Circulation Editors’ Picks

<i>Circulation:</i> Clinical Summaries

Left ventricular systolic dysfunction without heart failure (HF), also known as asymptomatic left ventricular systolic dysfunction (ALVSD), is at least as prevalent in the general population as left ventricular systolic dysfunction with heart failure (HF-LVSD). However, the clinical characteristics of ALVSD have not been well defined in an elderly population. Our aim is to evaluate the clinical features of elderly community-based individuals with ALVSD. The Cardiovascular Health Study is a multicenter cohort study designed to assess cardiovascular risk factors and outcomes in a population 65 years and older. This study quantifies baseline demographic variables and cardiovascular risk factors in participants with ALVSD. Comparisons were made with two reference groups: individuals with HF-LVSD, and those with normal left ventricular systolic function without HF (NL-LVSF). ALVSD was present in 385 of 5152 participants (7.5%) at baseline, whereas HF-LVSD was present in 84 participants (1.6%). Among those with ALVSD, 251 (65.2%) had borderline ejection fraction (EF) (45–54%), and 134 (34.8%) had impaired EF (&lt; 45%). ALVSD was associated with elevated cardiovascular risk factors and comorbidities compared to NL-LVSF but lower than those in individuals with HF-LVSD (see table ). Among participants with ALVSD, impaired EF was associated with male sex and higher prevalence of coronary disease and LVH compared with borderline LV function. ALVSD is more common than HF-LVSD in community-dwelling elderly individuals. Furthermore, it is characterized by more cardiac risk factors and comorbidities than those with NL-LVSF, but less than those with HF-LVSD. The severity of systolic dysfunction is associated with comorbid cardiovascular risk factors. ALVSD may identify an important group of individuals at high risk for heart failure and cardiovascular mortality. Comparison of Clinical Characteristics Between ALVSD, NL-LVSF, and HF-LVSD

We evaluated data on blacks and whites with acute ST-segment-elevation myocardial infarction treated with either fibrinolysis or primary percutaneous coronary intervention from the National Registry of Myocardial Infarction (NRMI)-4 and -5 participating centers between July 2000 and December 2006 to determine race-related differences in bleeding and outcomes. We found that among patients with ST-segment-elevation myocardial infarction receiving fibrinolysis, the bleeding rates were higher for blacks (n2283) than whites (n42 243; 10.9% versus 10.3%; adjusted odds ratio, 1.21; 95% confidence interval, 1.02-1.43). Similarly, in patients receiving primary percutaneous coronary intervention, the bleeding rates were higher in blacks (n2826) than whites (n46 332; 10.3% versus 7.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.13-1.56). Bleeding was associated with a higher risk of death in both ethnic groups. However, there was no overall racial difference in in-hospital mortality among those with bleeding or without bleeding treated with either fibrinolysis or primary percutaneous coronary intervention. We concluded that race-related differences existed in bleeding risk among patients with ST-segmentelevation myocardial infarction receiving reperfusion therapy that portend poor prognosis. Thus, the efficacy and safety of many new drugs or treatment strategies for any disease observed in clinical trials that enroll predominantly white patients may not be similar in other ethnic groups that are underrepresented in these trials.

Introduction: Higher body mass index and obesity are associated with a higher risk of diabetes and heart failure (HF) development. However, the contribution of measures of body composition such as fat mass (FM), lean mass (LM), and central adiposity (waist circumference, WC) towards the risk of HF, and if these relationships are modified by diabetes status (DM) is unknown. Methods: Adults from visit 5 of the Atherosclerosis Risk in Communities Study without prevalent HF were included. FM and LM were measured using bioelectric impedance. Multivariable adjusted Cox proportional hazards models were created to evaluate the associations of FM, LM, and WC with the risk of HF after adjustment for potential confounders ( see Fig legend ). Multiplicative interaction testing and stratified analysis by DM status were performed using adjusted Cox models and restricted cubic splines to evaluate whether the association of body composition parameters and risk of HF were modified by DM status. Results: The present study included 5,555 participants (58.3% women, 79.3% white). Over a median follow-up of 4.6 years, there were 254 HF events (4.6%). In the overall cohort, higher LM was significantly associated with higher risk of HF (aHR [95% CI] per 1 SD higher LM: 1.34 [1.13-1.60]) with no interaction by DM status. However, the associations of FM and WC with risk of HF were modified by DM status (p-interaction: FM*diabetes = 0.03, WC*diabetes = 0.008). Higher FM and WC were each significantly associated with higher risk of HF in adults with DM (aHR [95% CI] per 1-SD higher FM: 1.23 [1.01-1.49], per 1SD higher WC: 1.57 [1.31 - 1.89]) but not among those without DM at baseline (aHR [95% CI] FM: 0.99 [0.80 - 1.23], WC: 1.06 [0.87 - 1.30]) ( Figure ). Conclusions: Higher LM was significantly associated with a higher risk of HF irrespective of diabetes status. In contrast, the association of FM and WC with the risk of HF was modified by the presence of DM such that higher FM and WC were associated with a higher risk of HF among adults with DM but not those without DM.

Midwall fractional shortening (MWFS) is a measure of left ventricular (LV) systolic function that is more reliable in case of concentric LV geometry compared to LV ejection fraction (LVEF). We hypothesized that MWFS might predict heart failure (HF) and death in a high-risk asymptomatic population, beyond other echocardiographic parameters. Among 4047 subjects aged ≥55/≤80 years followed by 10 general practitioners in northern Italy, the DAVID-Berg study prospectively enrolled 623 asymptomatic outpatients at increased risk for HF. Baseline evaluation included clinical visit, electrocardiogram, N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiogram. Mean age of the population was 69 ± 7 years, 56% were men, 88% had hypertension, mean LVEF was 61 ± 9%, and mean MWFS 16.2 ± 3.3. During a median follow-up of 5.7 years, 95 subjects experienced HF/death events. At Cox analysis, lower MWFS was the only echocardiographic parameter, among structural/functional ones, associated with higher risk of HF/death [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.84-0.95, Padjusted < 0.001]. The risk of HF/death related to clinical data and NT-proBNP (baseline model) was reclassified by echocardiography only when MWFS was included into the model (baseline C-statistics 0.761; adding conventional structural/functional echocardiographic data 0.776, P = 0.09; adding MWFS 0.791, P = 0.007). Compared to subjects with normal LVEF and MWFS, only subjects with combined systolic dysfunction (11% of the population) were at higher risk (P = 0.001 for both abnormal; P > 0.24 for either LVEF or MWFS abnormal). DAVID-Berg data suggest to include MWFS assessment in clinical practice, a simple and reliable echocardiographic parameter able to improve risk stratification in subjects at high risk for HF.

Recognizing Pregnancy-Associated Cardiovascular Risk Factors

Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established. Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models. Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75-1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44-0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24-0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82-0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69-0.94]). Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Does Metformin Interfere With the Cardiovascular Benefits of SGLT2 Inhibitors? Questions About Its Role as the Cornerstone of Diabetes Treatment

Background— Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). Methods and Results— Patients ≥30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). Conclusions— Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.

Psoriasis is a chronic inflammatory disease that involves complex pathogenic interactions between the innate and adaptive immune systems, affecting approximately 2% of the population. In patients with psoriasis, the incidence of several important diseases is reportedly higher than that observed in the general population. Among them, cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality in patients with psoriasis. Hence, effective and safe treatments are critical in lowering cardiovascular risk in this patient group. Systemic treatment of psoriasis and major adverse cardiovascular events (MACE) It has been identified that psoriasis is an independent risk factor for CVDs and is associated with an increased risk of MACE (a composite endpoint of myocardial infarction (MI), cerebrovascular accident, or cardiovascular death). Although the risk of MACE in patients with mild psoriasis remains relatively low, it could increase depending on disease severity and psoriasis duration.[1] The influence of various systemic psoriasis treatments on altering cardiovascular risks remains uncertain. Reportedly, the short-term risk of MACE did not substantially differ in patients with psoriasis treated with biologics when compared with a placebo. The impact of systemic psoriasis treatments on cardiovascular risks mainly depends on long-term effects. It has been reported that tumor necrosis factor-alpha (TNF-α) inhibitors and methotrexate (MTX) could reduce the risk of MACE in patients with psoriasis, whereas acitretin failed to demonstrate a notable impact. Cyclosporine A (CsA) is known to cause myocardial damage by generating reactive oxygen species. In the case of interleukin (IL)-12/23 inhibitors, ustekinumab reported some concerns of increased MACE during the initial analysis. However, in recent years, several studies have identified no increased or even a decreased risk of MACE with long-term ustekinumab therapy. Notably, another IL-12/23 inhibitor, briakinumab, increased the risk of MACE in 5 studies, resulting in the discontinuation of all briakinumab trials in 2011. Tofacitinib, a Janus kinase inhibitor, has been approved for use in psoriasis and is associated with a low incidence of MACE.[2,3] This lowered cardiovascular risk could be attributed to the inhibition of inflammation by reducing oxidized low-density lipoprotein (LDL)-mediated cytotoxicity and improving endothelial viability. In the case of IL-23 and IL-17 inhibitors, no increase in the rate of MACE was observed in patients with psoriasis treated with tildrakizumab, guselkumab, risankizumab, secukinumab, or ixekizumab. In an established mouse model of psoriasis, IL-23 and IL-17 inhibitors improved skin inflammation, decreased the number of circulating neutrophils, and increased thrombosis clotting times, suggesting that they might improve CVD. Further investigations are warranted to confirm whether these agents possess cardioprotective effects. In patients treated with MTX and TNF-α inhibitors, the incidence of MACE was compared among four studies, revealing controversial results. Two studies reported that TNF-α inhibitors presented a greater cardioprotective effect, whereas the other two studies reported that MTX and TNF-α inhibitors demonstrated similar effects. Three clinical trials revealed that MACE rates did not significantly differ in patients with psoriasis treated with ustekinumab and TNF-α inhibitors, guselkumab and adalimumab, secukinumab, and etanercept, respectively.[4] In terms of the mechanism of action, tofacitinib and etanercept predominantly reduce inflammatory and cardiovascular proteins such as IL-6, chemokine (C-C motif) ligand 20, and C-X-C motif chemokine ligand 10, with IL-17A significantly reduced only in responders to either treatment, which was reported as a potential mechanistic link between psoriasis and CVDs. This could explain why only responders to TNF-α inhibitor therapy demonstrated a reduced MI rate when compared with non-responders. Based on current evidence, the ranking of cardioprotective effects among different anti-psoriatic therapies remains unclear. However, if systemic therapy is considered within the setting of CVDs or risks, TNF-α inhibitors and MTX demonstrate the best evidence of beneficial effects. It is believed that anti-psoriatic treatments can block the common pathway of CVDs and psoriasis or reduce circulating inflammatory and other proteins associated with cardiovascular risks. However, the specific mechanism has not been comprehensively elucidated. Systemic treatment of psoriasis and cardiovascular burden It is speculated that psoriasis may induce systemic inflammation, endothelial dysfunction, and atherosclerosis, which are associated with higher incidences of ischemic heart disease, peripheral vascular disease, and atrial fibrillation in psoriasis. Currently, there is no consensus on whether systemic psoriasis treatment can improve or worsen arterial plaques, vascular function, and vascular inflammation. Systemic treatment of psoriasis was associated with a reduced non-calcified coronary plaque burden, suggesting that modulating remote sites of inflammation may translate into a reduced risk of coronary artery disease.[5] Conversely, a significant progression in carotid intima-media thickness (IMT) was observed in patients treated with TNF-α inhibitors, revealing the occurrence of arterial remodeling in patients with psoriasis despite improvement in clinical status. In a group of patients without initial calcified atherosclerotic plaques and treated with TNF-α inhibitors, a significant decrease in IMT was observed, whereas the other group with initial plaques showed an increasing IMT tendency, suggesting that TNF-α inhibitors could decrease IMT in patients with psoriasis specifically presenting no irreversible atherosclerotic plaques. Additionally, tofacitinib reportedly decreased carotid IMT. The effects of MTX, IL-17, and IL-12/23 inhibitors on IMT need to be further investigated to validate previous findings. No significant changes in IMT values were observed in patients with psoriasis treated with biologics targeting the IL-23/IL-17 axis (ustekinumab, secukinumab, ixekizumab), indicating that anti-IL-23/IL-17 might have a neutral effect on atherosclerosis. However, another study revealed that the IMT decreased significantly after treatment with anti-IL-12/23 and MTX in patients with moderate and severe psoriasis.[6] Additionally, IL-17 inhibitors reportedly demonstrate a beneficial effect on CVD risk by improving endothelial and coronary microcirculatory functions; however, whether TNF-α inhibitors demonstrate these effects remains controversial. The impact of traditional psoriasis treatments on vascular inflammation remains unclear, and the effects of biologics are controversial. Reportedly, biologic therapy is associated with a significant decrease in the fat attenuation index (FAI), a novel imaging biomarker that assesses coronary inflammation. Associations with FAI were consistent among patients receiving different biologic agents, including anti-TNF-α and anti-IL-12/23, or anti-IL-17 therapy.[7] Furthermore, ustekinumab treatment was significantly associated with decreased systemic and vascular inflammation measured via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in patients with psoriasis.[8] Conversely, three studies showed no difference in vascular inflammation measured using 18F-FDG PET/CT in patients treated with TNF-α inhibitors, ustekinumab, and secukinumab, respectively.[9,10] Tofacitinib effectively suppressed tissue-resident memory T cells and inhibited core vasculogenic effector pathways; however, real-world data is currently scarce. Systemic treatment of psoriasis and cardiovascular risk factors/markers In patients with psoriasis, especially those with moderate-to-severe psoriasis requiring systemic treatment, the prevalence rates of cardiovascular risk factors are significantly increased. A meta-analysis showed that patients with psoriasis presented higher values of total cholesterol, LDL, triglycerides, systolic blood pressure, diastolic blood pressure, body mass index (BMI), waist circumference, fasting glucose, non-fasting glucose, and hemoglobin A1c (HbA1c). Herein, we summarized evidence demonstrating that the systemic treatment of psoriasis could reduce or increase these cardiovascular risks. Obesity During conventional therapy, MTX did not increase the body weight and BMI of patients with psoriasis. Regarding biological agents, TNF-α inhibitors were associated with increased body weight and BMI; however, IL-12/23 and IL-17 inhibitors and apremilast could induce weight loss. Interestingly, patients receiving MTX during infliximab treatment are reportedly leaner, indicating that the simultaneous use of MTX could limit the weight gain caused by TNF-α inhibitors. Furthermore, it has been reported that obesity can compromise the effectiveness of systemic psoriasis treatments (conventional and biological therapies), and in obese patients, weight loss could improve metabolic parameters, as well as the responsiveness to psoriasis therapies. Diabetes mellitus Apremilast reportedly improved glucose metabolism, whereas CsA is known to increase the risk of diabetes. In a study utilizing TNF-α inhibitors and ustekinumab, insulin resistance and glycemia were reportedly improved. Other anti-psoriatic therapies have not been associated with significant differences in altered HbA1c or fasting glucose levels. In recent years, some antidiabetic drugs, including metformin, pioglitazone, liraglutide, and acarbose, have been shown to alleviate psoriasis, whereas the regular use of insulin might worsen psoriasis. Notably, the combined administration of TNF-α inhibitors and some antidiabetic medications such as sulfonylureas, meglitinides, and insulin might increase the risk of hypoglycemia in patients with psoriasis. Dyslipidemia Based on the included studies, MTX, IL-17, and IL-12/23 inhibitors reportedly demonstrate a marginal effect on lipid metabolism, whereas CsA and acitretin are related to dyslipidemia. Acitretin and CsA have been associated with an elevated risk of hypercholesterolemia and hypertriglyceridemia. There remain several controversies regarding the effect of TNF-α inhibitors on lipid metabolism. Although tofacitinib increased total cholesterol, LDL, and high-density lipoprotein (HDL) levels in a dose-dependent manner, total cholesterol:HDL and LDL:HDL ratios, definite predictors of MACE, were unaltered. Hypertension Several studies have revealed that CsA could increase the risk of or even worsen hypertension. There is no evidence that other systemic psoriasis treatments affect blood pressure. CsA significantly elevated blood pressure when compared with a placebo in a dose-dependent manner, increasing the risk of stroke, MI, heart failure, and other CVDs. However, the increased blood pressure was reversible after ceasing CsA administration. C-reactive protein (CRP) CRP, which is a marker of systemic inflammation and CVD risk, was significantly increased in patients with moderate-to-severe psoriasis. It has been reported that biological agents, including TNF-α inhibitors, ustekinumab, ixekizumab, and tofacitinib, could reduce CRP, whereas secukinumab failed to reduce this biomarker. Moreover, patients with a lower response to etanercept and ustekinumab presented higher CRP levels. This relationship was not observed in groups treated with secukinumab, suggesting that higher CRP levels might be associated with the lower efficacy of etanercept and ustekinumab, while not affecting the efficacy of secukinumab.[11] Conclusions Various anti-psoriasis drugs have different effects on CVDs and cardiovascular risk factors (Supplementary Table 1, https://links.lww.com/CM9/A395). The specific clinical situation of patients with psoriasis, especially cardiovascular complications, should be carefully considered when selecting appropriate treatment. For psoriasis patients with arterial plaques or a high risk of MACE, MTX and TNF-α inhibitors remain good options. Moreover, IL-17 and IL-12/23 inhibitors are effective in reducing arterial plaques. Patients with dyslipidemia should avoid CsA and acitretin. Similarly, CsA is not recommended in patients with hypertension, and obese patients should avoid TNF-α inhibitors. Conflicts of interest None.

Prognostic implications of subclinical left ventricular dilatation and systolic dysfunction in men free of overt cardiovascular disease (the framingham heart study)

Increased levels of physical activity, including structured exercise programming, are widely believed to be one of the most beneficial and cost-effective interventions for patients who have cardiovascular disease or are at risk for its development. There are a wide variety of epidemiologic 1–3 and intervention 4–6 studies demonstrating that a physically active lifestyle is related to a reduced incidence of cardiovascular disease development, an improved prognosis in patients with established disease, and an improved functional capacity. Data from meta-analytic studies of randomized trials, 4,5 intervention studies, 7–9 and more recent cost-effectiveness studies 10,11 have demonstrated the value of formal exercise and risk factor management programs in patients with established cardiovascular disease. It seems conservative to assert that the agreement within the healthcare community that "exercise is good for you" is nearly as universal as the assertion that "smoking is bad for you." And yet, bad things occasionally happen during exercise. A number of individuals either die or have a myocardial infarction during exercise. Because of the incongruity of exercise-related cardiovascular complications, such events become newsworthy because they represent a "man bites dog" type of event. Beyond their immediate impact on the stricken individual, such events erode confidence in the importance of lifestyle change as a therapeutic tool in the prevention and treatment of patient's cardiovascular disease. The purposes of the following discussion are to provide perspective regarding fatal and life-threatening complications during exercise training in adults with or without known cardiovascular disease, identify the factors that might predispose adults to such complications, and examine how the exercise industry is addressing these risks. Bad outcomes during exercise training are related to several causative factors. Exercise-related death in the young is primarily related to undiagnosed congenital abnormalities, drug use, or trauma. Although quite tragic when it occurs, the incidence of such events is rare. However, it is not the main focus of this discussion and has been reviewed adequately elsewhere. 12 The historical risk of exercise-related complications in adults dates to antiquity, at least to the time of Phillapides' death after his historic marathon-length run to report victory over the Persians. As long ago as the 19th century, there was concern regarding the risk of overexertion injuries during rowing competitions in England. In contemporary times, concern regarding the risk of exercise increased after the quantum jump in fitness exercise by the adult public after the publication of Aerobics by Cooper 13 in 1968. Several reports during the decade after the publication of Aerobics suggested that there appeared to be a noticeable association between acute myocardial infarction and/or sudden death immediately preceded by heavy exertion. 14–17 This same literature demonstrated that most of the exertion-related deaths in adults were related to previously undiagnosed atherosclerotic coronary artery disease. In 1993, in a pair of papers published in the same issue of the New England Journal of Medicine, Mittleman et al 18 and Willich et al 19 demonstrated that unaccustomed heavy exertion was related to the triggering of acute myocardial infarction, with the risk being mostly during the exertion itself or in the hour after exertion. These same studies demonstrated that the relative risk from heavy exertion was strongly influenced by the individual's habitual exercise pattern. Individuals who exercised frequently were much less likely to trigger a myocardial infarction than individuals who were relatively sedentary. In a follow-up study, Albert et al 20 demonstrated that habitual exercise strongly decreased the risk that unaccustomed vigorous exertion would trigger sudden death. Death during recreational exercise is predominantly related to atherosclerotic disease. Rogosta et al 21 demonstrated that 88% of exertion-related deaths were consistent with atherosclerotic disease, and that only 7% of the deaths were in individuals with no known history of or risk factors for atherosclerotic disease. This suggests that a significant percentage of these exertion-related deaths might have been prevented if appropriate screening had been used. In the presence of atherosclerotic coronary artery disease, exercise-related deaths are primarily related to plaque rupture and thrombus formation, leading to myocardial infarction or arrhythmia. In individuals with no prior history of cardiovascular disease, the presentation is primarily acute myocardial infarction over sudden cardiac death, by a nearly 7:1 ratio. However, in patients with known cardiovascular disease sudden cardiac death, presumably from scar-related arrhythmia, is the more common presentation, by a 5:1 ratio over acute myocardial infarction. 22–24 Understanding the risk of life-threatening emergencies during exercise training is complicated by the way in which the risk is computed. Most physicians and healthcare workers are accustomed to reporting the risk of graded exercise testing, which is approximately 6 in 10,000 tests according to the classic data of Rochimis and Blackburn, 25 but is significantly less in more recent studies. 26,27 However, studies of the risk of exercise training generally report the risk of exercise training in terms of events per participant hours. This represents something of an apples-and-oranges type of comparison that is hard to put into perspective. In this review, we have converted the risk of both exercise testing and exercise training into the common units of events per 10,000 participant hours. To do this we have assumed that the risk period for exercise testing is 0.75 hours (0.25 hours for testing and 0.50 hours for recovery). We have taken the reported risk for exercise training at face value because it appears from the studies that the time base included both exercise and recovery at the facility. On this basis, the risk of life-threatening complications for both exercise testing and exercise training has been calculated in common units. The key numbers to remember for contemporary exercise testing appear to be approximately 1.59/10,000 hours for clinically indicated exercise tests 26 and 1.06/10,000 hours for screening exercise tests. 27 It is important to note that the risk of exercise testing has been getting safer, thus the denominator of the equation comparing exercise testing and exercise training is not entirely constant. The earliest large report of the risk of exercise training in patients with known cardiovascular disease appears to be that of Haskell in 1978. 24 His report was based on a survey of several gymnasium-based rehabilitation programs (Phase III-IV in today's classification system). At the time, many of these programs had minimal monitoring capabilities and included patients who had residual ischemia and would be considered high risk based on contemporary classification schemes. 28 He noted a risk of complications during exercise of 0.45/10,000 hours (Figure 1). This risk is approximately 17 times less than graded exercise testing according to the contemporaneous data of Rochemis and Blackburn 25 (Figure 2). Significantly, during the same time period, Hassock and Hartwig 29 evaluated risk factors for complications in a gymnasium-based rehabilitation program. They observed that patients with one or more risk factors including relatively well preserved exercise capacity, significant ischemia during exercise testing, persistence of ischemia into the recovery period after exercise testing, and frequent violation of the target heart rate during exercise training were the patients most likely to have complications during exercise training. In simple terms, exercise training in the presence of significant myocardial ischemia appeared to be a prime risk factor for exertion-related complications.Figure 1.: Risk of serious complications during exercise training per 10,000 patient hours in patients with cardiovascular disease (left) and healthy individuals (right). The number next to each author's name denotes the year of publication. Note that the absolute risk in patients is, if anything, less than in healthy individuals. Also note the markedly lower rate of complications in rehabilitation programs after the beginning of the 1980s, potentially attributable to better clinical experience with exercising patients, more stable patients given the surgical and pharmacologic options developed during the 1980s, and the availability of telemetry during exercise sessions.Figure 2.: Risk of serious complication during exercise training in patients with cardiovascular disease (left) and healthy individuals (right), normalized to estimates of the risk of exercise testing contemporary with the report. Note that exercise training is relatively safer in patients than in healthy individuals, partially because the risk of exercise testing in this population is very low.In a more recent review of the risk of complications during outpatient rehabilitation, which included monitored programs and patients with the revascularization and medical options of the early 1980s, Van Camp 23 observed a risk of complications during exercise training of 0.08/10,000 hours, which is 19 times less than the now-reduced risk estimates for graded exercise testing (Figures 1 and 2). The most recent estimates of the risk of complications during cardiac rehabilitation programs (0.08-0.15/10,000 hours) is substantially unchanged from Van Camp's estimate, 30–32 which is 10 to 17 times less than graded exercise testing. With the development of new models for delivering monitored rehabilitation, including transtelephonic monitoring, the risk appears to be somewhat higher than in facility-based programs but still quite low at 0.42/10,000 hours, 33 which is four times less than graded exercise testing. Estimates of the risk of exercise-related complications in healthy adults is more complex in that many reports have focused on deaths, whereas the data from rehabilitation programs generally include both death and life-threatening complications. From a series of early studies, the risk of death during exercise in apparently healthy individuals appears to range from 0.01 to 0.20/10,000 hours, which is anywhere from 6 to 90 times safer than the standard risk of clinically indicated exercise tests, or 1 to 60 times safer than the lower risk of graded exercise testing conducted for screening purpose. 34–37 In very well-screened individuals and with fully qualified exercise leadership, Gibbons et al 38 reported a risk of death of 0.03/10,000 hours in healthy individuals. Assuming that the risk of life-threatening complications is approximately seven-times the risk of death, then the risk of fatal and life-threatening complications in healthy individuals is approximately 0.24/10,000 hours, which is actually higher than that observed in contemporary cardiac rehabilitation populations (0.10/10,000 hours). However, because healthy individuals are likely to be performing higher intensity exercise, and with less professional supervision than patients in rehabilitation programs, this does not seem unreasonable. The most recent data in healthy individuals are based on a retrospective review of member deaths in a large commercial health club chain, 39 which approximates 0.04 deaths/10,000 hours. Assuming a 7:1 complication: death ratio, the net risk of complications is approximately 0.32/10,000 hours, which also is higher than observed in cardiac rehabilitation populations. Significantly, in this data set a large proportion of the deaths were in members who exercised infrequently or who had only recently begun to exercise, which is consistent with the data on triggering myocardial infarction by exercise 18–20 and on the risk-related to exercise above the ischemic threshold. 29 Further evidence of the risk of unaccustomed strenuous exercise can be found in the data concerning snow shoveling as a trigger for acute coronary syndromes. 40 To further understand the risk of exercise, one needs to appreciate the practical realities of 10,000 person hours. In an idealized world where each exerciser was exercising 30 minutes per day, 5 days per week, each person would accumulate 130 hours of exercise a year. On this basis, 77 individuals exercising for 1 year equals 10,000 person hours. Using a complication rate of 0.10/10,000 person hours, which seems to be the median for contemporary clinical populations, one would expect 1 complication per 770 participants per year. Assuming that each exerciser accumulates only 2.5 sessions per week, which seems more in line with reality, one might then expect one complication per 1500 participants per year. Using the most idealized complication rate of approximately 0.03/10,000 person hours in prospectively healthy, fully screened, and well-supervised participants, one life-threatening complication might be expected in every 2564 participants per year if one assumes a high frequency of exercise. If one assumes a lower frequency of exercise (2.5 sessions per week), then one complication might be expected in every 5000 participants. The higher risk estimate (1 in 2564) may be spuriously high as in the 2.9 million members evaluated by Franklin, 39 one would expect 1136 life-threatening complications, versus 71 fatal events and a projected 568 serious complications (at a 7:1 life-threathening:fatal ratio). However, at a lower frequency of exercise, and with an expected complication rate of 1 for every 5000 participants, Franklin's observations fit predictions reasonably well. Can the risk of complications during exercise training be reduced? The data are in broad agreement that both exertion-related sudden cardiac death and acute myocardial infarction are related to pre-existing coronary artery disease, often not diagnosed, and that the risk strongly depends on exercise intensity. The data also broadly indicate that once the initial weeks of exercise are completed, more intense exercise is of less relative risk. These observations suggest that the two primary strategies for minimizing risk are appropriate screening of prospective exercisers to identify individuals with a high risk of occult coronary artery disease and appropriate control of exercise intensity, particularly during the first few weeks of an exercise program. Given these recommendations, it is interesting to note that the health club industry does a very poor job of screening prospective participants. If only young and prospectively healthy individuals used these facilities, there might be less concern. However, there is clear evidence that the health club industry is attracting a progressively older clientele and is beginning to serve a significant number of patients with stable cardiovascular disease. McInnis et al 41 evaluated pre-enrollment screening at both association (eg, higher quality) and nonassociation health clubs in Massachusetts using a survey that addressed a description of the facility, the number and qualifications of the staff, the size and demographics of the membership (including whether special populations were being served) the programs offered, the policies and practice patterns for emergency procedures, and the history of emergency events. Disturbingly, they noted that only 61% of clubs always screen their participants, with the association clubs being no better than nonassociation clubs. Of the 61% of clubs that screened participants, only 49% required some sort of physician clearance when the screening indicated a potential problem. Of the 61% of clubs that screened clients, only 77% required some sort of physician clearance in clients with known cardiovascular disease. Clearly, despite clear professional society guidelines indicating that participants should be screened and that the patient's physician should be involved when screening indicates potential problems, 42 health clubs are not identifying potential problems before they get to the exercise floor. Most disturbingly, 45% of the clubs never practice or review emergency procedures, and only 24% practice more than twice a year. Recommendations from the American Heart Association/American College of Sports Medicine indicate that emergency practice should occur a minimum of four times per year. Although still not very encouraging, association clubs did somewhat better than nonassociation clubs regarding staff qualifications: 43% versus 16% of clubs had fitness staff with at least bachelor's degree in a relevant major. However, in facilities that offered special programs for the elderly or patients with known heart disease, only 38% of facilities had fitness staff composed completely of individuals with formal academic training. Other, potentially more definitive, evidence of the professional competence of the staff such as professional society certification was not addressed in this study. In a more recent survey or 122 clubs in Ohio, representing more than 110,000 members and with special population programs offered in 52% of clubs, McInnis et al 43 found that 17% had a documented cardiovascular emergency in the previous 12 months. Despite this clear risk to the safety of their participants, 28% failed to use pre-entry screening, 53% had no written emergency plan, and 92% failed to practice quarterly emergency drills. Interestingly, 82% of the staff members were unaware of the AHA/ACSM guidelines, 42 and only 3% of facilities had automated external defibrillator. On the basis of these data, we can only note that it is a good thing that the risk of exercise is intrinsically low, because the health club industry is apparently doing little to reduce the risk. Although abnormal screening exercise electrocardiogram findings do identify a population at an increased risk for activity-related acute cardiac events, the sensitivity of the procedure is not very high, 22 particularly for identifying unstable plaques that can rupture and lead to acute myocardial infarction. Thus, it may be argued that a preliminary period of comparatively lower intensity exercise training at the onset of a training program, which is known to be associated with a reduced risk of triggering acute events, 18–20 may be a more effective strategy for reducing the risk of exercise-related complications than screening exercise tests, which are likely to be too expensive to be practical in any case. CONCLUSION Although exercise-related acute myocardial infarction and sudden cardiac death occur with more than occasional frequency, the absolute risk is quite low. In general, the risk in patients with known cardiovascular disease participating in medically supervised programs is on the order of 0.10/10,000 patient hours, or approximately 10 to 12 times less risky than graded exercise testing in clinical populations. In this population sudden cardiac death is likely to be the predominant manner of presentation, which suggests that an appropriate emergency response system, including the ability to deliver electrical therapy, be in place. The risk seems to be higher in patients who have just begun to exercise or who develop significant myocardial ischemia during exercise, suggesting that well-qualified exercise leadership is essential in terms of minimizing the risk. Because there is some evidence that the physiologic ventilatory threshold occurs before the ischemic threshold, 44 and because simple monitoring strategies such as the ability to talk comfortably during exercise seem to mark the ventilatory threshold well, 45 it may be that keeping exercise intensity at a level where the patient is comfortable speaking may meaningfully contribute to the safety of exercise training. In apparently healthy individuals, the risk of exercise training may vary significantly. In well-screened and well-supervised individuals, it may be as low as 0.03/10,000 hours, although a risk of approximately 0.2/10,000 patient hours seems to be a more defensible median value, which is approximately four times less than the already low risk of exercise testing in this population. This risk is the same, or perhaps slightly higher, as in cardiac rehabilitation programs, probably because the intensity of training usually is higher, is much less well regulated, and the participants are very much less well screened than patients in rehabilitation programs. In this population, acute myocardial infarction seems to be the more likely presentation of complications. Complications are related to the frequency of exercise and how long the participant has been participating, with relatively inexperienced participants being at particular risk. Clearly, better screening of participants, improved supervision aimed at moderating the intensity of the early weeks of exercise, and the employment of demonstrably qualified staff will contribute to reducing this risk.

Introduction: Intensive blood pressure (BP) control is associated with a significant reduction in the risk of heart failure (HF) or all-cause death. However, the extent to which intensive BP control-associated HF risk reduction is mediated by changes in subclinical markers of cardiovascular (CV) disease (CVD) and stage B HF is not well-characterized. Methods: Participants of the Systolic Blood Pressure Intervention Trial (SPRINT) with hypertension and available data on subclinical CVD markers at baseline and follow-up (1- or 2-year visit) were included. The key subclinical markers of CVD analyzed included chronic myocardial injury (assessed by high-sensitivity cardiac troponin I [hs-cTnI]), neurohormonal stress (assessed by N-terminal pro-B-type natriuretic peptide [NT-proBNP]), left ventricular (LV) mass (assessed by electrocardiogram Cornell voltage [CV]), and arterial stiffness (assessed by estimated pulse wave velocity [ePWV]). A counterfactual framework was used to assess the effects of the exposure and mediator on key outcomes, including 1) HF / all-cause death; 2) atherosclerotic CVD (ASCVD), including nonfatal myocardial infarction, nonfatal stroke, or CV death. Results: The present study included 8,872 participants (35% women, 31% Black). Over the 3.3-year median follow-up, there were 333 (3.8%) HF / all-cause death events and 200 (2.3%) ASCVD events. Reductions in neurohormonal stress and LV mass mediated up to 15% of the reduction in risk of HF / all-cause death with intensive BP control (Table). In contrast, treatment-related changes in chronic myocardial injury and arterial stiffness did not mediate the benefits of intensive BP reduction on HF / all-cause death risk. Furthermore, changes in any subclinical CVD markers did not mediate the effect of intensive BP control on ASCVD risk (Table). Conclusions: In this post-hoc analysis of SPRINT, improvements in neurohormonal stress and LV mass, as identified by surrogate markers of hs-cTnI and CV, were important mediators of the beneficial effects of intensive BP control in reducing the risk of HF / all-cause death. Mediators of the effect of intensive vs. standard BP control for reducing HF / all-cause death differ from those for ASCVD.

The natriuretic peptides are counterregulatory hormones involved in volume homeostasis and cardiovascular remodeling. The prognostic significance of plasma natriuretic peptide levels in apparently asymptomatic persons has not been established. We prospectively studied 3346 persons without heart failure. Using proportional-hazards regression, we examined the relations of plasma B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide to the risk of death from any cause, a first major cardiovascular event, heart failure, atrial fibrillation, stroke or transient ischemic attack, and coronary heart disease. During a mean follow-up of 5.2 years, 119 participants died and 79 had a first cardiovascular event. After adjustment for cardiovascular risk factors, each increment of 1 SD in log B-type natriuretic peptide levels was associated with a 27 percent increase in the risk of death (P=0.009), a 28 percent increase in the risk of a first cardiovascular event (P=0.03), a 77 percent increase in the risk of heart failure (P<0.001), a 66 percent increase in the risk of atrial fibrillation (P<0.001), and a 53 percent increase in the risk of stroke or transient ischemic attack (P=0.002). Peptide levels were not significantly associated with the risk of coronary heart disease events. B-type natriuretic peptide values above the 80th percentile (20.0 pg per milliliter for men and 23.3 pg per milliliter for women) were associated with multivariable-adjusted hazard ratios of 1.62 for death (P=0.02), 1.76 for a first major cardiovascular event (P=0.03), 1.91 for atrial fibrillation (P=0.02), 1.99 for stroke or transient ischemic attack (P=0.02), and 3.07 for heart failure (P=0.002). Similar results were obtained for N-terminal pro-atrial natriuretic peptide. In this community-based sample, plasma natriuretic peptide levels predicted the risk of death and cardiovascular events after adjustment for traditional risk factors. Excess risk was apparent at natriuretic peptide levels well below current thresholds used to diagnose heart failure.

Evidence from some studies suggest that osteoarthritis (OA) patients are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) that are not in accordance with their cardiovascular (CV) or gastrointestinal (GI) risk profiles. However, no such study has been carried out in the United States. Therefore, we sought to examine the prevalence and predictors of potentially inappropriate NSAIDs use in older adults (age > 65) with OA using machine learning with real-world data from Optum De-identified Clinformatics® Data Mart. We identified a retrospective cohort of eligible individuals using data from 2015 (baseline) and 2016 (follow-up). Potentially inappropriate NSAIDs use was identified using the type (COX-2 selective vs. non-selective) and length of NSAIDs use and an individual’s CV and GI risk. Predictors of potentially inappropriate NSAIDs use were identified using eXtreme Gradient Boosting. Our study cohort comprised of 44,990 individuals (mean age 75.9 years). We found that 12.8% individuals had potentially inappropriate NSAIDs use, but the rate was disproportionately higher (44.5%) in individuals at low CV/high GI risk. Longer duration of NSAIDs use during baseline (AOR 1.02; 95% CI:1.02–1.02 for both non-selective and selective NSAIDs) was associated with a higher risk of potentially inappropriate NSAIDs use. Additionally, individuals with low CV/high GI (AOR 1.34; 95% CI:1.20–1.50) and high CV/low GI risk (AOR 1.61; 95% CI:1.34–1.93) were also more likely to have potentially inappropriate NSAIDs use. Heightened surveillance of older adults with OA requiring NSAIDs is warranted.