Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association.

Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.

Higher Activation of the Rostromedial Prefrontal Cortex During Mental Stress Predicts Major Cardiovascular Disease Events in Individuals With Coronary Artery Disease.

BACKGROUND: Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE. METHODS: Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization. RESULTS: We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08-1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03). CONCLUSIONS: Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

Circulating Progenitor Cells and Cognitive Impairment in Men and Women with Coronary Artery Disease.

BACKGROUND: Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). OBJECTIVE: To assess the association between CPCs and memory performance among individuals with CAD. METHODS: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45med/CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations enriched for hematopoietic and endothelial progenitors. RESULTS: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all < 0.05). There was a significant interaction in the magnitude of this association with race (p < 0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. CONCLUSION: Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study.

Posttraumatic stress disorder is associated with enhanced interleukin-6 response to mental stress in subjects with a recent myocardial infarction.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is prevalent among patients who survived an acute coronary syndrome, and is associated with adverse outcomes, but the mechanisms underlying these associations are unclear. Individuals with PTSD have enhanced sensitivity of the noradrenergic system to stress which may lead to immune activation. We hypothesized that survivors of a myocardial infarction (MI) who have PTSD would show an enhanced inflammatory response to acute psychological stress compared to those without PTSD. METHODS: Individuals with a verified history of MI within 8 months and a clinical diagnosis of current PTSD underwent a mental stress speech task. Inflammatory biomarkers including interleukin-6 (IL-6), high-sensitivity C reactive protein (HsCRP), matrix metallopeptidase 9 (MMP-9), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and monocyte chemoattractant protein (MCP)-1 were measured at rest and 90 min after mental stress. RESULTS: Among 271 patients in the study (mean age 51 ±â€¯7 years, 50% female, 60% African-American), the prevalence of PTSD was 12%. Mental stress resulted in a significant increase in IL-6, but the increase was more marked in patients with PTSD (126% increase) than those without (63% increase) (p = 0.001). MCP-1 showed a modest increase with stress which was similar in patients with PTSD (9% increase) and without PTSD (6% increase) (p = 0.35). CRP did not increase with stress in either group. CONCLUSION: MI patients with current PTSD exhibit enhanced IL-6 response to psychosocial stress, suggesting a mechanistic link between PTSD and adverse cardiovascular outcomes as well as other diseases associated with inflammation.

Young Women With Coronary Artery Disease Exhibit Higher Concentrations of Interleukin-6 at Baseline and in Response to Mental Stress.

Background Young women with coronary artery disease ( CAD ), a group with high psychosocial burden, were previously shown to have higher levels of interleukin-6 ( IL -6) compared with men of similar age. We sought to examine IL -6 response to acute stress in CAD patients across sex and age, and contrast results to healthy controls and other biomarkers known to increase with mental stress (monocyte chemoattractant protein-1 and matrix metallopeptidase-9) and known limited stress-reactivity (high-sensitivity C-reactive protein). Methods and Results Inflammatory biomarkers were measured at rest and 90 minutes after mental stress (speech task) among 819 patients with CAD and 89 healthy controls. Repeated-measures models were used to investigate age (continuous) and sex differences across time, before and after adjusting for demographics, CAD risk factors, depressive symptoms, medication use, and CAD severity. Among patients with CAD , the mean age was 60 years (range, 25-79) and 31% were women. Younger women with CAD had significantly higher concentrations of IL -6 at rest, 90 minutes after mental stress, as well as a higher response to stress, compared with similarly aged men ( P<0.05 for sex by age interactions). In contrast, IL -6 increased with age, and there were no sex differences in IL -6 levels or response to stress among controls. Inflammatory responses to stress for high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, and matrix metallopeptidase-9 among CAD patients were similar in women and men. Conclusions IL -6 response to mental stress are higher in young women with CAD than men of similar age.

Progenitor Cells and Clinical Outcomes in Patients With Acute Coronary Syndromes.

RATIONALE: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). OBJECTIVE: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. METHODS AND RESULTS: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31-2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18-5.13) increase in all-cause mortality, P=0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. CONCLUSIONS: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

High-Sensitivity Troponin I Levels and Coronary Artery Disease Severity, Progression, and Long-Term Outcomes.

BACKGROUND: The associations between high-sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. METHODS AND RESULTS: In 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all-cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD, 20% had 1-vessel CAD, 20% had 2-vessel CAD, and 26% had 3-vessel CAD. After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18-0.44; P<0.001) and with CAD progression (log 2 ß=0.36; 95% confidence interval, 0.14-0.58; P=0.001). hsTnI level was also a significant predictor of incident death, cardiovascular death, myocardial infarction, revascularization, and cardiac hospitalizations, independent of the aforementioned covariates and CAD severity. CONCLUSIONS: Higher hsTnI levels are associated with the underlying burden of coronary atherosclerosis, more rapid progression of CAD, and higher risk of all-cause mortality and incident cardiovascular events. Whether more aggressive treatment aimed at reducing hsTnI levels can modulate disease progression requires further investigation.

Inflammatory response to mental stress and mental stress induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia (MSIMI) is associated with increased risk of adverse cardiovascular outcomes, yet the underlying mechanisms are not well understood. We measured the inflammatory response to acute laboratory mental stress in patients with coronary artery disease (CAD) and its association with MSIMI. We hypothesized that patients with MSIMI would have a higher inflammatory response to mental stress in comparison to those without ischemia. METHODS: Patients with stable CAD underwent 99mTc sestamibi myocardial perfusion imaging during mental stress testing using a public speaking stressor. MSIMI was determined as impaired myocardial perfusion using a 17-segment model. Inflammatory markers including interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metallopeptidase 9 (MMP-9) and high-sensitivity C reactive protein (hsCRP) were measured at rest and 90 min after mental stress. Results were validated in an independent sample of 228 post-myocardial infarction patients. RESULTS: Of 607 patients analyzed in this study, (mean age 63 ±â€¯9 years, 76% male), 99 (16.3%) developed MSIMI. Mental stress resulted in a significant increase in IL-6, MCP-1, and MMP-9 (all p <0.0001), but not hsCRP. However, the changes in these markers were similar in those with and without MSIMI. Neither resting levels of these biomarkers, nor their changes with mental stress were significantly associated with MSIMI. Results in the replication sample were similar. CONCLUSION: Mental stress is associated with acute increases in several inflammatory markers. However, neither the baseline inflammatory status nor the magnitude of the inflammatory response to mental stress over 90 min were significantly associated with MSIMI.

Relation of Changes in Body Fat Distribution to Oxidative Stress.

Android fat is a surrogate measure of visceral obesity in the truncal region. Both visceral adiposity and oxidative stress (OS) are linked to cardiometabolic risk factors and clinical cardiovascular disease. However, whether body fat distribution (android vs gynoid) is associated with OS remains unknown. We hypothesized that increased android fat will be associated with greater OS. Body fat distribution and markers of OS, including plasma levels of reduced (cysteine and glutathione) and oxidized (cystine and glutathione disulfide) aminothiols, were estimated in 711 volunteers (67% female, 23% black, mean age 48 ± 11) enrolled in the Emory Georgia Tech Predictive Health study. At 1 year, 498 subjects had repeat testing. At baseline, anthropometric and fat distribution indexes, including body mass index, waist circumference, weight/hip ratio, and android and gynoid fat mass correlated with lower plasma concentrations of glutathione and higher cystine levels indicative of higher OS. At 1 year, the change in android but not gynoid fat mass or body mass index negatively correlated with the change in the plasma glutathione level after adjustment for cardiovascular risk factors. Increased body fat, specifically android fat mass, is an independent determinant of systemic OS, and its change is associated with a simultaneous change in OS, measured as plasma glutathione. In conclusion, our findings suggest that excess android or visceral fat contributes to the development of cardiovascular disease through modulating OS.

Association Between Living in Food Deserts and Cardiovascular Risk.

BACKGROUND: Food deserts (FD), neighborhoods defined as low-income areas with low access to healthy food, are a public health concern. We evaluated the impact of living in FD on cardiovascular risk factors and subclinical cardiovascular disease (CVD) with the hypothesis that people living in FD will have an unfavorable CVD risk profile. We further assessed whether the impact of FD on these measures is driven by area income, individual household income, or area access to healthy food. METHODS AND RESULTS: We studied 1421 subjects residing in the Atlanta metropolitan area who participated in the META-Health study (Morehouse and Emory Team up to Eliminate Health Disparities; n=712) and the Predictive Health study (n=709). Participants' zip codes were entered into the United States Food Access Research Atlas for FD status. Demographic data, metabolic profiles, hs-CRP (high-sensitivity C-reactive protein) levels, oxidative stress markers (glutathione and cystine), and arterial stiffness were evaluated. Mean age was 49.4 years, 38.5% male and 36.6% black. Compared with those not living in FD, subjects living in FD (n=187, 13.2%) had a higher prevalence of hypertension and smoking, higher body mass index, fasting glucose, and 10-year risk for CVD. They also had higher hs-CRP (P=0.014), higher central augmentation index (P=0.015), and lower glutathione level (P=0.003), indicative of increased oxidative stress. Area income and individual income, rather than food access, were associated with CVD risk measures. In a multivariate analysis that included food access, area income and individual income, both low-income area and low individual household income, were independent predictors of a higher 10-year risk for CVD. Only low individual income was an independent predictor of higher hs-CRP and augmentation index. CONCLUSIONS: Although living in FD is associated with a higher burden of cardiovascular risk factors and preclinical indices of CVD, these associations are mainly driven by area income and individual income rather than access to healthy food.

Progenitor Cells and Clinical Outcomes in Patients With Heart Failure.

BACKGROUND: Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events. METHODS AND RESULTS: We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34+ and CD34+/CXCR+ cell count remained independently associated with a diagnosis of HF (P<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects with HF, there were 98 (19.1%) all-cause deaths during a 2.2±1.5-year follow-up. In a Cox regression model adjusting for clinical variables, hematopoietic-enriched PCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were independent predictors of all-cause death (hazard ratio 2.0, 1.6, 1.6-fold higher mortality, respectively; P<0.03) among HF patients. Endothelial-enriched PCs (CD34+/VEGF+) were independent predictors of mortality in patients with HF with preserved ejection fraction only (hazard ratio, 5.0; P=0.001). CONCLUSIONS: PC levels are lower in patients with HF, and lower PC counts are strongly and independently predictive of mortality. Strategies to increase PCs and exogenous stem cell therapies designed to improve regenerative capacity in HF, especially, in HF with preserved ejection fraction, need to be further explored.

Association between oxidative stress and atrial fibrillation.

BACKGROUND: Oxidative stress (OS) may be a key mechanism underlying the development of atrial fibrillation (AF) in experimental studies, but data in humans remain limited. OBJECTIVE: Systemic OS can be estimated by measurements of circulating levels of the aminothiols including glutathione, cysteine, and their oxidized products. We tested the hypothesis that the redox potentials of glutathione (EhGSH) and cysteine will be associated with prevalent and incident AF. METHODS: Plasma levels of aminothiols were measured in 1439 patients undergoing coronary angiography, of whom 148 (10.3%) had a diagnosis of AF. After a median follow-up of 6.3 years, 104 of 917 patients (11.5%) developed incident AF. Multivariate logistic regression and Cox regression models were used to determine whether OS markers were independent predictors of prevalent and incident AF after adjustment for traditional risk factors, heart failure, coronary artery disease, and high-sensitivity C-reactive protein level. RESULTS: For each 10% increase in EhGSH, the odds of prevalent AF was 30% higher (odds ratio [OR] 1.3; 95% confidence interval [CI] 1.1-1.7; P = .02) and 90% higher (OR 1.9; 95% CI 1.3-2.7; P = .004) when the median was used as a cutoff. The EhGSH level above the median was more predictive of chronic AF (OR 4.0; 95% CI 1.3-12.9; P = .01) than of paroxysmal AF (OR 1.7; 95% CI 1.1-2.7; P = .03). Each 10% increase in EhGSH level was associated with a 40% increase in the risk of incident AF (hazard ratio 1.4; 95% CI 1.1-1.7; P = .01). CONCLUSION: Increased OS measured by the redox potentials of glutathione is associated with prevalent and incident AF. Therapies that modulate OS need to be investigated to treat and prevent AF.

Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

BACKGROUND AND AIMS: Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study. METHODS: SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD. RESULTS: Plasma suPAR levels were 22.5% (p < 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (≥2 compared to single site) p < 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p < 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p < 0.001 for all]. CONCLUSIONS: Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation.

Navigating air travel and cardiovascular concerns: Is the sky the limit?

As the population ages and our ability to care for patients with cardiac disease improves, an increasing number of passengers with cardiovascular conditions will be traveling long distances. Many have had cardiac symptoms, recent interventions, devices, or surgery. Air travel is safe for most individuals with stable cardiovascular disease. However, a thorough understanding of the physiologic changes during air travel is essential given the potential impact on cardiovascular health and the risk of complications in passengers with preexisting cardiac conditions. It is important for clinicians to be aware of the current recommendations and precautions that need to be taken before and during air travel for passengers with cardiovascular concerns.

Telomere Shortening, Regenerative Capacity, and Cardiovascular Outcomes.

RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (

Effects of a Health-Partner Intervention on Cardiovascular Risk.

BACKGROUND: Lifestyle modifications are first-line measures for cardiovascular disease prevention. Whether lifestyle intervention also preserves cardiovascular health is less clear. Our study examined the role of a Health Partner-administered lifestyle intervention on metrics of ideal cardiovascular health. METHODS AND RESULTS: A total of 711 university employees (48±11 years; 66% women, 72% Caucasian/22.5% African Americans) enrolled in a program that promoted healthier lifestyles at Emory University (Atlanta, GA). Anthropometric, laboratory, and physical activity measurements were performed at baseline and at 6 months, 1 year, and 2 years of follow-up. Results were utilized by the Health Partner to generate a personalized plan aimed at meeting ideal health metrics. Compared to baseline, at each of the 6-month, 1-year, and 2-year follow-up visits, systolic blood pressure was lower by 3.6, 4.6, and 3.3 mm Hg (P<0.001), total cholesterol decreased by 5.3, 6.5, and 6.4 mg/dL (P<0.001), body mass index declined by 0.33, 0.45, and 0.38 kg/m2 (P<0.001), and the percentage of smokers decreased by 1.3%, 3.5%, and 3.5% (P<0.01), respectively. Changes were greater in those with greater abnormalities at baseline. Finally, the American Heart Association "Life's Simple 7" ideal cardiovascular health score increased by 0.28, 0.40, and 0.33 at 6 month, 1 year, and 2 years, respectively, compared to baseline visit. CONCLUSIONS: A personalized, goal-directed Health Partner intervention significantly improved the cardiometabolic risk profile and metrics of cardiovascular health. These effects were evident at 6 months following enrollment and were sustained for 2 years. Whether the Health Partner intervention improves long-term morbidity and mortality and is cost-effective needs further investigation.

Age and Human Regenerative Capacity Impact of Cardiovascular Risk Factors.

RATIONALE: We investigated aging of human endogenous reparative capacity and aimed to clarify whether it is affected by presence of cardiovascular disease or its risk factors (RFs). OBJECTIVE: Circulating progenitor cell (PC) levels reflect endogenous regenerative potential. The effect on PC of healthy aging compared with aging with RFs or cardiovascular disease (CVD) is unknown. We examined whether exposure to RF and CVD leads to an accelerated decline in circulating PC with increasing age. METHODS AND RESULTS: In 2792 adult subjects, 498 were free of RFs (smoking, diabetes mellitus, hypertension, or hyperlipidemia), 1036 subjects had 1 to 2 RF, and 1253 had ≥3 RFs or CVD. PC were enumerated by flow cytometry as CD45(med+) mononuclear cells expressing CD34 and subsets coexpressing CD133, CXCR4, and vascular endothelial growth factor receptor-2 epitopes. Younger age, male sex, and larger body size correlated with higher PC counts (P<0.01). After multivariable adjustment, both age and RF categories were independently associated with PC counts (P<0.05), with lower PC counts in older subjects and those with higher RF burden or CVD. PC counts remained unchanged with increasing age in healthy individuals. There were significant interactions between age and RF categories (P≤0.005), such that for younger subjects (<40 years), RFs were associated with increased PC counts, whereas for older subjects (>60 years), RFs and CVD were associated with lower PC counts. CONCLUSIONS: Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization, whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.

Elevated Soluble Fms-Like Tyrosine Kinase-1 and Placental-Like Growth Factor Levels Are Associated With Development and Mortality Risk in Heart Failure.

BACKGROUND: Vascular endothelial dysfunction may play an important role in the progression of heart failure (HF). We hypothesize that elevated levels of vascular markers, placental-like growth factor, and soluble Fms-like tyrosine kinase-1 (sFlt-1) are associated with adverse outcomes in patients with HF. We also assessed possible triggers of sFlt-1 elevation in animal HF models. METHODS AND RESULTS: We measured plasma placental-like growth factor and sFlt-1 in 791 HF patients undergoing elective coronary angiogram. Median (interquartile range) placental-like growth factor and sFlt-1 levels were 24 (20-29) and 382 (277-953) pg/mL, respectively. After 5 years of follow-up, and after using receiver operator characteristic curves to determine optimal cutoffs, high levels of sFlt-1 (≥ 280 pg/mL; adjusted hazard ratio, 1.47; 95% confidence interval, 1.03-2.09; P=0.035) but not placental-like growth factor (≥ 25 pg/mL; adjusted hazard ratio, 1.26; 95% confidence interval, 0.94-1.71, P=0.12) were associated with adverse cardiovascular outcomes. In addition, significant elevation of sFlt-1 levels was observed in left anterior descending artery ligation and transverse aortic constriction HF mouse models after 4 and 8 weeks of follow-up, suggesting vascular stress and ischemia as triggers for sFlt-1 elevation in HF. CONCLUSIONS: Circulating sFlt-1 is generated as a result of myocardial injury and subsequent HF development. Elevated levels of sFlt-1 are associated with adverse outcomes in stable patients with HF.

An unusual case of fever of unknown origin.

Mycobacterium avium complex (MAC) infection is a common complication of the later stages of AIDS. Extrapulmonary infection with MAC in HIV-negative patients is considered uncommon. We report a case of a young female who presented with fever of unknown origin on multiple occasions and failed to be diagnosed with MAC by acid-fast stain initially. Subsequently, the patient presented with pancytopenia due to bone marrow biopsy-proven infection with MAC. The patient was not on any immunosuppressant regimen.

Acral gangrene as a presentation of non-uremic calciphylaxis.

We are describing a case of 55-year-old obese female with significant history of uncontrolled rheumatoid arthritis, who recently had decreased her immune-suppression medications. She presented with extensive acral gangrene involving multiple fingers and toes. Clinical picture and laboratory findings were suggestive of vasculitis; however, skin biopsy established diagnosis of calciphylaxis, in settings of normal kidney function. Patient was treated with sodium thiosulfate with gradual improvement in her skin lesions.