Physical Activity and Cardiac Morphologic Adaptations.

Chronic and intense exercise programs lead to cardiac adaptations, followed by increased left ventricular wall thickness and cavity diameter, at times meeting the criteria for left ventricular hypertrophy (LVH), commonly referred to as "athlete's heart". Recent studies have also reported that extremely vigorous exercise practices have been associated with heightened left ventricular trabeculation extent, fulfilling noncompaction cardiomyopathy criteria, as part of exercise-induced structural adaptation. These changes are specific to the exercise type, intensity, duration, and volume and workload demands imposed on the myocardium. They are considered physiologic adaptations not associated with a negative prognosis. Conversely, hypertrophic cardiac adaptations resulting from chronic elevations in blood pressure (BP) or chronic volume overload due to valvular regurgitation, lead to compromised cardiac function, increased cardiovascular events, and even death. In younger athletes, hypertrophic cardiomyopathy (HCM) is the usual cause of non-traumatic, exercise-triggered sudden cardiac death. Thus, an extended cardiac examination should be performed, to differentiate between HCM and non-pathological exercise-related LVH or athlete's heart. The exercise-related cardiac structural and functional adaptations are normal physiologic responses designed to accommodate the increased workload imposed by exercise. Thus, we propose that such adaptations are defined as "eutrophic" hypertrophy and that LVH is reserved for pathologic cardiac adaptations. Systolic BP during daily activities may be the strongest predictor of cardiac adaptations. The metabolic demand of most daily activities is approximately 3-5 metabolic equivalents (METs) (1 MET = 3.5 mL of O 2 kg of body weight per minute). This is similar to the metabolic demand of treadmill exercise at the first stage of the Bruce protocol. Some evidence supports that an exercise systolic BP response ≥ 150 mmHg at the end of that stage is a strong predictor of left ventricular hypertrophy, as this BP reflects the hemodynamic burden of most daily physical tasks. Aerobic training of moderate intensity lowers resting and exercise systolic BP at absolute workloads, leading to a lower hemodynamic burden during daily activities, and ultimately reducing the stimulus for LVH. This mechanism explains the significant LVH regression addressed by aerobic exercise intervention clinical studies.

Progression to Insulin Therapy in Patients With Type 2 Diabetes According to Cardiorespiratory Fitness, Body Mass Index, and Statin Therapy.

OBJECTIVE: To evaluate the association between statin therapy, cardiorespiratory fitness (CRF), body mass index (BMI), and progression to insulin therapy in type 2 diabetes mellitus (T2DM). METHODS: Participants were patients with T2DM (mean age, 62.7±8.4 years; men, 178,992; women, 8360) not treated with insulin, with no evidence of uncontrolled cardiovascular disease, who completed an exercise treadmill test between October 1, 1999, and September 3, 2020. Of these, 158,578 were treated with statins and 28,774 were not. We established 5 age-specific CRF categories according to peak metabolic equivalents of task achieved during an exercise treadmill test. RESULTS: During a median follow-up period of 9.0 years, 51,182 patients progressed to insulin therapy with an average annual incidence rate of 28.4 events/1000 person-years. The adjusted progression rate was 27% higher in statin-treated patients (hazard ratio [HR], 1.27; 95% CI, 1.24 to 1.31), related directly to BMI and inversely related to CRF. A progressively higher rate was noted in statin-treated vs non-statin-treated patients within all BMI categories, ranging from 23% for normal weight to 90% for those with BMI of 35 kg/m2 and higher. The statin-CRF interaction revealed 43% higher rate in the least-fit statin-treated patients (HR, 1.43; 95% CI, 1.35 to 1.51) and a progressive decline with increased CRF to 30% lower risk in highly fit statin-treated patients (HR, 0.70; 95% CI, 0.66 to 0.75). CONCLUSION: In patients with T2DM, the statin-related progression to insulin therapy was associated with relatively low CRF and high BMI levels. The progression rate was mitigated by increased CRF regardless of BMI. Clinicians should foster regular exercise for patients with T2DM to enhance CRF and to lessen the rate of progression to insulin therapy.

Impact of Cardiorespiratory Fitness on COVID-19-Related Outcomes: The Exercise Testing and Health Outcomes Study (ETHOS).

OBJECTIVE: To assess the association between cardiorespiratory fitness (CRF) and COVID-19-related health outcomes including mortality, hospitalization, and mechanical ventilation. PATIENTS AND METHODS: In a retrospective analysis of 750,302 patients included in the Exercise Testing and Health Outcomes Study, we identified 23,140 who had a positive result on COVID-19 testing between March 2020 and September 2021 and underwent a maximal exercise test in the Veterans Affairs Health Care System between October 1, 1999 to September 3, 2020. The association between CRF and risk for severe COVID-19 outcomes, including mortality, hospitalization due to COVID-19, and need for intubation was assessed after adjustment for 15 covariates. Patients were stratified into 5 age-specific CRF categories (Least-Fit, Low-Fit, Moderate-Fit, Fit, and High-Fit), based on peak metabolic equivalents achieved. RESULTS: During a median of follow-up of 100 days, 1643 of the 23,140 patients (7.1%) died, 4995 (21.6%) were hospitalized, and 927 (4.0%) required intubation for COVID-19-related reasons. When compared with the Least-Fit patients (referent), the Low-Fit, Moderate-Fit, Fit, and High-Fit patients had hazard ratios for mortality of 0.82 (95% CI, 0.72 to 0.93), 0.73 (95% CI, 0.63 to 0.86), 0.61 (95% CI, 0.53 to 0.72), and 0.54 (95% CI, 0.45 to 0.65), respectively. Patients who were more fit also had substantially lower need for hospital admissions and intubation. Similar patterns were observed for elderly patients and subgroups with comorbidities including hypertension, diabetes, cardiovascular disease, and chronic kidney disease; for each of these conditions, those in the High-Fit category had mortality rates that were roughly half those in the Low-Fit category. CONCLUSION: Among patients positive for COVID-19, higher CRF had a favorable impact on survival, need for hospitalization, and need for intubation regardless of age, body mass index, or the presence of comorbidities.

Cardiorespiratory fitness and risk of heart failure with preserved ejection fraction.

AIMS: Preventive strategies for heart failure with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence. METHODS AND RESULTS: We assessed CRF in US Veterans (624 551 men; mean age 61.2 ± 9.7 years and 43 179 women; mean age 55.0 ± 8.9 years) by a standardized ETT performed between 1999 and 2020 across US Veterans Affairs Medical Centers. All had no evidence of heart failure or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age- and gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n = 139 434) ≥1.0 year apart. During a median follow-up of 10.1 years (interquartile range 6.0-14.3 years), providing 6 879 229 person-years, there were 16 493 HFpEF events with an average annual rate of 2.4 events per 1000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% confidence interval [CI] 0.46-0.51) compared with least fit (≤4.9 METs; referent). Being unfit carried the highest risk (HR 2.88, 95% CI 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit. CONCLUSIONS: Higher CRF levels are independently associated with lower HFpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF.

Stroke Incidence in Patients With Hypertension According to Cardiorespiratory Fitness.

BACKGROUND: Hypertension and physical inactivity are risk factors for stroke. The effect of cardiorespiratory fitness (CRF) on stroke risk in patients with hypertension has not been assessed. We evaluated stroke incidence in patients with hypertension according to CRF and changes in CRF. METHODS: We included 483 379 patients with hypertension (mean age±SD; 59.4±9.0 years) and no evidence of unstable cardiovascular disease as indicated by a standardized exercise treadmill test. Patients were assigned to 5 age- and sex-specific CRF categories based on peak metabolic equivalents achieved at the initial exercise treadmill test and in 4 categories based on metabolic equivalent changes over time (n=110 576). Multivariable Cox models, adjusted for age, and comorbidities were used to estimate hazard ratios and 95% CIs for stroke risk. RESULTS: During a median follow-up of 10.6 (interquartile range, 6.6-14.6) years, 15 925 patients developed stroke with an average yearly rate of 3.1 events/1000 person-years. Stroke risk declined progressively with higher CRF and was 55% lower for the High-fit individuals (hazard ratio, 0.45 [95% CI, 0.42-0.48]) compared with the Least-fit. Similar associations were observed across the race, sex, and age spectra. Poor CRF was the strongest predictor of stroke risk of all comorbidities studied (hazard ratio, 2.24 [95% CI, 2.10-2.40]). Changes in CRF reflected inverse and proportional changes in stroke risk. CONCLUSIONS: Poor CRF carried a greater risk than any of the cardiac risk factors in patients with hypertension, regardless of age, race, or sex. The lower stroke risk associated with improved CRF suggests that increasing physical activity, even later in life, may reduce stroke risk.

Changes in Cardiorespiratory Fitness and Survival in Patients With or Without Cardiovascular Disease.

BACKGROUND: The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF assessment. The impact of CRF change on mortality risk is not well-defined. OBJECTIVES: This study sought to evaluate changes in CRF and all-cause mortality. METHODS: We assessed 93,060 participants aged 30-95 years (mean 61.3 ± 9.8 years). All completed 2 symptom-limited exercise treadmill tests, 1 or more years apart (mean 5.8 ± 3.7 years) with no evidence of overt cardiovascular disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change) observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-cause mortality. RESULTS: During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF ≥1.0 MET were associated with inverse and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% increase (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD. CONCLUSIONS: Changes in CRF reflected inverse and proportional changes in mortality risk for those with and without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health significance.

Cardiorespiratory Fitness and Mortality Risk Across the Spectra of Age, Race, and Sex.

BACKGROUND: Cardiorespiratory fitness (CRF) is inversely associated with all-cause mortality. However, the association of CRF and mortality risk for different races, women, and elderly individuals has not been fully assessed. OBJECTIVES: The aim of this study was to evaluate the association of CRF and mortality risk across the spectra of age, race, and sex. METHODS: A total of 750,302 U.S. veterans aged 30 to 95 years (mean age 61.3 ± 9.8 years) were studied, including septuagenarians (n = 110,637), octogenarians (n = 26,989), African Americans (n = 142,798), Hispanics (n = 35,197), Native Americans (n = 16,050), and women (n = 45,232). Age- and sex-specific CRF categories (quintiles and 98th percentile) were established objectively on the basis of peak METs achieved during a standardized exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for mortality across the CRF categories. RESULTS: During follow-up (median 10.2 years, 7,803,861 person-years of observation), 174,807 subjects died, averaging 22.4 events per 1,000 person-years. The adjusted association of CRF and mortality risk was inverse and graded across the age spectrum, sex, and race. The lowest mortality risk was observed at approximately 14.0 METs for men (HR: 0.24; 95% CI: 0.23-0.25) and women (HR: 0.23; 95% CI: 0.17-0.29), with no evidence of an increase in risk with extremely high CRF. The risk for least fit individuals (20th percentile) was 4-fold higher (HR: 4.09; 95% CI: 3.90-4.20) compared with extremely fit individuals. CONCLUSIONS: The association of CRF and mortality risk across the age spectrum (including septuagenarians and octogenarians), men, women, and all races was inverse, independent, and graded. No increased risk was observed with extreme fitness. Being unfit carried a greater risk than any of the cardiac risk factors examined.

Exercise capacity and mortality in older men: a 20-year follow-up study.

BACKGROUND: Epidemiological findings, based largely on middle-aged populations, support an inverse and independent association between exercise capacity and mortality risk. The information available in older individuals is limited. METHODS AND RESULTS: Between 1986 and 2008, we assessed the association between exercise capacity and all-cause mortality in 5314 male veterans aged 65 to 92 years (mean+/-SD, 71.4+/-5.0 years) who completed an exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. We established fitness categories based on peak metabolic equivalents (METs) achieved. During a median 8.1 years of follow-up (range, 0.1 to 25.3), there were 2137 deaths. Baseline exercise capacity was 6.3+/-2.4 METs among survivors and 5.3+/-2.0 METs in those who died (P<0.001) and emerged as a strong predictor of mortality. For each 1-MET increase in exercise capacity, the adjusted hazard for death was 12% lower (hazard ratio=0.88; confidence interval, 0.86 to 0.90). Compared with the least fit individuals (< or =4 METs), the mortality risk was 38% lower for those who achieved 5.1 to 6.0 METs (hazard ratio=0.62; confidence interval, 0.54 to 0.71) and progressively declined to 61% (hazard ratio=0.39; confidence interval, 0.32 to 0.49) for those who achieved >9 METs, regardless of age. Unfit individuals who improved their fitness status with serial testing had a 35% lower mortality risk (hazard ratio=0.65; confidence interval, 0.46 to 0.93) compared with those who remained unfit. CONCLUSIONS: Exercise capacity is an independent predictor of all-cause mortality in older men. The relationship is inverse and graded, with most survival benefits achieved in those with an exercise capacity >5 METs. Survival improved significantly when unfit individuals became fit.

Exercise blood pressure, cardiorespiratory fitness and mortality risk.

OBJECTIVE: To assess the cardiorespiratory fitness (CRF) impact on the association between exercise blood pressure (BP) and mortality risk. PATIENTS AND METHODS: We assessed CRF in 15,004 US Veterans (mean age 57.5 ± 11.2 years) who completed a standardized treadmill test between January 1, 1988 and July 28, 2017 and had no evidence of ischemia. They were classified as Unfit or Fit according to the age-specific metabolic equivalents (METs) achieved <50% (6.2 ± 1.6 METs; n = 8440) or ≥ 50% (10.5 ± 2.4 METs; n = 6264). To account for the impact of resting systolic BP (SBP) on outcomes, we calculated the difference (Peak SBP-Resting SBP) and termed it SBP-Reserve. We noted a significant increase in mortality associated with SBP-Reserve ≤52 mmHg and stratified the cohort accordingly (SBP-Reserve ≤52 mmHg and > 52 mmHg). We applied multivariable Cox models to estimate hazard ratios (HR) and 95% confidence interval (CIs) for outcomes. RESULTS: Mortality risk was significantly elevated only in Unfit individuals with SBP-Reserve ≤52 mmHg compared to those with SBP-Reserve >52 mmHg (HR = 1.35; CI: 1.24-1.46; P < 0.001). We then assessed the CRF and SBP-Reserve interaction on mortality risk with Fit individuals with SBP-Reserve >52 mmHg serving as the referent. Mortality risk was 92% higher (HR = 1.92%; 95% CI: 1.77-2.09; P < 0.001) in Unfit individuals with SBP-Reserve ≤52 mmHg and 47% higher (HR = 1.47; 95% CI: 1.33-1.62; P < 0.001) in those with SBP-Reserve >52 mmHg. CONCLUSION: Low CRF was associated with increased mortality risk regardless of peak exercise SBP. The risk was substantially higher in individuals unable to augment their exercise SBP >52 mmHg beyond resting levels.

The Growing Epidemic of Diabetes Mellitus.

BACKGROUND: During the past decades, the prevalence of diabetes (DM) has increased significantly, mainly as a result of continuous rise in the incidence of type 2 DM. According to World Health Organization statistics, >422 million adults globally were suffering from DM in 2014 and a continuous rise in DM prevalence is expected. OBJECTIVE: The present review considers recent epidemiological data providing worldwide estimates regarding the incidence of DM. METHODS: A comprehensive literature search was conducted to identify available data from epidemiological studies evaluating the current burden of DM. RESULTS: Over the past few decades the prevalence of DM has risen significantly in nearly all countries and may be considered as a growing epidemic. Urbanization and income status are major factors which influence current rates in the prevalence studies introducing interesting differences between several population groups. CONCLUSION: Having recognized the global burden of DM, we now realize the urgent need for effective interventions. In order to monitor the public-health strategies and design effective future interventions we need reliable global estimates regarding the prevalence of DM.

The effect of Mid-Day Sleep on blood pressure levels in patients with arterial hypertension.

STUDY OBJECTIVES: Lifestyle changes decrease blood pressure (BP) levels by 3-5 mmHg in hypertensive patients. We assessed the effect of mid-day sleep on BP levels in hypertensive patients. METHODS: We prospectively studied two hundred and twelve hypertensive patients. Mid-day sleep duration, lifestyle habits, anthropometric characteristics, office BP, ambulatory BP monitoring, pulse wave velocity (PWV), augmentation index (AI) were recorded. A standard echocardiographic evaluation was performed. RESULTS: 53.8% were females, mean age was 62.5±11.0 years and mean body mass index was 28.9±5.4kg/m2. Mean average 24h systolic and diastolic BP (SBP & DBP) was 129.9±13.2/76.7±7.9 mmHg respectively. The majority was non-smokers (70.3%) and did not have diabetes (74.7%). The mean midday sleep duration was 48.7±54.3 min. Average 24h SBP (127.6±12.9 mmHg vs 132.9±13.1 mmHg), average daytime SBP & DBP were lower in patients who sleep at midday, compared to those who do not (128.7±13/76.2±11.5 vs 134.5±13.4/79.5±10.4 mmHg) (p<0.005). The effect was not correlated to the dipping status. Midday sleep duration was negatively correlated with average 24h SBP & daytime SBP. In a linear regression model, for every 60 min of midday sleep, 24h average SBP decreases by 3 mmHg (p<0.001). There were no differences in the number of antihypertensive medications, PWV, AI or echocardiographic indices between study groups. CONCLUSIONS: Mid-day sleep significantly decreases average 24h and daytime SBP/DBP in hypertensives. Its effect seems to be as potent as other well-established lifestyle changes and is independent of dipping status.

Exercise capacity and mortality in black and white men.

BACKGROUND: Exercise capacity is inversely related to mortality risk in healthy individuals and those with cardiovascular diseases. This evidence is based largely on white populations, with little information available for blacks. METHODS AND RESULTS: We assessed the association between exercise capacity and mortality in black (n=6749; age, 58+/-11 years) and white (n=8911; age, 60+/-11 years) male veterans with and without cardiovascular disease who successfully completed a treadmill exercise test at the Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, Calif. Fitness categories were based on peak metabolic equivalents (METs) achieved. Subjects were followed up for all-cause mortality for 7.5+/-5.3 years. Among clinical and exercise test variables, exercise capacity was the strongest predictor of risk for mortality. The adjusted risk was reduced by 13% for every 1-MET increase in exercise capacity (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.88; P<0.001). Compared with those who achieved <5 METs, the mortality risk was approximately 50% lower for those with an exercise capacity of 7.1 to 10 METs (hazard ratio, 0.51; 95% confidence interval, 0.47 to 0.56; P<0.001) and 70% lower for those achieving >10 METs (hazard ratio, 0.31; 95% confidence interval, 0.26 to 0.36; P<0.001). The findings were similar for those with and without cardiovascular disease and for both races. CONCLUSIONS: Exercise capacity is a strong predictor of all-cause mortality in blacks and whites. The relationship was inverse and graded, with a similar impact on mortality outcomes for both blacks and whites.

A graded association of exercise capacity and all-cause mortality in males with high-normal blood pressure.

INTRODUCTION: Information regarding the effect of exercise capacity on mortality risk in individuals with high-normal blood pressure is severely limited. Thus, we evaluated the association of exercise capacity and all-cause mortality in individuals with high-normal blood pressure. METHODS: Exercise test was performed in 1727 males with high-normal blood pressure at two Veteran sites (Washington, DC, and Palo Alto, CA). Fitness status was assessed in metabolic equivalents (METs) at exercise peak. All-cause mortality was recorded for a mean follow-up period of 9.8+/-6.0 years. RESULTS: Exercise capacity was inversely associated with all-cause mortality, and the association was independent of traditional cardiovascular risk factors. For each 1 MET increase in exercise capacity, the adjusted mortality risk was reduced by 13%, underscoring the strong predictive value of exercise capacity that was confirmed by ROC analysis. Data analysis according to fitness levels revealed a threshold level of 4 METs, over which the mortality risk was progressively reduced by 30% (hazard ratio=0.70; CI 0.51-0.95) for those who achieved 4.1-6.0 METs and 61% (hazard ratio=0.39; CI 0.26-0.57) for those who achieved 8.1-10 METs. No additional reductions in risk were noted until the MET level achieved exceeded 12 METs. CONCLUSIONS: We observed a strong, inverse, graded and independent association between exercise capacity and all-cause mortality in individuals with high-normal blood pressure. Our findings indicate that a shift of the fitness curve to the right is associated with significant survival benefits, and even slight differences in fitness levels are associated with substantial reductions in mortality risk.

Is very low LDL-C harmful?

BACKGROUND: Low-density Lipoprotein Cholesterol (LDL-C) is a major Cardiovascular (CV) risk factor. Accumulating evidence supports a linear association between LDL-C levels and CV risk. However, the lower limit of LDL-C that might offer CV benefits without any safety concerns is still a topic of debate. OBJECTIVE: The purpose of this review is to present the safety of reducing LDL-C to low levels as it comes from major lipid-lowering drug studies, and to discuss data on several safety events that have been associated with low LDL-C levels. METHODS: A comprehensive literature search was performed to identify available data from clinical studies evaluating the association of low LDL-C with safety outcomes. RESULTS: Several large trials have evaluated the safety or reducing LDL-C to levels lower than 50 mg/dl or even lower than 25 mg/dl, more commonly with the use of a combination of statins with ezetimibe or proprotein convertase subtilisin kexin 9 inhibitors. In almost all trials, CV benefits were observed with LDL-C levels of 50 mg/dl or less compared with higher levels. In terms of safety, reduction of LDL-C to such levels was not associated with any significant adverse event. Of importance, cancer and hemorrhagic stroke incidences were not increased in patients attaining LDL-C lower than 40-50 mg/dl. Data regarding the impact of lowering LDL-C with neurocognitive disorders are contradictory; nevertheless, most studies stand in favor of neurocognitive safety with LDL-C reductions to low levels. CONCLUSION: Achieving an LDL-C of 40-50 mg/dl seems to be safe, and importantly might offer CV beneficial effects. Data for attaining levels below 25 mg/dl is limited, however in favor of such reductions.

Lifestyle Modifications in Non-Alcoholic Fatty Liver Disease and Non- Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases worldwide, affecting more than 30% of general population. High-fat diets, physical inactivity and obesity, all prevalent in the western societies, are strongly associated with the development and progression of NAFLD. Current drug therapies have not consistently shown substantial beneficial effects. Thus, lifestyle modification appears to be the optimal intervention in combating the disease. Accordingly, several studies have concluded that weight loss, via increase in physical activity, and dietary interventions could potential ameliorate biochemical, histological, and structural abnormalities of non-alcoholic fatty liver disease. The aim of this review is to summarize the findings of these lifestyle intervention studies and discuss the implementation of each intervention, and its effectiveness in the management of the disease in everyday clinical practice.

Adverse Effects of Mineralocorticoid Receptor Antagonist Administration.

BACKGROUND: Mineralocorticoid receptor antagonists consist of a class of drugs with pleiotropic beneficial effects in several cardiovascular diseases. However, physicians frequently overlook their use due to the adverse effects of such agents. OBJECTIVES: To determine the adverse effects of mineralocorticoid receptor antagonists and to suggest clinically meaningful options. We present data on the two most administered agents of this class: spironolactone and eplerenone. METHOD: We conducted an in-depth review of the existing international literature to draft a mini review about the mineralocorticoid receptor antagonists-related side effects. RESULT: Mineralocorticoid receptor antagonists are associated with increased risk of hyperkalemia and acute deterioration of renal function. Of note, these adverse effects are dose-dependent, more common during the initial period of treatment, and are usually reversed after the withdrawal of therapy. Sex-related adverse events are noted mainly in spironolactone while switching to eplerenone could attenuate those. CONCLUSION: Mineralocorticoid receptor antagonists therapy is significantly limited due to their side effects. The development of novel non-steroidal mineralocorticoid receptor antagonists could substantially widen the use of such agents.

Sodium-glucose Cotransporter 2 Inhibitors: Potential Cardiovascular and Mortality Benefits.

BACKGROUND: The impact of overt diabetes and poor glycemic control on the risk of cardiovascular disease is well established. Among patients with type 2 diabetes, several studies demonstrated a significant increase in coronary artery disease-related death and cardiovascular events associated with HbA1c levels of greater than 7% compared with lower levels. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. OBJECTIVES: To summarize data on the potential mechanisms of SGLT-2 inhibition that could exert cardiovascular benefits in patients with diabetes mellitus. METHOD: We conducted an in-depth literature search of SGLT-2 inhibitors and potential cardiovascular benefits and mechanisms that mediate those effects. RESULTS: In diabetes, expression of the SGLT-2 genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening hyperglycemia. SGLT-2 inhibition should offer potential cardiovascular protection in diabetic patients via attenuating hyperglycemia, blood pressure, body weight, hyperuricemia, and diabetic nephropathy. CONCLUSION: The initial data of SGLT-2 inhibitors suggest beneficial effects on cardiovascular risk among patients with diabetes mellitus. Several mechanisms are hypothesized to mediate the abovementioned benefits. Future randomized, controlled studies are needed in order to unveil the contribution of each mechanism to these outcomes.

Sodium-glucose Cotransporter 2 Inhibitors: The Pleiotropic Mechanisms of Actions.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are a new class of oral antidiabetic drugs. So far, there are three agents approved for use in Europe and in the USA, two in Japan and another four agents under testing. OBJECTIVE: The purpose of this study is to describe the mechanism of action and the favorable and adverse effects of SGLT-2 inhibitors. METHOD: A thorough review of literature indexed in PubMed, Scopus and Cochrane databases were conducted. Original papers, review papers and their relevant references in English, from 2005 to February 2017, were included. RESULTS: The main mechanism of action is the glycosuria induced by the inhibition of SGLT-2, located in the early segment of the proximal convoluted tubule. Along with large amounts of glucose, sodium, water and uric acid are also excessively excreted in urine. These actions have various, both desired and adverse, consequent implications in kidneys, blood pressure, cardiovascular system and other systems. Moreover, SGLT-2 inhibitors act directly to organs other than the kidneys, as SGLT-2 can be expressed there. CONCLUSION: The underlying mechanisms responsible for the SGLT-2 inhibitor actions, are pleiotropic and occur in the kidneys, as well as in other target organs. The comprehension of these mechanisms, not only permits us to understand their actions better, but it could also help us to predict more of their undisclosed favorable actions, as well as their rare adverse effects.

Pulse Wave Velocity: Retrospective Analysis in a Balkan Normotensive and Hypertensive Population: A Study of 9923 Patients.

We compared pulse wave velocity (PWV) between hypertensive patients and control patients to identify demographics and patient characteristics related to PWV. We retrospectively analyzed 9923 participants (3105 controls and 6818 hypertensive patients) from 5 outpatient hypertensive clinics (in Serbia and Greece). Pulse wave velocity had different distribution between controls and hypertensive patients ( P < .001). The magnitude of PWV increase was related to blood pressure (BP) category (from optimal to stage III hypertension; P < .001). Even in hypertensive patients with systolic BP (SBP) <140 and/or diastolic BP (DBP) <90 mm Hg, PWV was greater than in control patients ( P < .001). Pulse wave velocity was associated with almost all baseline characteristics of hypertensive patients (body mass index [BMI], gender, age, SBP, DBP, smoking status, and heart rate; P < .001). This association remained after adjustment of PWV confounders. There were 2231 (32.7%) hypertensive patients who had reached SBP <140 mm Hg and DBP <90 mm Hg. Pulse wave velocity was increased in hypertensive patients, and the degree of PWV increase was associated with baseline BP as well as with anthropometric parameters (eg, BMI, gender, age, heart rate, and smoking status).

Left ventricular hypertrophy in athletes and hypertensive patients.

Systemic hypertension and physical exercise are both associated with cardiac adaptations. The impact is most prominent on the left side of the heart, which hypertrophies leading to left ventricular hypertrophy. This article reviews structural and functional cardiac changes seen in hypertensive and athlete's hearts.