Cardiovascular Disease Screening in Women: Leveraging Artificial Intelligence and Digital Tools.

Cardiovascular disease remains the leading cause of death in women. Given accumulating evidence on sex- and gender-based differences in cardiovascular disease development and outcomes, the need for more effective approaches to screening for risk factors and phenotypes in women is ever urgent. Public health surveillance and health care delivery systems now continuously generate massive amounts of data that could be leveraged to enable both screening of cardiovascular risk and implementation of tailored preventive interventions across a woman's life span. However, health care providers, clinical guidelines committees, and health policy experts are not yet sufficiently equipped to optimize the collection of data on women, use or interpret these data, or develop approaches to targeting interventions. Therefore, we provide a broad overview of the key opportunities for cardiovascular screening in women while highlighting the potential applications of artificial intelligence along with digital technologies and tools.

Cholesterol Management in the Era of PCSK9 Inhibitors.

PURPOSE OF REVIEW: Cholesterol management in the current era is discussed. Aggressive reduction of low density lipoprotein (LDL) cholesterol plays a key role in primary and secondary prevention of heart disease. Statins are the recommended first-line therapy in patients with hyperlipidemia; however, additional complementary approaches are frequently needed for patients who fail to reach their target LDL. RECENT FINDINGS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide dramatic lowering of LDL and promise outcome benefit. Despite great enthusiasm about their cardiovascular benefit, concerns have been raised regarding their cost and added value to the healthcare system. Although cost-effectiveness studies have yielded inconclusive results, analyses suggest that the current cost of PCSK9 inhibitors is disproportionately high and must be significantly reduced to add positive net benefit to healthcare system. PCSK9 inhibitors significantly lower LDL cholesterol. Further outcome data and cost-effectiveness analyses are needed to overcome the current barriers with PCSK9 inhibitors that patients, physicians, and payers face.

The Challenges of Prevention, Diagnosis and Treatment of Ischemic Heart Disease in Women.

Increasing evidence suggests that there are significant differences in the presentation, diagnosis and treatment of ischemic heart disease in women compared to men. Women often present with atypical symptoms, and this, in association with a consistent underestimation of their risk for ischemic heart disease, leads to underdiagnosis and undertreatment in women. Cardiovascular risk factors unique to women have only recently been recognized, and moreover, traditional risk factors have recently been shown to have greater impacts on women. Consequently, women suffer more disability and poorer clinical outcomes, with higher cardiovascular morbidity and mortality. These discrepancies may in part be secondary to the higher prevalence of nonobstructive coronary artery disease in women with persistent chest pain symptoms as compared to men when evaluated invasively. Focused diagnostic and therapeutic strategies unique to women are thus needed, but unfortunately, such sex-specific guidelines do not yet exist, largely due to lack of awareness, both on the part of providers and patients, as well as a paucity of evidence-based research specific to women. Although underutilized in women, diagnostic modalities, including functional and anatomic cardiac tests as well as physiologic assessments of endothelial and microvascular function, are useful for establishing the diagnosis and prognosis of suspected ischemic heart disease in women. This review discusses the current challenges of prevention, diagnosis and treatment of ischemic heart disease in women.

Incidence of Severe Adverse Drug Reactions to Ultrasound Enhancement Agents in a Contemporary Echocardiography Practice.

OBJECTIVES: Prior data indicate a very rare risk of serious adverse drug reaction (ADR) to ultrasound enhancement agents (UEAs). We sought to evaluate the frequency of ADR to UEA administration in contemporary practice. METHODS: We retrospectively reviewed 4 US health systems to characterize the frequency and severity of ADR to UEA. Adverse drug reactions were considered severe when cardiopulmonary involvement was present and critical when there was loss of consciousness, loss of pulse, or ST-segment elevation. Rates of isolated back pain and headache were derived from the Mayo Clinic Rochester stress echocardiography database where systematic prospective reporting of ADR was performed. RESULTS: Among 26,539 Definity and 11,579 Lumason administrations in the Mayo Clinic Rochester stress echocardiography database, isolated back pain or headache was more frequent with Definity (0.49% vs 0.04%, P < .0001) but less common with Definity infusion versus bolus (0.08% vs 0.53%, P = .007). Among all sites there were 201,834 Definity and 84,943 Lumason administrations. Severe and critical ADR were more frequent with Lumason than with Definity (0.0848% vs 0.0114% and 0.0330% vs 0.0010%, respectively; P < .001 for each). Among the 3 health systems with >2,000 Lumason administrations, the frequency of severe ADR with Lumason ranged from 0.0755% to 0.1093% and the frequency of critical ADR ranged from 0.0293% to 0.0525%. Severe ADR rates with Definity were stable over time but increased in more recent years with Lumason (P = .02). Patients with an ADR to Lumason since the beginning of 2021 were more likely to have received a COVID-19 vaccination compared with matched controls (88% vs 75%; P = .05) and more likely to have received Moderna than Pfizer-Biotech (71% vs 26%, P < .001). CONCLUSION: Severe and critical ADR, while rare, were more frequent with Lumason, and the frequency has increased in more recent years. Additional work is needed to better understand factors, including associations with recently developed mRNA vaccines, which may be contributing to the increased rates of ADR to UEA since 2021.

Sleep apnea treatment after stroke (SATS) trial: is it feasible?

Sleep apnea affects more than half of patients with acute ischemic stroke and is associated with poor stroke outcome. This pilot study assessed the feasibility of a randomized, sham-controlled continuous positive airway pressure (CPAP) trial in subjects with acute ischemic stroke. Subjects identified with sleep apnea based on an apnea-hypopnea index≥5 on overnight polysomnography or portable respiratory monitoring within 7 days of onset of stroke symptoms were randomized to receive active or sham CPAP for a 3-month period. Objective usage was ascertained by compliance data cards. Subjects, treating physicians, and outcome assessors were masked to intervention allocation. Among 87 subjects who provided consent, 74 were able to complete sleep apnea screening, 54 (73%) of whom had sleep apnea. Thirty-two subjects agreed to randomization. Of the 15 subjects who commenced active titration, 11 (73%) took the device home, and 8 (53%) completed the 3-month follow-up. Of the 17 subjects who commenced sham titration, 11 (65%) took the sham device home and completed the 3-month follow-up. The median cumulative usage hours over the 90 days were similar in the active group (53 hours; interquartile range, 22-173 hours) and the sham group (74 hours; interquartile range, 17-94 hours), and blinding to subject condition was successfully maintained. This first-ever randomized, sham-controlled trial of CPAP in patients with recent stroke and sleep apnea demonstrates that sham treatment can be an effective placebo.

Obstructive sleep apnea in patients with acute aortic dissection.

BACKGROUND: Obstructive sleep apnea (OSA) imposes an afterload burden on the left ventricle and increases the pressure gradient across the aortic wall. Thus, OSA may increase the risk for aortic dissection (AD). METHODS: This study enrolled 40 subjects with acute AD from four institutions; 37 completed the modified Berlin Questionnaire and 31 underwent attended overnight polysomnography. Aortic diameter was measured on a computed tomography scan at seven locations from the sinotubular junction to the diaphragm. RESULTS: Twenty-seven subjects had type A dissection; 13 had type B. In those who had polysomnography apnea-hypopnea index (AHI) ranged from 0.7 to 89. Prevalence of OSA (AHI ≥ 5) was 61%. Nocturnal presentation (10 p.m.-7 a.m.) did not differ by presence/absence of OSA. The modified Berlin Questionnaire was not predictive of the presence of OSA. Among type A subjects with polysomnography (n = 23), aortic diameters at all locations were greater in the OSA group though differences were not statistically significant. Summating aortic diameters at the seven locations also yielded a numerically larger mean value in the OSA group versus the non-OSA group. CONCLUSIONS: In this sample of patients with acute dissection, OSA was prevalent but was not associated with a nocturnal presentation. The presence of underlying OSA may be associated with larger aortic diameters at the time of dissection compared to patients without OSA. Though differences did not meet statistical significance the current series is limited by small numbers.

Real-world performance, long-term efficacy, and absence of bias in the artificial intelligence enhanced electrocardiogram to detect left ventricular systolic dysfunction.

Aims: Some artificial intelligence models applied in medical practice require ongoing retraining, introduce unintended racial bias, or have variable performance among different subgroups of patients. We assessed the real-world performance of the artificial intelligence-enhanced electrocardiogram to detect left ventricular systolic dysfunction with respect to multiple patient and electrocardiogram variables to determine the algorithm's long-term efficacy and potential bias in the absence of retraining. Methods and results: Electrocardiograms acquired in 2019 at Mayo Clinic in Minnesota, Arizona, and Florida with an echocardiogram performed within 14 days were analyzed (n = 44 986 unique patients). The area under the curve (AUC) was calculated to evaluate performance of the algorithm among age groups, racial and ethnic groups, patient encounter location, electrocardiogram features, and over time. The artificial intelligence-enhanced electrocardiogram to detect left ventricular systolic dysfunction had an AUC of 0.903 for the total cohort. Time series analysis of the model validated its temporal stability. Areas under the curve were similar for all racial and ethnic groups (0.90-0.92) with minimal performance difference between sexes. Patients with a 'normal sinus rhythm' electrocardiogram (n = 37 047) exhibited an AUC of 0.91. All other electrocardiogram features had areas under the curve between 0.79 and 0.91, with the lowest performance occurring in the left bundle branch block group (0.79). Conclusion: The artificial intelligence-enhanced electrocardiogram to detect left ventricular systolic dysfunction is stable over time in the absence of retraining and robust with respect to multiple variables including time, patient race, and electrocardiogram features.

Waist-To-Hip Ratio Predicts Abnormal Overnight Oximetry in Men Independent of Body Mass Index.

Background: Ambulatory overnight oximetry (OXI) has emerged as a cost-effective initial test for sleep disordered breathing. Obesity is closely associated with obstructive sleep apnea (OSA); however, whether body mass index (BMI) or waist-to-hip ratio (WHR) predicts abnormal overnight OXI remains unknown. Methods: We performed a retrospective cross-sectional study of 393 men seen in the Executive Health Program at Mayo Clinic in Rochester, Minnesota who underwent ambulatory overnight OXI ordered by preventive medicine physicians between January 1, 2004 through December 31, 2010. We compared participant/spouse-reported symptoms (sleepiness, snoring), physician indications for OXI (obesity, fatigue), Epworth Sleepiness Scale scores, anthropomorphic measurements (WHR, BMI), and comorbid medical conditions (hypertension, diabetes) with OXI results. Results: 295 of the 393 men who completed OXI had abnormal results. During multivariate analysis, the strongest independent predictor of abnormal OXI for men was WHR (≥1.0, OR = 5.59) followed by BMI (≥30.0 kg/m2, OR = 2.75), age (≥55 yrs, OR = 2.06), and the presence of snoring (OR = 1.91, P < 0.05 for all). A strong association was observed between WHR and abnormal OXI in obese (BMI ≥ 30.0 kg/m2, OR = 6.28) and non-obese (BMI < 29.9 kg/m2, OR = 6.42, P < 0.01 for both) men. Furthermore, 88 men with abnormal OXI underwent polysomnography with 91% being subsequently diagnosed with OSA. Conclusions: In ambulatory, predominantly middle-aged men undergoing preventive services evaluation many physician indications for OXI were not predictors of abnormal results; however, WHR strongly predicted abnormal OXI in obese and non-obese men. As such, we suggest middle-aged men who snore and have a WHR ≥1.0 should be directly referred to a sleep clinic for polysomnography.

Cardiovascular and Autonomic Responses to Energy Drinks-Clinical Implications.

There is an increasing consumption of energy drinks both in the United States and worldwide. The components of these beverages are sometimes unclear but commonly include caffeine, sugars, taurine, and B-vitamins. Young people, particularly those engaged in sports, studying, and in the military are especially likely to be consumers of energy drinks. While limited data are available regarding their autonomic and hemodynamic effects, current literature suggests that energy drink consumption is accompanied by increases in blood pressure, sympathetic drive, and also in QT prolongation. There are no systematic long term studies identifying consequences of frequent energy drink consumption. However, multiple anecdotal reports implicate energy drinks in adverse cardiovascular events including atrial fibrillation, ventricular arrhythmia, myocardial infarction, and sudden death. Events such as atrial fibrillation may even occur in otherwise healthy subjects with structurally normal hearts. It is likely that these cardiovascular outcomes are triggered by the hemodynamic, autonomic, and electrocardiographic responses to energy drink consumption. What remains unclear is how concomitant use of other stimulants such as amphetamines and nicotine may interact to potentiate neural and circulatory responses and cardiovascular consequences when combined with energy drinks.

Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Plasma Ceramide Levels.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that provide striking lowering of low-density lipoprotein cholesterol (LDL-C) when added to maximum tolerated therapy in patients with hypercholesterolemia. Ceramides, novel cardiac risk markers, have been associated with increased cardiovascular mortality, independent of traditional cardiovascular risk factors. The Ceramide Risk Score (CRS) predicts the likelihood of adverse cardiovascular events within 1 to 3 years in patients with coronary artery disease. The effect of PCSK9 inhibition on plasma ceramides is not well known. The study examines the effect of PCSK9 inhibitors on plasma ceramides and CRS in patients with clinical indication for this therapy. Retrospective chart review of consecutive patients with hypercholesterolemia on PCSK9 inhibitors was conducted (n = 24; Mayo Clinic 2015 to 2018). Plasma ceramides were measured before the initiation of PCSK9 inhibitors and 2 to 12 months after treatment. CRS was calculated before and after therapy based on individual plasma concentrations of 4 ceramides. Treatment with PCSK9 inhibitors was associated with significant reduction in mean CRS and individual ceramides levels (p <0.0001). CRS significantly improved with PCSK9 therapy. PCSK9 inhibitors significantly decreased LDL-C levels by 63% (p <0.0001). The absolute reduction in CRS did not correlate with the absolute reduction in LDL-C (r = 0.31; confidence interval -0.10 to 0.64), indicating that CRS may evaluate a different pathway for risk reduction beyond LDL-C lowering. In conclusion, treatment with PCSK9 inhibitors is associated with significant reduction in CRS and distinct ceramide levels.

Obstructive sleep apnea and aldosterone.

BACKGROUND: Obstructive sleep apnea (OSA) is a major risk factor for hypertension and has been associated with increased risk for cardiovascular morbidity. A dysregulated renin-angiotensin-aldosterone system may contribute to excess sodium retention and hypertension and may be activated in OSA. We tested the hypothesis that serum levels of aldosterone and plasma renin activity (PRA) are increased by apneic sleep in subjects without cardiovascular disease, compared to healthy control subjects. METHODS AND RESULTS: Plasma aldosterone level was measured in 21 subjects with moderate to severe OSA and was compared to 19 closely matched healthy subjects. Plasma renin activity (PRA) was measured in 19 OSA patients and in 20 healthy controls. Aldosterone and PRA were measured before sleep (9 pm), after 5 hrs of untreated OSA ( 2am) and in the morning after awakening (6 am). There were no baseline (9pm) differences in serum aldosterone levels and PRA between the healthy controls and OSA patients (aldosterone: 55.2 +/- 9 vs 56.0 +/- 9 pg/mL; PRA: 0.99 +/- 0.15 vs. 1.15 +/- 0.15 ng/mL/hr). Neither several hours of untreated severe OSA nor CPAP treatment affected aldosterone levels and PRA in OSA patients. Diurnal variation of both aldosterone and PRA was observed in both groups, in that morning renin and aldosterone levels were higher than those measured at night before sleep. CONCLUSIONS: Our study shows that patients with moderate to severe OSA without co-existing cardiovascular disease have plasma aldosterone and renin levels similar to healthy subjects. Neither untreated OSA nor CPAP treatment acutely affect plasma aldosterone or renin levels.

Comparison of cardiac structural and functional changes in obese otherwise healthy adults with versus without obstructive sleep apnea.

Obstructive sleep apnea (OSA) and obesity have been linked to systolic and diastolic dysfunction of the left ventricle. Right ventricular function is poorly understood in the 2 clinical conditions. Data from this study show that otherwise healthy obese patients with OSA had increased an left atrial volume index compared with similarly obese patients without OSA (16.3 +/- 1.2 ml/m in obese patients without OSA vs 20.2 +/- 1.0 ml/m in those with OSA, p = 0.02) and altered diastolic function reflected by changes in mitral annular late diastolic velocity (-5.7 +/- 0.7 cm/s in obese patients without OSA vs -7.3 +/- 0.7 cm/s in those with OSA, p = 0.007), mitral annular early diastolic velocity (-7.9 +/- 0.6 cm/s in obese patients without OSA vs -6.4 +/- 0.3 cm/s in those with OSA, p = 0.05), and early to late diastolic annular ratio >1 (82% of obese patients without OSA vs 26% of those with OSA, p = 0.001), which may be signs of early subclinical impairment of cardiac function. Importantly, healthy obese subjects had similarly increased left ventricular mass compared with obese patients with OSA but normal diastolic function and left atrial size. There was a trend toward abnormal right ventricular filling in patients with OSA, measured by altered superior vena cava diastolic velocity during expiration (-15 +/- 2 cm/s in obese patients without OSA vs -10 +/- 3 cm/s in those with OSA, p = 0.2) and a tendency toward diastolic dysfunction reflected by decreased lateral tricuspid annular early diastolic velocity (-7.2 +/- 0.5 cm/s in obese patients without OSA vs -6.1 +/- 0.5 cm/s in those with OSA, p = 0.1) beyond that seen in obesity alone. In conclusion, OSA independent of obesity may induce cardiac changes that could predispose to atrial fibrillation and heart failure.

Familial premature coronary artery disease mortality and obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is linked to both coronary artery disease (CAD) and sudden death, but any causal role remains unclear. A family history of premature CAD and related mortality is an independent risk factor for the development of CAD. We hypothesized that OSA is associated with a family history of premature mortality from ischemic heart disease. METHODS: We prospectively studied 588 subjects who underwent polysomnography from May 2000 to June 2004. Demographics, comorbidities, family history of cardiovascular disease, and the ages and causes of death for 10 strata of family members were recorded for all subjects. We excluded those subjects with known causes of premature cardiac death, such as hypertrophic cardiomyopathy and long-QT syndrome. OSA was defined by American Academy of Sleep Medicine criteria (ie, apnea-hypopnea index >or= 5). Premature CAD mortality was defined as death due to ischemic heart disease or sudden cardiac death before 55 years of age (men) or 65 years of age (women). RESULTS: Polysomnography confirmed OSA in 316 subjects and excluded it in 202 subjects. The unadjusted odds ratio (OR) for OSA and a family history of premature CAD mortality was 2.11 (95% confidence interval [CI], 1.10 to 4.31; p = 0.031). After adjusting for each subject's sex, body mass index, and history of CAD, there was a significant and independent association between OSA and family history of premature CAD mortality (OR, 2.13; 95% CI, 1.04 to 4.66; p = 0.046). CONCLUSIONS: Regardless of their own CAD status, people with OSA are more likely than those without OSA to have a family history of premature CAD mortality.

Hemodynamic and autonomic effects of smokeless tobacco in healthy young men.

OBJECTIVES: The aim of this study was to investigate the acute hemodynamic and autonomic effects of smokeless tobacco. BACKGROUND: Smokeless tobacco use is increasing. Its cardiovascular effects are not well understood. METHODS: Sixteen healthy, male, habitual snuff tobacco users (aged 22 +/- 1 year) were studied, using a randomized, double-blind, placebo-controlled, crossover design with two separate experimental sessions: placebo and tobacco. Muscle sympathetic nerve activity (MSNA), electrocardiogram, blood pressure, calf blood flow, nicotine, and catecholamines were measured. RESULTS: Snuff tobacco increased plasma nicotine from 2.8 +/- 0.5 ng/ml to 10.4 +/- 1.1 ng/ml. Mean blood pressure increased by 10 +/- 1 mm Hg, and heart rate increased by 16 +/- 2 beats/min. Peripheral vascular resistance, MSNA, and norepinephrine concentration did not change with tobacco, but epinephrine increased by approximately 50%. CONCLUSIONS: Oral snuff tobacco increases heart rate, blood pressure, and epinephrine. Despite the increase in blood pressure, there is no decrease in either MSNA or peripheral vascular resistance. Smokeless tobacco is a powerful autonomic and hemodynamic stimulus. Catecholamine release from the adrenal medulla likely contributes to this response.

Serum amyloid a in obstructive sleep apnea.

BACKGROUND: Patients with severe obstructive sleep apnea (OSA) may have increased risk for cardiovascular and cerebrovascular diseases. Serum amyloid A (SAA) protein has recently been linked to the development of atherosclerosis, stroke, diabetes, and dementia. We tested the hypothesis that plasma SAA levels are increased in otherwise healthy subjects with OSA. METHODS AND RESULTS: Plasma SAA levels were measured in 10 male patients with moderate to severe OSA before sleep, after 5 hours of untreated OSA, and in the morning after effective continuous positive airway pressure treatment. SAA levels were also measured in 10 closely matched control subjects at similar time points. Baseline plasma SAA levels before sleep were strikingly higher in patients with moderate to severe OSA than in controls (18.8+/-2.6 versus 7.2+/-2.6 microg/mL, respectively; P=0.005) and remained unchanged in both groups throughout the night. SAA levels in 10 male patients with mild OSA were comparable with controls (P=0.46). Plasma SAA in 7 female patients with moderate to severe OSA was also markedly higher compared with matched control female subjects (24.1+/-2.4 versus 10.2+/-2.4 microg/mL, respectively; P=0.0013) but was not different from male patients with moderate to severe OSA (P=0.3). There was a significant positive correlation between SAA and apnea-hypopnea index (r=0.40, P=0.03). CONCLUSIONS: Plasma SAA levels are more than 2-fold greater in patients with moderate to severe OSA compared with subjects with mild OSA or healthy controls regardless of gender. Elevated SAA may contribute to any increased risk for cardiovascular and neuronal dysfunction in patients with OSA.

Early morning attenuation of endothelial function in healthy humans.

BACKGROUND: Cardiovascular events such as myocardial infarction, sudden death, and stroke have a peak incidence in the early hours after waking. The mechanisms involved in this circadian variation are not clear. Endothelial dysfunction is associated with increased risk for cardiovascular events. We tested the hypothesis that endothelial function is reduced in the early morning, around the time of waking, compared with measurements obtained both before sleep and later in the day in healthy humans. METHODS AND RESULTS: We studied 30 subjects (19 men, 11 women; mean age, 41.6 years). All participants underwent polysomnography to exclude obstructive sleep apnea or other sleep disorders. Brachial artery flow-mediated endothelium-dependent vasodilation (FMD) and endothelium-independent dilation (non-FMD) were measured on 3 different occasions: before subjects went to sleep (9 PM), the next morning immediately after waking (6 AM), and during the late morning 5 hours after waking (11 AM). All subjects had normal sleep with good sleep efficiency of 84+/-2%. Compared with before sleep, FMD decreased markedly in the early morning after waking and recovered by late morning (9 pm, 7.5+/-1%; 6 am, 4.4+/-0.7%; 11 am, 7.7+/-1%; P=0.02). Non-FMD was similar for the 3 periods of observation (9 pm, 17.3+/-1.6%; 6 am, 17.2+/-1.3%; 11 am, 18.5+/-1.7%). CONCLUSIONS: FMD is blunted in the early morning in healthy subjects. Decreased endothelial function in the early morning may have implications for our understanding of the morning peak in cardiac and vascular events.

Independent association between plasma leptin and C-reactive protein in healthy humans.

BACKGROUND: C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables. METHODS AND RESULTS: We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P=0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R=0.61, P<0.0001) and men (R=0.55, P<0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P=0.01) and men (F=5.69, P=0.02). When only subjects with BMI <25 kg/m2 were considered (n=47), CRP was not linked to BMI (R=0.02, P=0.96), but a significant association between leptin and CRP was still evident (R=0.55, P<0.0001). CONCLUSIONS: Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.