Asymptomatic myocardial ischemia forecasts adverse events in cardiovascular magnetic resonance dobutamine stress testing of high-risk middle-aged and elderly individuals.

BACKGROUND: Current guidelines for assessing the risk of experiencing a hospitalized cardiovascular (CV) event discourage stress testing of asymptomatic individuals; however, these recommendations are based on evidence gathered primarily from those aged < 60 years, and do not address the possibility of unrecognized "silent myocardial ischemia" in middle aged and older adults. METHODS: We performed dobutamine cardiovascular magnetic resonance (CMR) stress testing in 327 consecutively recruited participants aged > 55 years without CV-related symptoms nor known coronary artery disease, but otherwise at increased risk for a future CV event due to pre-existing hypertension or diabetes mellitus for at least 5 years. After adjusting for the demographics and CV risk factors, log-rank test and Cox proportional hazards models determined the additional predictive value of the stress test results for forecasting hospitalized CV events/survival. Either stress-induced LV wall motion abnormalities or perfusion defects were used to indicate myocardial ischemia. RESULTS: Participants averaged 68 ± 8 years in age; 39% men, 75% Caucasian. There were 38 hospitalized CV events or deaths which occurred during a mean follow-up of 58 months. Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival (p <  0.001), but this finding was more evident in men (p <  0.001) versus women (p = 0.27). The crude hazard ratio (HR) of myocardial ischemia for CV events/survival was 3.13 (95% CI: 1.64-5.93; p < 0.001). After accounting for baseline demographics, CV risk factors, and left ventricular ejection fraction/mass, myocardial ischemia continued to be associated with CV events/survival [HR: 4.07 (95% CI: 1.95-8.73) p < 0.001]. CONCLUSIONS: Among asymptomatic middle-aged individuals with risk factors for a sentinel CV event, the presence of myocardial ischemia during dobutamine CMR testing forecasted a future hospitalized CV event or death. Further studies are needed in middle aged and older individuals to more accurately characterize the prevalence, significance, and management of asymptomatic myocardial ischemia. TRIAL REGISTRATION: ( ClinicalTrials.gov identifier): NCT00542503 and was retrospectively registered on October 11th, 2007.

The effect of Aliskiren on exercise capacity in older patients with heart failure and preserved ejection fraction: A randomized, placebo-controlled, double-blind trial.

In older patients (70 ± 7 years) with chronic well-compensated heart failure with preserved ejection and controlled blood pressure, 6 months treatment with aliskiren (direct renin inhibitor) showed non-significant trends for modest improvements in peak exercise oxygen consumption (14.9 ± 0.2 mL kg-1 min-1 versus 14.4 ± 0.2 mL kg-1 min-1; P = .10, trend) and ventilatory anaerobic threshold (888 ± 19 mL/min versus 841 ± 18 mL/min; P = .08).

Evaluation of laboratory tests for cirrhosis and for alcohol use, in the context of alcoholic cirrhosis.

Laboratory tests can play an important role in assessment of alcoholic patients, including for evaluation of liver damage and as markers of alcohol intake. Evidence on test performance should lead to better selection of appropriate tests and improved interpretation of results. We compared laboratory test results from 1578 patients between cases (with alcoholic cirrhosis; 753 men, 243 women) and controls (with equivalent lifetime alcohol intake but no liver disease; 439 men, 143 women). Comparisons were also made between 631 cases who had reportedly been abstinent from alcohol for over 60 days and 364 who had not. ROC curve analysis was used to estimate and compare tests' ability to distinguish patients with and without cirrhosis, and abstinent and drinking cases. The best tests for presence of cirrhosis were INR and bilirubin, with areas under the ROC curve (AUCs) of 0.91 ± 0.01 and 0.88 ± 0.01, respectively. Confining analysis to patients with no current or previous ascites gave AUCs of 0.88 ± 0.01 for INR and 0.85 ± 0.01 for bilirubin. GGT and AST showed discrimination between abstinence and recent drinking in patients with cirrhosis, including those without ascites, when appropriate (and for GGT, sex-specific) limits were used. For AST, a cut-off limit of 85 units/L gave 90% specificity and 37% sensitivity. For GGT, cut-off limits of 288 units/L in men and 138 units/L in women gave 90% specificity for both and 40% sensitivity in men, 63% sensitivity in women. INR and bilirubin show the best separation between patients with alcoholic cirrhosis (with or without ascites) and control patients with similar lifetime alcohol exposure. Although AST and GGT are substantially increased by liver disease, they can give useful information on recent alcohol intake in patients with alcoholic cirrhosis when appropriate cut-off limits are used.

Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction.

OBJECTIVES: To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF). DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Academic medical center, Winston-Salem, North Carolina. PARTICIPANTS: Older adults (N = 80, aged 71 ± 1; 80% female) with stable compensated HFpEF and controlled blood pressure (BP). MEASUREMENTS: Participants were randomized into a 9-month treatment of spironolactone 25 mg/d vs placebo. Assessments were peak exercise oxygen consumption (VO2 ), 6-minute walk test, Minnesota Living with Heart Failure Questionnaire (MLHFQ), cardiac magnetic resonance imaging, Doppler echocardiography, and vascular ultrasound. RESULTS: Seventy-one participants completed the trial: 37 in the spironolactone group and 34 in the placebo group. Adherence according to pill count was excellent (spironolactone 95%, placebo 97%). Mean spironolactone dose was 24.3 ± 2.9 mg/d and was well tolerated. Spironolactone significantly reduced systolic and diastolic BP at rest and peak exercise. At 9-month follow-up, baseline-adjusted peak VO2, the primary outcome, was 13.5 ± 0.3 mL/kg per minute in the spironolactone group versus 13.9 ± 0.3 mL/kg per minute in the placebo group (adjusted mean difference -0.4 mL/kg per minute; 95% confidence interval = -1.1-0.4 mL/kg per minute; P = .38). The 95% confidence intervals of spironolactone's effect on peak VO2 (-8.2% to 3.2%) excluded a clinically significant beneficial effect. There were also no significant differences in 6-minute walk distance, arterial stiffness, left ventricular (LV) mass, LV mass/end-diastolic volume, or MLHFQ score. CONCLUSION: In older adults with stable compensated HFpEF, 9 months of spironolactone 25 mg/d was well tolerated and reduced BP but did not improve exercise capacity, quality of life, LV mass, or arterial stiffness.

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction.

Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n = 26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 s vs 520 ± 257 s (p = 0.04) for the placebo group and 384 ± 129 s vs 483 ± 258 s for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 s vs 601 ± 38 s (p < 0.05) for the placebo group and 690 ± 38 s vs 772 ± 95 s for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

A Novel Rehabilitation Intervention for Older Patients With Acute Decompensated Heart Failure: The REHAB-HF Pilot Study.

OBJECTIVES: This study sought to assess a novel physical rehabilitation intervention in older patients hospitalized for acute decompensated heart failure (ADHF). BACKGROUND: After ADHF, older patients, who are frequently frail with multiple comorbidities, have prolonged and incomplete recovery of physical function and remain at high risk for poor outcomes. METHODS: The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) pilot study was a 3-site, randomized, attention-controlled pilot study of a tailored, progressive, multidomain physical rehabilitation intervention beginning in the hospital and continuing for 12 weeks post-discharge in patients ≥60 years hospitalized with ADHF. The primary purpose was to assess the feasibility and reasonableness of the hypothesis that the novel rehabilitation intervention would improve physical function (Short Physical Performance Battery [SPPB]) over 3 months and reduce all-cause rehospitalizations over 6 months. RESULTS: The study enrolled 27 patients with ADHF (ages 60 to 98 years; 59% women; 56% African American; 41% with preserved ejection fraction [≥45%]). At baseline, participants had marked impairments in physical function, multiple comorbidities, and frailty. Study retention (89%) and intervention adherence (93%) were excellent. At 3 months, an intervention effect size was measured for the SPPB score of +1.1 U (7.4 ± 0.5 U vs. 6.3 ± 0.5 U), and at 6 months an effect size was observed for an all-cause rehospitalization rate of -0.48 (1.16 ± 0.35 vs. 1.64 ± 0.39). The change in SPPB score was strongly related to all-cause rehospitalizations, explaining 91% of change. CONCLUSIONS: These findings support the feasibility and rationale for a recently launched, National Institutes of Health-funded trial to test the safety and efficacy of this novel multidomain physical rehabilitation intervention to improve physical function and reduce rehospitalizations in older, frail patients with ADHF with multiple comorbidities. (Rehabilitation and Exercise Training After Hospitalization [REHAB-HF]; NCT01508650; A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial: Design and rationale.

BACKGROUND: Acute decompensated heart failure (ADHF) is a leading cause of hospitalization in older persons in the United States. Reduced physical function and frailty are major determinants of adverse outcomes in older patients with hospitalized ADHF. However, these are not addressed by current heart failure (HF) management strategies and there has been little study of exercise training in older, frail HF patients with recent ADHF. HYPOTHESIS: Targeting physical frailty with a multi-domain structured physical rehabilitation intervention will improve physical function and reduce adverse outcomes among older patients experiencing a HF hospitalization. STUDY DESIGN: REHAB-HF is a multi-center clinical trial in which 360 patients ≥60 years hospitalized with ADHF will be randomized either to a novel 12-week multi-domain physical rehabilitation intervention or to attention control. The goal of the intervention is to improve balance, mobility, strength and endurance utilizing reproducible, targeted exercises administered by a multi-disciplinary team with specific milestones for progression. The primary study aim is to assess the efficacy of the REHAB-HF intervention on physical function measured by total Short Physical Performance Battery score. The secondary outcome is 6-month all-cause rehospitalization. Additional outcome measures include quality of life and costs. CONCLUSIONS: REHAB-HF is the first randomized trial of a physical function intervention in older patients with hospitalized ADHF designed to determine if addressing deficits in balance, mobility, strength and endurance improves physical function and reduces rehospitalizations. It will address key evidence gaps concerning the role of physical rehabilitation in the care of older patients, those with ADHF, frailty, and multiple comorbidities.

Absolute bioavailability and safety of a novel rivastigmine nasal spray in healthy elderly individuals.

AIMS: To test the feasibility of a novel rivastigmine nasal spray as prospective treatment for dementia. METHODS: A single dose, crossover absolute bioavailability and safety study was conducted with rivastigmine intravenous solution (1 mg) and nasal spray (3.126 mg) in eight healthy elderly individuals, aged 58-75 years. RESULTS: Absolute bioavailability (F) of the nasal spray was significant at 0.62 (0.15) for F > 0 (P < 0.001, n = 8). The systemic dose absorbed was 2.0 (0.6) mg, time to maximum plasma concentration was 1.1 (0.5) h and maximum plasma concentration was 6.9 (2.0) ng ml-1 . The NAP226-90 to rivastigmine AUC0-∞ ratio was 0.78 (0.19). The single dose safety was good with two of five mild adverse events related to the nasal spray. Nasal and throat irritation were perceived as mild and transient, and both had resolved at 20 min post-nasal dose. An estimated dose of two or three sprays twice-daily with nasal spray would deliver comparable rivastigmine exposure and efficacy as a 6-9.7 mg day-1 oral dose and a 10 cm2 transdermal patch, respectively. CONCLUSIONS: The rivastigmine nasal spray had superior absolute bioavailability compared to historical values for oral capsule and transdermal patch determined by other researchers. It had rapid onset of action, low NAP226-90 to rivastigmine exposure ratio and a favourable safety and tolerability profile. The ability to achieve adjustable, individual, twice-daily dosing during waking hours has good potential to minimise undesirable cholinergic burden and sleep disturbances whilst delivering an effective dose for the treatment of dementia associated with Alzheimer's and Parkinson's disease.

Beta-Blocker Use Is Associated with Higher Renal Tissue Oxygenation in Hypertensive Patients Suspected of Renal Artery Stenosis.

BACKGROUND: Chronic renal hypoxia influences the progression of chronic kidney disease (CKD). Blood oxygen level-dependent (BOLD) magnetic resonance (MR) is a noninvasive tool for the assessment of renal oxygenation. The impact of beta-blockers on renal hemodynamics and oxygenation is not completely understood. We sought to determine the association between beta-blocker use, renal cortical and medullary oxygenation, and renal blood flow in patients suspected of renal artery stenosis. METHODS: We measured renal cortical and medullary oxygenation using BOLD MR and renal artery blood flow using MR phase contrast techniques in 38 participants suspected of renal artery stenosis. RESULTS: Chronic beta-blocker therapy was associated with improved renal cortical (p < 0.001) and medullary (p = 0.03) oxygenation, while the use of calcium channel blockers or diuretics showed no association with either cortical or medullary oxygenation. Receipt of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with reduced medullary oxygenation (p = 0.01). In a multivariable model, chronic receipt of beta-blockers was the only significant predictor of renal tissue oxygenation (ß = 8.4, p = 0.008). Beta-blocker therapy was not associated with significant changes in renal artery blood flow, suggesting that improved renal oxygenation may be related to reduced renal oxygen consumption. CONCLUSIONS: In addition to known benefits to reduce cardiovascular mortality in patients with renal disease, beta-blockers may reduce or prevent the progression of renal dysfunction in patients with hypertension, diabetes, and renovascular disease, partly by reducing renal oxygen consumption. These observations may have important implications for the treatment of patients with CKD.

Anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors.

BACKGROUND: Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. METHODS AND RESULTS: We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64±12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pretreatment cancer (27.8±0.7%; P<0.01) or cancer-free comparators (26.9±0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). CONCLUSIONS: Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities, suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen.

Comparison of Frequency of Frailty and Severely Impaired Physical Function in Patients ≥60 Years Hospitalized With Acute Decompensated Heart Failure Versus Chronic Stable Heart Failure With Reduced and Preserved Left Ventricular Ejection Fraction.

Older patients with acute decompensated heart failure (ADHF) have persistently poor outcomes including frequent rehospitalization despite guidelines-based therapy. We hypothesized that such patients have multiple, severe impairments in physical function, cognition, and mood that are not addressed by current care pathways. We prospectively examined frailty, physical function, cognition, mood, and quality of life in 27 consecutive older patients with ADHF at 3 medical centers and compared these with 197 participants in 3 age-matched cohorts: stable heart failure (HF) with preserved ejection fraction (n = 80), stable HF with reduced ejection fraction (n = 56), and healthy older adults (n = 61). Based on Fried criteria, frailty was present in 56% of patients with ADHF versus 0 for the age-matched chronic HF and health cohorts. Patients with ADHF had markedly reduced Short Physical Performance Battery score (5.3 ± 2.8) and 6-minute walk distance (178 ± 102 m) (p <0.001 vs other cohorts), with severe deficits in all domains of physical function: balance, mobility, strength, and endurance. In the patients with ADHF, cognitive impairment (78%) and depression (30%) were common, and quality of life was poor. In conclusion, older patients with ADHF are frequently frail with severe and widespread impairments in physical function, cognition, mood, and quality of life that may contribute to their persistently poor outcomes, are frequently unrecognized, are not addressed in current ADHF care paradigms, and are potentially modifiable with targeted interventions.

One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction.

OBJECTIVES: This study sought to determine whether a relatively low single dose or a week-long dosage of dietary inorganic nitrate could improve exercise tolerance in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Exercise intolerance is the primary manifestation of HFpEF and is largely due to noncardiac factors that reduce oxygen delivery to active skeletal muscles. A recent study showed improved exercise capacity in patients with HFpEF after a single, acute dose of beetroot juice (BRJ) (12.9 mmol inorganic nitrate) while another recent study showed neutral and negative effects of an organic nitrate. METHODS: Twenty HFpEF patients (69 ± 7 years of age ) were enrolled in an initial cross-over design comparing a single, acute dose of BRJ (6.1 mmol nitrate) to a nitrate-depleted placebo BRJ. A second phase, 1 week of daily doses, used an all-treated design in which patients consumed BRJ for an average of 7 days. The primary outcome of the study was submaximal aerobic endurance, measured as cycling time to exhaustion at 75% of measured maximal power output. RESULTS: No adverse events were associated with the intervention. Submaximal aerobic endurance improved 24% after 1 week of daily BRJ dosing (p = 0.02) but was not affected by the single, acute dose of the BRJ compared to placebo. Consumption of BRJ significantly reduced resting systolic blood pressure and increased plasma nitrate and nitrite in both of the dosing schemes. CONCLUSIONS: One week of daily dosing with BRJ (6.1 mmol inorganic nitrate) significantly improves submaximal aerobic endurance and blood pressure in elderly HFpEF patients.

Adiposity Is Associated with Gender-Specific Reductions in Left Ventricular Myocardial Perfusion during Dobutamine Stress.

BACKGROUND: Obesity and visceral adiposity are increasingly recognized risk factors for cardiovascular disease. Visceral fat may reduce myocardial perfusion by impairing vascular endothelial function. Women experience more anginal symptoms compared to men despite less severe coronary artery stenosis, as assessed by angiography. Women and men have different fat storage patterns which may account for the observed differences in cardiovascular disease. Therefore, our objective was to evaluate the relationship between visceral adipose tissue distributions and myocardial perfusion in men and women. METHODS: Visceral and subcutaneous fat distributions and myocardial perfusion were measured in 69 men and women without coronary artery disease using magnetic resonance imaging techniques. Myocardial perfusion index was quantified after first-pass perfusion with gadolinium contrast at peak dose dobutamine stress. RESULTS: We observed inverse relationships between female gender (r = -0.35, p = 0.003), pericardial fat (r = -0.36, p = 0.03), intraperitoneal fat (r = -0.37, p = 0.001), and retroperitoneal fat (r = -0.36, p = 0.002) and myocardial perfusion index. Visceral fat depots were not associated with reduced myocardial perfusion at peak dose dobutamine in men. However, in women, BMI (r = -0.33, p = 0.04), pericardial fat (r = -0.53, p = 0.02), subcutaneous fat (r = -0.39, p = 0.01) and intraperitoneal fat (r = -0.30, p = 0.05) were associated with reduced myocardial perfusion during dobutamine stress. CONCLUSIONS: Higher visceral fat volumes are associated with reduced left ventricular myocardial perfusion at peak dose dobutamine stress in women but not in men. These findings suggest that visceral fat may contribute to abnormal microcirculatory coronary artery perfusion syndromes, explaining why some women exhibit more anginal symptoms despite typically lower grade epicardial coronary artery stenoses than men.

Brain MRI Volume Findings in Diabetic Adults With Albuminuria: The ACCORD-MIND Study.

BACKGROUND: Albuminuria is associated with cognitive impairment in people with type 2 diabetes mellitus (T2DM). The brain volume correlates of albuminuria in people with T2DM have not been well investigated. METHODS: We examined 502 individuals with T2DM (9-12 years duration; mean age ~62 years) who had a brain MRI at baseline and at 40 months. Baseline MRI findings were examined by the presence or absence of albuminuria (≥30mg/g creatinine). Changes in MRI findings were examined by whether albuminuria was persistent, intermittent, or absent during follow-up. RESULTS: At baseline, participants with albuminuria (28.7% of the cohort) had more abnormal white matter volume (AWMV) than participants without albuminuria on unadjusted analysis. This difference was attenuated with adjustment for systolic blood pressure, which was higher in participants with albuminuria than in those without albuminuria. During ~3.5 years of follow-up, participants with persistent albuminuria (15.8%) had a greater increase in new AWMV than participants without albuminuria (59.8%) or those with intermittent albuminuria on unadjusted analysis. This difference was attenuated with adjustment for age and systolic blood pressure. There were no significant differences in gray matter volume and total brain volume between participants with or without albuminuria at baseline or during follow-up. There was no significant effect modification of these findings by estimated glomerular filtration rate (eGFR) at baseline or change in eGFR during follow-up. CONCLUSIONS: In this diabetic cohort, baseline albuminuria and persistent albuminuria were not independently associated with any significant differences in brain volume measurements compared with participants without albuminuria.

Alterations in levels and ratios of n-3 and n-6 polyunsaturated fatty acids in the temporal cortex and liver of vervet monkeys from birth to early adulthood.

Deficiencies in omega-3 (n-3) long chain polyunsaturated fatty acids (LC-PUFAs) and increases in the ratio of omega-6 (n-6) to n-3 LC-PUFAs in brain tissues and blood components have been associated with psychiatric and developmental disorders. Most studies have focused on n-3 LC-PUFA accumulation in the brain from birth until 2years of age, well before the symptomatic onset of such disorders. The current study addresses changes that occur in childhood and adolescence. Postmortem brain (cortical gray matter, inferior temporal lobe; n=50) and liver (n=60) from vervet monkeys fed a uniform diet from birth through young adulthood were collected from archived tissues. Lipids were extracted and fatty acid levels determined. There was a marked reduction in the ratio of n-6 LC-PUFAs, arachidonic acid (ARA) and adrenic acid (ADR), relative to the n-3 LC-PUFA, docosahexaenoic acid (DHA), in temporal cortex lipids from birth to puberty and then a more gradual decrease though adulthood. This decrease in ratio resulted from a 3-fold accumulation of DHA levels while concentrations of ARA remained constant. Early childhood through adolescence appears to be a critical period for DHA accretion in the cortex of vervet monkeys and may represent a vulnerable stage where lack of dietary n-3 LC-PUFAs impacts development in humans.

Impact of methods used to express levels of circulating fatty acids on the degree and direction of associations with blood lipids in humans.

Numerous studies have examined relationships between disease biomarkers (such as blood lipids) and levels of circulating or cellular fatty acids. In such association studies, fatty acids have typically been expressed as the percentage of a particular fatty acid relative to the total fatty acids in a sample. Using two human cohorts, this study examined relationships between blood lipids (TAG, and LDL, HDL or total cholesterol) and circulating fatty acids expressed either as a percentage of total or as concentration in serum. The direction of the correlation between stearic acid, linoleic acid, dihomo-γ-linolenic acid, arachidonic acid and DHA and circulating TAG reversed when fatty acids were expressed as concentrations v. a percentage of total. Similar reversals were observed for these fatty acids when examining their associations with the ratio of total cholesterol:HDL-cholesterol. This reversal pattern was replicated in serum samples from both human cohorts. The correlations between blood lipids and fatty acids expressed as a percentage of total could be mathematically modelled from the concentration data. These data reveal that the different methods of expressing fatty acids lead to dissimilar correlations between blood lipids and certain fatty acids. This study raises important questions about how such reversals in association patterns impact the interpretation of numerous association studies evaluating fatty acids and their relationships with disease biomarkers or risk.

Prognostic utility of cardiovascular magnetic resonance upright maximal treadmill exercise testing.

BACKGROUND: Left ventricular wall motion abnormalities (LVWMA) observed during cardiovascular magnetic resonance (CMR) pharmacologic stress testing can be used to determine cardiac prognosis, but currently, information regarding the prognostic utility of upright maximal treadmill induced LVWMA is unknown. Our objective was to determine the prognostic utility of upright maximal treadmill exercise stress CMR. METHODS: One hundred and fifteen (115) men and women with known or suspected coronary arteriosclerosis and an appropriate indication for cardiovascular (CV) imaging to supplement ST segment stress testing underwent an upright treadmill exercise CMR stress test in which LVWMA were identified before and immediately after exercise. Personnel blinded to results determined the post-test incidence of cardiac events (cardiac death, myocardial infarctions [MI], and unstable angina warranting hospital admission or coronary arterial revascularization). RESULTS: All participants completed the testing protocol, with 90% completing image acquisition within 60 s of exercise cessation. MI or cardiac death occurred in 3% of individuals without and 17% of individuals with inducible LVWMA (p = 0.024). The combination of MI, cardiac death, and unstable angina warranting hospitalization occurred in 14% of individuals without and 47% of individuals with inducible LVWMA (p = 0.002). The addition of CMR imaging identified those at risk for future events (p = 0.002), as opposed to the electrocardiogram stress test alone (p = 0.63). CONCLUSIONS: In patients with or suspected of coronary arteriosclerosis and appropriate indication for imaging to supplement ST segment analysis during upright treadmill exercise, the presence of inducible LVWMA during treadmill exercise stress CMR supplements ST segment monitoring and helps identify those at risk of the future combined endpoints of myocardial infarction, cardiac death, and unstable angina warranting hospitalization.

Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality: The Cardiovascular Health Study.

OBJECTIVES: The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF). BACKGROUND: Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk. METHODS: We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk. RESULTS: Mean age of participants was 79.2 ± 6.3 years with 52% being men. Sixty percent of participants had ≥3 comorbidities, and only 2.5% had none. Twenty-two percent and 44% of participants had ≥1 activity of daily living (ADL) and ≥1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19%, 56%, and 83%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95% CI: 1.22 to 1.92), depression (HR: 1.44; 95% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95% CI: 1.07 to 2.04 for ≥2 IADL impaired), and cognitive impairment (HR: 1.33; 95% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality. CONCLUSIONS: Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

Mechanism of decreased sensitivity of dobutamine associated left ventricular wall motion analyses for appreciating inducible ischemia in older adults.

BACKGROUND: Dobutamine associated left ventricular (LV) wall motion analyses exhibit reduced sensitivity for detecting inducible ischemia in individuals with increased LV wall thickness. This study was performed to better understand the mechanism of this reduced sensitivity in the elderly who often manifest increased LV wall thickness and risk factors for coronary artery disease. METHODS: During dobutamine cardiovascular magnetic resonance (DCMR) stress testing, we assessed rate pressure product (RPP), aortic pulse wave velocity (PWV), LV myocardial oxygen demand (pressure volume area, PVA, mass, volumes, concentricity, and the presence of wall motion abnormalities (WMA) and first pass gadolinium enhanced perfusion defects (PDs) indicative of ischemia in 278 consecutively recruited individuals aged 69 ± 8 years with pre-existing or known risk factors for coronary artery disease. Each variable was assessed independently by personnel blinded to participant identifiers and analyses of other DCMR or hemodynamic variables. RESULTS: Participants were 80% white, 90% hypertensive, 43% diabetic and 55% men. With dobutamine, 60% of the participants who exhibited PDs had no inducible WMA. Among these participants, myocardial oxygen demand was lower than that observed in those who had both wall motion and perfusion abnormalities suggestive of ischemia (p = 0.03). Relative to those with PDs and inducible WMAs, myocardial oxygen demand remained different in these individuals with PDs without an inducible WMA after accounting for LV afterload and contractility (p = 0.02 and 0.03 respectively), but not after accounting for either LV stress related end diastolic volume index (LV preload) or resting concentricity (p = 0.31-0.71). CONCLUSIONS: During dobutamine stress testing, elderly patients experience increased LV concentricity and declines in LV preload and myocardial oxygen demand, all of which are associated with an absence of inducible LV WMAs indicative of myocardial ischemia. These findings provide insight as to why dobutamine associated wall motion analyses exhibit reduced sensitivity for identifying inducible ischemia in elderly. TRIAL REGISTRATION: This study was registered with Clinicaltrials.gov (NCT00542503).

Learning Ability as a Function of Practice: Does It Apply to Farmworkers?

OBJECTIVE: Farmworkers experience significant work-related health risks including pesticide-associated cognitive impairment. Practice effect is a surrogate for learning ability. This study examined differences in cognitive function and learning capacity in Latino farmworkers and nonfarmworkers. METHODS: Tasks of learning and short-term memory, executive function and working memory, perceptual coding, and psychomotor function were assessed at baseline and 3-month follow-up in 136 farmworkers and 116 nonfarmworkers. RESULTS: Farmworkers had better performance on visuospatial learning and short-term memory at baseline (P < 0.05). Nevertheless, nonfarmworkers showed more practice effects, or improvement on cognitive performance, at 3-month follow-up relative to farmworkers. Furthermore, the amount of improvement on visuospatial learning ability, short-term visuospatial memory, and perceptual coding ability was significantly higher in nonfarmworkers than in farmworkers. CONCLUSIONS: Practice effects may serve as an additional cognitive readout to differentiate healthy individuals from those with cognitive impairment.