, Cochrane Library and Web of Science, out of the 3440 initially identified, 13 studies were selected. Non-adherence in a primary prevention population was associated with a graded increase in CV risk. Individuals taking statins for secondary prevention were at particular risk when taking statin with highly variable adherence. Moreover, particular attention is warranted for non-adherence in diabetic and rheumatoid arthritis populations, as non-adherence is significantly associated with CV risk as early as 1 month following discontinuation. Statin adherence, therefore, represents an important modifiable risk factor. Numerous interventions to improve adherence have shown promise, including copayment reduction, automatic reminders, mail-order pharmacies, counseling with a health professional, and fixed-dose combination therapy. Given the complexity of causes underlying statin non-adherence, successful strategies will likely need to be tailored to each patient.

Differences in arterial stiffness at rest and after acute exercise between young men and women

There is controversy as to whether there are sex differences in arterial stiffness. Acute physical stress can elicit vascular abnormalities not present at rest. Our objective was to assess sex differences in arterial stiffness at rest and in response to acute physical stress. Healthy young men (n=67) and women (n=55) underwent pulse wave analysis and carotid-femoral pulse wave velocity measurements at rest and 2, 5, 10 and 15 min following an exercise test to exhaustion. At rest, aortic systolic, diastolic, pulse and mean pressures were all significantly higher in men as was aortic pulse pressure at 10 and 15 min post exercise and aortic systolic pressure at 15 min. Carotid-femoral pulse wave velocity was significantly higher in men (6.0±0.7 m s−1 vs. 5.6±0.6 m s−1, P=0.03) at rest and at all time points post exercise. Heart rate-adjusted augmentation index was significantly lower (−10.7±10.2% vs. −4.0±10.9, P<0.0001) and subendocardial viability ratio was significantly higher (176.2±43.8% vs. 163.4±40.9, P=0.04) in men at rest. To our knowledge, this is the first study to assess sex differences in the arterial stiffness response to acute physical stress in young men and women. Although we were not able to elicit differences in vascular function after adjustment, which were not present at rest, we found that young men and women exhibit differences in arterial stiffness at rest and after acute physical stress.

A systematic review on the effect of acute aerobic exercise on arterial stiffness reveals a differential response in the upper and lower arterial segments.

The objective of this systematic review was to provide insight into the controversy that still abounds as to the impact of acute aerobic exercise on immediate changes in arterial stiffness. Electronic databases were searched to identify articles assessing the effects of acute aerobic exercise on parameters of arterial stiffness. Eligible studies included arterial stiffness measurements before and after acute aerobic exercise in healthy human subjects. Forty-three studies were included. The effect of acute aerobic exercise on arterial stiffness was found to be dependent on the anatomical segment assessed, and on the timing of the measurement post-exercise. Arterial stiffness of the central and upper body peripheral arterial segments was found to be increased relative to resting values immediately post-exercise (0–5 min), whereas, thereafter (>5 min), decreased to a level at or below resting values. In the lower limbs, proximal to the primary working muscles, arterial stiffness decreased immediately post-exercise (0–5 min), which persisted into the recovery period post-exercise (>5 min). This systematic review reveals a differential response to acute exercise in the lower and upper/central arterial segments in healthy adult subjects. We further showed that the effect of acute aerobic exercise on arterial stiffness is dependent on the timing of the measurements post-exercise. Therefore, when assessing the overall impact of exercise on arterial stiffness, it is important to consider the arterial segment being analyzed and measurement time point, as failure to contextualize the measurement can lead to conflicting results and misleading clinical inferences.

The effect of oral contraceptive pills and the natural menstrual cYCLe on arterial stiffness and hemodynamICs (CYCLIC).

Background: Over 100 million women currently use oral contraceptive pills (OCPs) worldwide. However, little is known about the effects of OCPs on arterial stiffness and hemodynamics. Furthermore, whether arterial stiffness and hemodynamics vary throughout the natural menstrual cycle remains controversial. Herein, we estimated the effect of the natural menstrual cycle and OCP use on arterial stiffness and hemodynamics. Methods: Healthy, nonsmoking women, aged 18–30 years, were recruited if they had regular menstrual cycles and never used OCPs (OCP nonuser group), or were using low-dose OCPs for at least 6 months (OCP user group). Using applanation tonometry, three assessments of arterial stiffness and central and peripheral hemodynamics were performed in a randomized order: during the early follicular (days 3–6), late follicular (days 14–16), and luteal (days 22–26) phases. Within group and between group comparisons were performed using general linear models. Results: Sixty women (21.7 ± 2.8 years) were recruited. Compared with OCP nonusers, OCP users had significantly increased aortic and peripheral SBPs during the active OCP use, but not during the inert tablet phase. No differences in arterial stiffness were noted. Conclusion: OCP use was associated with significant increases in aortic and peripheral blood pressures, but not with increased arterial stiffness. Given the widespread OCP use, future longitudinal studies are needed to confirm our findings and assess the long-term effect of OCPs on arterial stiffness and hemodynamics.

Carotid Endarterectomy Improves Peripheral but not Central Arterial Stiffness

OBJECTIVE Carotid endarterectomy (CEA) reduces the risk of cerebrovascular events due to the presence of atherosclerotic plaque in the internal carotid artery. Arterial stiffness is an indicator of cardiovascular risk and strongly associates with the development of atherosclerosis. This study aims to assess the short-term effect of CEA on arterial stiffness and haemodynamics. DESIGN Prospective observational study. METHODS Measurements of arterial stiffness and haemodynamics, including carotid-femoral pulse wave velocity (cfPWV), carotid-radial PWV (crPWV), augmentation pressure, augmentation index, subendocardial viability ratio, central pressures and pulse pressure amplification, were performed pre- and 6 weeks post-CEA on both surgical and non-surgical sides. RESULTS Fifty-nine patients completed the study (n = 46 men, age 68.9 ± 10.1 years). crPWV was decreased after CEA on the surgical (P = 0.01) and non-surgical side (P = 0.0008), AIx75 tended to decrease only on the surgical side (P = 0.06). cfPWV did not change significantly on either side. CONCLUSION We assessed, for the first time, the short-term effect of CEA on arterial stiffness and haemodynamics. CEA improved peripheral but not central arterial stiffness. This study provides evidence for significant changes in certain arterial stiffness and haemodynamic parameters. Longer-term follow-up will assess whether these changes are sustained and whether CEA is associated with further haemodynamic benefits.

From rest to stressed: endothelin-1 levels in young healthy smokers and non-smokers

INTRODUCTION Endothelin-1 (ET-1) is a potent vasoconstrictor produced by vascular endothelial cells, and a known marker of endothelial dysfunction. However, the acute and chronic effects of smoking and nicotine gum on the ET-1 response to acute physical stress in young healthy smokers have not been investigated. METHODS Healthy smokers (n=35) and non-smokers (n=35) underwent an exercise test to exhaustion (maximal oxygen consumption) on a treadmill. Smokers were assessed a) after 12h smoking abstinence (termed chronic smoking), b) immediately after smoking one cigarette (termed acute smoking), and c) immediately after chewing nicotine gum. Blood was drawn immediately pre-exercise, and 3 minutes post-exercise. During exercise, cardiorespiratory parameters were obtained breath-by-breath using an automated metabolic cart. Plasma ET-1 levels were quantified using enzyme-linked immunosorbent-assay. The above protocol was designed to incorporate exercise as a vascular stressor to reveal changes that would not be detected at rest. RESULTS Mean age was 28.6±7.2 years and body mass index (BMI) was 23.6±3.2 kg/m(2). Post-exercise ET-1 levels were significantly lower than pre-exercise levels in non-smokers (P<0.001) and smokers under all three conditions (P=0.005, P<0.001, P=0.001, respectively). There were no differences in post-exercise ET-1 levels between non-smokers and smokers under all three conditions, however the absolute and relative decrease in ET-1 levels was significantly smaller in chronic smokers compared with non-smokers (P=0.007 and P=0.004). Chronic smokers had a significantly lower exercise-induced change in tidal volume (P=0.050), fraction of expired CO2 (P=0.021), oxygen consumption (P=0.005), carbon dioxide elimination (P=0.004) and peak expiratory flow (P=0.003) compared with non-smokers. Furthermore, the decrease in ET-1 observed in non-smokers in response to exercise was significantly associated with exercise induced-changes in inspiratory time, time for a tidal volume cycle, respiratory frequency, inspired minute ventilation and peak inspiratory flow. CONCLUSIONS An acute decrease of circulating ET-1 in response to acute maximal exercise in young healthy individuals was noted. Chronic smokers had a significantly diminished decrease in ET-1 compared with non-smokers, however there were no significant differences in the ET-1 response between smokers under the three smoking conditions. Smokers were not able to achieve the same exercise-induced changes in cardiorespiratory parameters as non-smokers. By incorporating exercise as a vascular stressor in our study, we have taken a novel approach to provide evidence of an altered ET-1 and cardiorespiratory response that would not otherwise be observed at rest in young active healthy smokers.

Pulse Pressure Amplification and Arterial Stiffness in Low-Risk, Uncomplicated Pregnancies.

Background: Arterial stiffness, a composite indicator of vascular health and predictor of future cardiovascular (CV) disease and events, was assessed in low-risk, uncomplicated pregnancies. Methods: Women with low-risk pregnancy were recruited consecutively (recruitment across the 3 trimesters). Vessel hemodynamics and arterial stiffness were measured every 4 weeks from recruitment until delivery and at 6.5 weeks postpartum. Results: Sixty-three women (maternal age: 32.7 ± 4.9 years) with low-risk, uncomplicated pregnancy were recruited. Mean arterial pressure (P = .04) and aortic pulse pressure (P = .03) decreased during pregnancy, whereas heart rate gradually increased until delivery (P = .0002) and decreased postpartum (P = .06). Pulse pressure amplification (PPA) and carotid-to-radial pulse wave velocity initially decreased in the second trimester, followed by a steady increase until delivery (P = .01 and P = .04, respectively). Interestingly, PPA sharply decreased postpartum (P = .01). Augmentation index and the subendocardial viability ratio significantly increased postpartum (P = .03 and .02, respectively). Conclusion: The PPA increased steadily after the second trimester and was sharply decreased postpartum in low-risk, uncomplicated pregnancy. Longer and larger longitudinal studies will evaluate changes in PPA and its potential as a marker of CV risk later in women’s life.

The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized Controlled Trial in a Hemodialysis Population

OBJECTIVES Regular exercise is known to reduce arterial stiffness (AS) in hemodialysis patients. However, the impact of a more realistic intradialytic form of exercise, such as pedaling, is unclear. We aimed to examine (i) the effect of intradialytic pedaling exercise on AS over 4 months and (ii) the longer term effect of pedaling on AS 4 months after exercise cessation. METHODS Patients on stable in-center hemodialysis (3 x/week) were randomly assigned 1:1 to either intradialytic pedaling exercise (EX) or to a control group receiving usual hemodialysis (nonEX) for 4 months. At baseline and 4 months, peripheral and central blood pressure (BP) indices, heart rate (HR), augmentation index HR corrected (AIx75), and carotid-femoral pulse wave velocity (cfPWV) were assessed (applanation tonometry). Measurements were repeated in the EX group 4 months postexercise cessation. RESULTS As per protocol analysis was completed in 10 EX group participants (58 ± 17 years, body mass index 26 ± 4 kg/m2) and 10 nonEX group participants (53 ± 15 years, body mass index 27 ± 6 kg/m2). Peripheral and central BP was unchanged in both groups. AIx75 was unchanged in the EX group, however, a significant median increase of 3.5% [interquartile range, IQR 1.0, 8.5] was noted in the nonEX group (P = 0.009). We noted a significantly greater absolute decrease in cfPWV in the EX group compared to controls: -1.00 [IQR -1.95, 0.05] vs. 0.20 [IQR -0.10, 0.90] (P = 0.033). Interestingly, the decrease in cfPWV observed in the EX group was partially reversed 4 months after exercise cessation. CONCLUSION Intradialytic pedaling exercise has a beneficial impact on AS. This relationship warrants further investigation. CLINICAL TRIALS REGISTRATION Trial Number #NCT03027778 (clinicaltrials.gov).