Angiopoietin-2 level as a tool for cardiovascular risk stratification in hypertensive type 2 diabetic subjects

Objectives: This observational cross-sectional study aimed to investigate the relationship between serum Angiopoietin-2 (Ang-2) levels and cardiovascular (CVD) risk factors in drug controlled hypertensive diabetic subjects without cardiovascular complications.

Methods: All subjects were evaluated for fasting blood glucose (FBG), HbA1c, liver enzymes, lipid profile and serum Ang-2.

Results: Mean serum Ang-2 level was significantly higher in hypertensive diabetic subjects. In bivariate analysis in diabetic subjects with cardiovascular risk factors, Ang-2 positively correlated with waist circumference, body mass index (BMI), systolic blood pressure (SBP), FBG, HbA1c and triglycerides. In multivariate linear regression analysis, this association remained significant with FBG and triglycerides. Ang-2 levels were independently associated with CVD risk factors in drug controlled Type 2 diabetes (T2D) subjects.

Conclusions: Further detailed studies in larger population with more attention is needed to consider Ang-2 level as a tool for CVD risk stratification in hypertensive diabetic subjects.     

Exercise capacity and mortality – a follow-up study of 3033 subjects referred to clinical exercise testing

Background: Exercise stress testing is used as a diagnostic and prognostic tool. We determined the prognostic significance of exercise test findings for cardiovascular (CVD) and all-cause mortality in men and women.

Material and methods: 3033 subjects underwent a symptom-limited bicycle exercise test. Exercise capacity was defined as the mean of last four minutes of exercise workload.

Results: During an average follow-up of 19 years, 186 (11.6%) CVD and 370 (20.6%) all-cause deaths in men and 57 (5.0%) CVD and 155 (12.5%) all-cause deaths in women occurred. Among exercise test variables (workload, ECG, BP, HR), exercise capacity was the strongest predictor of mortality. Low exercise capacity (1st quartile) was associated with a hazard ratio of 4.2 (95% CI: 1.7, 10.8) for CVD and 4.0 (95% CI: 2.5, 6.4) for all-cause mortality compared with high exercise capacity (4th quartile) among men and in women with a 5.4-fold (95% CI: 1.2, 24.0) risk for CVD and 2.3-fold (95% CI: 1.2, 4.3) risk for all-cause mortality, respectively. The relationship between other exercise test variables and mortality was much weaker.

Conclusions: Among exercise test variables exercise capacity was the strongest predictor of CVD and all-cause mortality in both genders, and especially CVD deaths in women.

• Key Messages

• Exercise capacity was the most powerful predictor of CVD and all-cause mortality in both men and women.

• Low exercise capacity is a strong predictor of CVD death, especially among women.

     

The current status of homocysteine as a risk factor for cardiovascular disease: a mini review

Introduction: Hyperhomocysteinemia has been considered as a risk factor for systemic atherosclerosis, cardiovascular disease (CVD) and stroke and many epidemiologic and case-controlled studies have demonstrated its association with these complications. In addition, treatment of hyperhomocysteinemia with folic acid ± B vitamins prevents the development of atherosclerosis, CVD and strokes. However, subsequent prospective, randomized, placebo-controlled trials have not shown an association of high homocysteine levels or their lowering with treatment with the incidence of atherosclerosis, CVD or strokes, due possibly, to the fortification of flower with folic acid. Therefore, at present, there is a controversy regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine.

Areas covered: For these reasons, a focused Medline search of the English language literature was conducted between 2010 and 2017 using the terms, homocysteine, risk factor, atherosclerosis, cardiovascular disease, stroke, treatment, and 38 papers with pertinent information were selected.

Expert commentary: The review of data disclosed that there is a great controversy regarding the significance of homocysteine as a risk factor for CVD and stroke. The data from these papers together with collateral literature will be discussed in this mini review.     

Is cardiovascular disease in patients with diabetes associated with serum levels of MMP-2, LOX,and the elastin degradation products ELM and ELM-2?

Background: Diabetes mellitus type 2 (T2DM) is a significant risk factor for the development of cardiovascular diseases (CVDs). In a previous microarray study of internal mammary arteries from patients with and without T2DM, we observed several elastin-related genes with altered mRNA-expression in diabetic patients, namely matrix metalloproteinase 2 (MMP-2), lysyl oxidase (LOX) and elastin itself. In this study we investigate whether the serum concentrations of elastin-related proteins correlate to signs of CVD in patients with T2DM.

Methods: Blood samples from 302 type 2 diabetic patients were analysed for MMP-2, LOX, and the elastin degradation products ELM and ELM2. The results were investigated for correlations to signs of CVD in different vascular territories, as determined by myocardial perfusion scintigraphy, carotid artery thickness and ankle-brachial blood pressure index.

Results: T2DM patients with peripheral arterial disease (low ankle-brachial index) (PAD) display higher levels of MMP-2 and ELM compared to patients without PAD. However, none of the proteins or degradation products correlated with myocardial ischemia or a combined measure of CVD-signs, including myocardial ischemia, increased carotid thickness and decreased ankle-brachial blood pressure.

Conclusions: Our results suggest that the diabetic environment affects the circulating amounts of MMP-2 and ELM in patients with PAD. However, the same connection could not be seen in diabetic patients with CVD broadly identified in three vascular territories. LOX and ELM-2 did not correlate to any type of CVD. Overall, serum levels of elastin-related molecules are only remotely related to CVD in type 2 diabetes.     

Population-level seasonality in cardiovascular mortality,blood pressure,BMI and inflammatory cells in UK biobank

Introduction: The risk of mortality from cardiovascular disease (CVD) is higher in wintertime throughout the world, but it is not known if this reflects annual changes in diet or lifestyle, or an endogenous photoperiodic mechanism that is sensitive to changes in day length.

Methods: Phenotypic data on cardiometabolic and lifestyle factors were collected throughout a 4 year time period from 502,642 middle-aged participants in UK Biobank. To assess the impact of seasonal environmental changes on cardiovascular risk factors, we linked these data to the outdoor temperature and day length at the time of assessment. Self-reported information on physical activity, diet and disease status were used to adjust for confounding factors related to health and lifestyle.

Results: Mortality related to CVD was higher in winter, as were risk factors for this condition including blood pressure, markers of inflammation and body mass index (BMI). These seasonal rhythms were significantly related to day length after adjustment for other factors that might affect seasonality including physical activity, diet and outdoor temperature.

Conclusions: The risk of CVD may be modulated by day length at temperate latitudes, and the implications of seasonality should be considered in all studies of human cardiometabolic health.

• Key messages

• In this cross-sectional study in UK Biobank, we report annual variations in cardiovascular risk factors and mortality that were associated with day length independent of environmental and lifestyle factors.

• These seasonal changes in day length might contribute to annual patterns in cardiovascular disease and mortality.

     

Joint associations of sauna bathing and cardiorespiratory fitness on cardiovascular and all-cause mortality risk: a long-term prospective cohort study

Purpose: We aimed to evaluate the joint impact of cardiorespiratory fitness (CRF) and frequency of sauna bathing (FSB) on the risk of cardiovascular and all-cause mortality.

Design: CRF measured by respiratory gas analyses and sauna exposure were assessed at baseline in a prospective study of 2277 men. CRF was categorized as low and high (median cut-offs) and FSB as low and high (≤2 and 3–7 sessions/week, respectively).

Results: During a median follow-up of 26.1 years, 520 cardiovascular and 1124 all-cause deaths occurred. Comparing high versus low CRF, the multivariate-adjusted hazard ratios (HRs) 95% CIs for cardiovascular and all-cause mortality were 0.51 (0.41–0.63) and 0.65 (0.57–0.75), respectively. Comparing high versus low FSB, the corresponding HRs were 0.74 (0.59–0.94) and 0.84 (0.72–0.97), respectively. Compared to low CRF & low FSB, the HRs of CVD mortality for high CRF & high FSB; high CRF & low FSB; and low CRF & high FSB were 0.42 (0.28–0.62), 0.50 (0.39–0.63) and 0.72 (0.54–0.97), respectively. For all-cause mortality, the corresponding HRs were 0.60 (0.48–0.76), 0.63 (0.54–0.74) and 0.78 (0.64–0.96), respectively.

Conclusions: A combination of high CRF and frequent sauna bathing confers stronger long-term protection on mortality outcomes compared with high CRF or high FSB alone.

• KEY MESSAGES

• Cardiorespiratory fitness (CRF) and frequency of sauna bathing are independently associated with reduced mortality risk; a combination of good CRF and frequent sauna bathing may confer additional survival benefits.

• In a population-based prospective cohort study, a combination of high CRF levels and frequent sauna bathing (3–7 sessions per week) was associated with a substantial risk reduction in fatal cardiovascular and all-cause mortality events compared with good CRF or frequent sauna bathing alone.

• A combination of good fitness levels produced by aerobic exercises and frequent sauna bathing may have added health benefits and confer more protection on the risk of mortality.

     

The impact of coffee consumption on blood pressure,cardiovascular disease and diabetes mellitus

Introduction: Coffee is the most widely consumed beverage, next to water. However, there has been a long-standing controversy regarding its safety on blood pressure (BP) and cardiovascular disease (CVD) and intuitively, physicians dissuaded their patients from coffee drinking.

Areas covered: This controversy was, primarily, based on older prospective studies or case reports, which showed a positive association of coffee drinking with the incidence of hypertension and CVD. In contrast to these reports, recent, well controlled, studies have demonstrated either a neutral or beneficial effect of moderate coffee consumption (3–4 cups/day), on BP, CVD, heart failure (HF), cardiac arrhythmias, or diabetes mellitus (DM). For the preparation of this special report, an English language focused search of the Medline database was conducted between 2010 and 2016 on studies with data on effect on the coffee consumption in patients with high BP, CVD, HF, cardiac arrhythmias or DM. Of the 94 abstracts reviewed, 34 pertinent papers were selected, and the findings from these papers together with collateral literature will be discussed in this special report.

Expert commentary: Based on the evidence from these studies, coffee consumption in moderation, is safe and is beneficial in both healthy persons as well as patients with high BP, CVD, HF, cardiac arrhythmias or DM. Therefore, coffee restriction is not warranted for these patients, although some caution should be exercised.     

Utilizing nutritional genomics to tailor diets for the prevention of cardiovascular disease: a guide for upcoming studies and implementations

Introduction: Personalized diets based on an individual’s genome to optimize the success of dietary intervention and reduce genetic cardiovascular disease (CVD) risk, is one of the challenges most frequently discussed in the scientific community.

Areas covered: The authors gathered literature-based evidence on nutritional genomics and CVD phenotypes, our own results and research experience to provide a critical overview of the current situation of using nutritional genomics to tailor diets for CVD prevention and to propose guidelines for future studies and implementations.

Expert commentary: Hundreds of studies on gene-diet interactions determining CVD intermediate (plasma lipids, hypertension, etc.) and final phenotypes (stroke, etc.) have furnished top-level scientific evidence for claiming that the genetic effect in cardiovascular risk is not deterministic, but can be modified by diet. However, despite the many results obtained, there are still gaps in practically applying a personalized diet design to specific genotypes. Hence, a better systemization and methodological improvement of new studies is required to obtain top-level evidence that will allow their application in the future precision nutrition/medicine. The authors propose several recommendations for tackling new approaches and applications.     

Association between cardiovascular diseases and mobility in persons with lower limb amputation: a systematic review

Purpose: Persons requiring a lower limb amputation often have cardiovascular diseases that reduce cardiac function, which may complicate recovery and rehabilitation after an amputation. This systematic review analysis the association between cardiovascular diseases and mobility in persons with a lower limb amputation.

Method: Four databases were searched for studies published before August 2016 using database-specific keywords and synonyms for amputation, cardiovascular diseases and mobility. Assessment of the publications was performed based on predefined criteria; first title and abstract and thereafter the full text.

Results: Of the 1704 titles and abstracts, 51 full texts were assessed. Ten studies were included. Cardiovascular diseases were associated with cardiac complications during rehabilitation. Prosthetic training improved cardiac function. Seven studies showed that cardiovascular diseases were associated with a smaller chance of becoming a prosthetic walker, and with poorer mobility outcomes.

Conclusion: Evidence for effects of cardiovascular diseases on mobility in persons with a lower limb amputation is heterogeneous. Cardiovascular diseases reduce the chance of becoming a prosthetic walker and reduce mobility outcomes after a lower limb amputation. More research with adequate quality about cardiovascular diseases in persons requiring a lower limb amputation is needed, to enable informed choices in the pre- and post-amputation rehabilitation.

• Implications for rehabilitation

• Data about the effect of cardiovascular diseases on mobility in persons with a lower limb amputation is limited.

• More research about cardiovascular diseases in persons requiring a lower limb amputation is needed, to enable informed choices in the pre- and post-amputation rehabilitation.

     

Cardiovascular impact of testosterone therapy for hypogonadism

Introduction: Since 2010 some evidence supporting the possible increased cardiovascular (CV) risk related to testosterone treatment (TTh) has created much debate in the scientific community. Based on these results, the US Food and Drug Administration agency has questioned TTh for aging men recognizing its value only for classical hypogonadism due to genetic or organic causes. To better clarify this topic, we scrutinized and summarized, also by using meta-analytic methods, the data generated during the last 7 years, as derived from the analysis of randomized controlled trials (RCTs) on TTh and CV risk.

Areas covered: Analysis included 31 RCTs published between 2010 and 2018. Retrieved trials included 2675 and 2308 patients in TTh and placebo groups, respectively. The analysis documented that TTh was not associated with an increased CV mortality or morbidity either when overall or major adverse CV events were considered.

Expert commentary: Despite present evidence it is important to recognize that the duration of the available trials is short (lower that 3 years) limiting final conclusions on this topic. In particular, the available information on possible long-term effects of TTh on CV risk is limited. Long-term safety studies are advisable to better clarify these points.     

Alirocumab for the treatment of hypercholesterolemia

Introduction: Alirocumab is a human monoclonal antibody inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered by subcutaneous injection every 2 weeks.

Area covered: Herein, the authors discuss the background to inhibition of PCSK9 and the pharmacodynamics, pharmacokinetics and clinical trials with alirocumab. Alirocumab produces substantial reductions in low density lipoprotein cholesterol (LDL-C) in patients with and without background statin treatment. The safety profile appears very promising from the relatively short term studies that have been completed but there are some remaining concerns about long term risks of neurocognitive events and developing diabetes.

Expert opinion: The profound reduction in LDL-C with alirocumab is most likely to translate into cardiovascular benefits in the ODYSSEY OUTCOMES trial and is unlikely in itself to result in any major adverse effects. The high cost and the current lack of long-term safety and efficacy data will restrict the use of alirocumab to patients who have high cardiovascular risk from established atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia and who are unable to achieve LDL-C targets with maximally tolerated dose of statins with or without other lipid-lowering drugs. When further data become available, these indications are likely to be expanded.     

Cholesteryl ester transfer protein inhibitors: challenges and perspectives

Introduction: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction.

Areas covered: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review.

Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.     

Alirocumab for the treatment of hyperlipidemia in high-risk patients: an updated review

Introduction: Alirocumab is a fully human immunoglobulin G1 monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved for the treatment of hypercholesterolemia in high-risk patients. The objective is to provide an updated review of the recent data published for alirocumab.

Areas covered: The efficacy and safety of alirocumab has been initially evaluated in a comprehensive phase 3 program conducted in more than 6 000 patients with primary non-familial and heterozygous familial hypercholesterolemia: alirocumab reduced LDL-cholesterol up to 62% in phase 3 with every 2-week dosing compared with placebo, and up to 36% compared with ezetimibe, with an excellent safety and tolerability profile. Herein, the author describes new efficacy and safety data obtained from complementary analyses of the phase 3 program submitted for approval and reports data from new specific trials.

Expert commentary: Based on current high pricing, the patient groups prioritized for alirocumab treatment are patients with heterozygous familial hypercholesterolemia and patients with atherosclerotic cardiovascular disease who have substantially elevated LDL cholesterol on maximally tolerated statin plus ezetimibe therapy. The ongoing ODYSSEY OUTCOMES trial will provide important information on the cost-effectiveness of alirocumab treatment.     

Evolocumab for the treatment of hypercholesterolemia

Introduction: Evolocumab is a fully human monoclonal immunoglobulin G2 directed against human proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered by subcutaneous injection every 2 weeks or once monthly.

Area covered: Herein, the authors discuss the rationale for inhibiting PCSK9 and describe the pharmacodynamics, pharmacokinetics and clinical trials with evolocumab. Evolocumab reduces low density lipoprotein cholesterol (LDL-C) levels by 50 to 60% in most patients with and without background treatment with statins or other lipid lowering agents. The safety profile appears satisfactory from the completed clinical studies and concerns regarding the risk of neurocognitive events have largely been dispelled.

Expert opinion: The reduction of LDL-C with evolocumab to previously unattainable levels has resulted in a reduction in the composite cardiovascular event endpoint in the FOURIER trial and this is likely to impact on future lipid management guidelines. The clinical outcome data and excellent tolerability profile clearly support the use of evolocumab in patients at high cardiovascular risk, including those with heterozygous or homozygous familial hypercholesterolemia, who are unable to achieve LDL-C targets with statins with or without other lipid-lowering drugs. The high cost of evolocumab will restrict its use, however.     

Chelation therapy to treat atherosclerosis,particularly in diabetes: is it time to reconsider?

Introduction: Case reports and case series have suggested a possible beneficial effect of chelation therapy in patients with atherosclerotic disease. Small randomized trials conducted in patients with angina or peripheral artery disease, however, were not sufficiently powered to provide conclusive evidence on clinical outcomes.

Areas covered: The Trial to Assess Chelation Therapy (TACT) was the first randomized trial adequately powered to detect the effects of chelation therapy on clinical endpoints. We discuss results and future research.

Expert commentary: Chelation reduced adverse cardiovascular events in a post myocardial infarction (MI) population. Patients with diabetes demonstrated even greater benefit, with a number needed to treat of 6.5 patients to prevent a cardiac event over 5 years, with a 41% relative reduction in risk of a cardiac event (p = 0.0002). These results led to the revision of the ACC/AHA guideline recommendations for chelation therapy, changing its classification from class III to class IIb. TACT2, a replicative trial, will assess the effects of chelation therapy on cardiovascular outcomes in diabetic patients with a prior myocardial infarction. We are seeking participating sites for TACT2.     

Exploring heart failure events in contemporary cardiovascular outcomes trials in type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (DM) and heart failure (HF) are closely related, with the onset of one serving as an independent risk factor for the development or progression of the other. The true impact of their relationship is poorly understood. Since various classes of glucose-lowering therapies have been shown to have differing impact on cardiovascular outcomes, cardiovascular effects of such therapies have been increasingly formally evaluated.

Areas covered: With the increasing prevalence of concomitant HF and type 2 DM, HF outcomes serve as important endpoints in trials of glucose-lowering therapies. A thorough literature search of recent cardiovascular outcome trials of glucose-lowering therapies was performed. The authors focus on the availability and extent of ascertainment of data related to HF outcomes in these contemporary clinical trial experiences.

Expert commentary: Although early cardiovascular outcome trials did not focus on HF events, these outcomes have been increasingly recognized as meaningful end points in cardiovascular outcome trials. The ascertainment of HF end point data needs to become routine and standardized.     

Predictive validity of the ACC/AHA pooled cohort equations in predicting residual-specific mortality in a national prospective cohort study of adults in the United States

Objective: The predictive validity of the Pooled Cohort risk (PCR) equations for residual-specific mortality (deaths not resulting from the 9 leading causes of death) among a national sample of U.S. adults has not previously been evaluated, which was the purpose of this study.

Methods: Data from the 1999–2010 National Health and Nutrition Examination Survey were used, with participants followed up through 31 December 2011 to ascertain mortality status. The analyzed sample included 11,171 cardiovascular disease-free adults (40–79 years of age). The 10-year risk of a first atherosclerotic cardiovascular disease (ASCVD) event was determined from the PCR equations.

Results: For the entire sample, 849,202 person-months occurred with an incidence rate of 0.29 (95% CI: 0.25–0.33) residual-specific deaths per 1,000 person-months. The unweighted median follow-up duration was 72 months. For all analyses, ASCVD risk score (via the PCR equations) was significantly associated with residual-specific mortality. In a fully adjusted model including moderate-to-vigorous physical activity (MVPA), obesity, age (yrs; continuous measure), gender (male/female) and race-ethnicity (Mexican American, non-Hispanic white, non-Hispanic black and other) as covariates, those with an ASCVD ≥ 20 (vs. < 20) had a 91% increased hazard of residual-specific death during the follow-up period (HR = 1.91; 95% CI: 1.10–3.31). Expressed as probability, there was a 66% chance that those with ASCVD ≥ 20 (vs. < 20) would have a residual specific-death during the follow-up period.

Conclusion: The 10-year predicted risk of a first ASCVD event via the PCR equations was directly associated with residual-specific mortality among those free of cardiovascular disease (CVD) at baseline, providing evidence of predictive validity of the PCR equations among this national sample of U.S. adults.