Snigdha Pusalavidyasagar

Day-Night Variation of Acute Myocardial Infarction in Obstructive Sleep Apnea

OBJECTIVES This study sought to evaluate the day-night variation of acute myocardial infarction (MI) in patients with obstructive sleep apnea (OSA). BACKGROUND Obstructive sleep apnea has a high prevalence and is characterized by acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of MI during the night. METHODS We prospectively studied 92 patients with MI for which the time of onset of chest pain was clearly identified. The presence of OSA was determined by overnight polysomnography. RESULTS For patients with and without OSA, we compared the frequency of MI during different intervals of the day based on the onset time of chest pain. The groups had similar prevalence of comorbidities. Myocardial infarction occurred between 12 am and 6 am in 32% of OSA patients and 7% of non-OSA patients (p = 0.01). The odds of having OSA in those patients whose MI occurred between 12 am and 6 am was 6-fold higher than in the remaining 18 h of the day (95% confidence interval: 1.3 to 27.3, p = 0.01). Of all patients having an MI between 12 am and 6 am, 91% had OSA. CONCLUSIONS The diurnal variation in the onset of MI in OSA patients is strikingly different from the diurnal variation in non-OSA patients. Patients with nocturnal onset of MI have a high likelihood of having OSA. These findings suggest that OSA may be a trigger for MI. Patients having nocturnal onset of MI should be evaluated for OSA, and future research should address the effects of OSA therapy for prevention of nocturnal cardiac events.

Modest Visceral Fat Gain Causes Endothelial Dysfunction in Healthy Humans

OBJECTIVES The aim of this study was to determine the impact of fat gain and its distribution on endothelial function in lean healthy humans. BACKGROUND Endothelial dysfunction has been identified as an independent predictor of cardiovascular events. Whether fat gain impairs endothelial function is unknown. METHODS A randomized controlled study was conducted to assess the effects of fat gain on endothelial function. Forty-three normal-weight healthy volunteers were recruited (mean age 29 years; 18 women). Subjects were assigned to gain weight (approximately 4 kg) (n=35) or to maintain weight (n=8). Endothelial function (brachial artery flow-mediated dilation [FMD]) was measured at baseline, after fat gain (8 weeks), and after weight loss (16 weeks) for fat gainers and at baseline and follow-up (8 weeks) for weight maintainers. Body composition was measured by dual-energy X-ray absorptiometry and abdominal computed tomographic scans. RESULTS After an average weight gain of 4.1 kg, fat gainers significantly increased their total, visceral, and subcutaneous fat. Blood pressure and overnight polysomnography did not change after fat gain or loss. FMD remained unchanged in weight maintainers. FMD decreased in fat gainers (9.1+/-3% vs. 7.8+/-3.2%, p=0.003) but recovered to baseline when subjects shed the gained weight. There was a significant correlation between the decrease in FMD and the increase in visceral fat gain (rho=-0.42, p=0.004), but not with subcutaneous fat gain (rho=-0.22, p=0.15). CONCLUSIONS In normal-weight healthy young subjects, modest fat gain results in impaired endothelial function, even in the absence of changes in blood pressure. Endothelial function recovers after weight loss. Increased visceral rather than subcutaneous fat predicts endothelial dysfunction. (Fat Gain and Cardiovascular Disease Mechanisms; NCT00589498).

Patients With Obstructive Sleep Apnea Exhibit Impaired Endothelial Function After Myocardial Infarction

BACKGROUND Impaired brachial flow-mediated dilation (FMD) is associated with risk for subsequent cardiovascular events in patients after myocardial infarction (MI). These patients often have obstructive sleep apnea (OSA). We tested the hypothesis that patients with OSA post MI will exhibit more severe impairment in FMD. METHODS We studied 64 patients with MI admitted to our hospital. OSA was determined using polysomnography. FMD was measured using high-resolution ultrasonography, with researchers blind to the OSA diagnosis. RESULTS The mean age was 60 ± 11 years, and the mean BMI was 29 (26, 32 kg/m(2)), 84% of patients were men, 39% had moderate to severe OSA (apnea-hypopnea index [AHI] > 15), and 31% of the patients had mild OSA (5 ≤ AHI < 15). FMD was severely impaired in patients with moderate to severe OSA (0.8% ± 0.7%) as compared with patients without OSA (4.7% ± 0.8%, P = .001) and with mild OSA (3.9% ± 0.8%, P = .015). Linear regression showed that FMD was associated with log nocturnal nadir oxygen saturation (minSaO(2)) (β = 31.17, P = .0001), age (β = -0.11, P = .006). MinSaO(2) was an independent predictor of FMD after adjustment for possible confounders (β = 26.15, P = .001). CONCLUSIONS FMD is severely impaired in patients with moderate to severe OSA post MI, which may be partially related to nocturnal hypoxemia. Patients with OSA may, therefore, be at higher risk for subsequent cardiovascular events after an MI. Identifying and treating OSA may have important implications in the long-term prognosis of patients post MI. Further studies are necessary to determine if the presence of OSA would affect the long-term occurrence of cardiovascular events after an MI.

Effects of weight gain and weight loss on regional fat distribution

BACKGROUND Normal-weight adults gain lower-body fat via adipocyte hyperplasia and upper-body subcutaneous (UBSQ) fat via adipocyte hypertrophy. OBJECTIVES We investigated whether regional fat loss mirrors fat gain and whether the loss of lower-body fat is attributed to decreased adipocyte number or size. DESIGN We assessed UBSQ, lower-body, and visceral fat gains and losses in response to overfeeding and underfeeding in 23 normal-weight adults (15 men) by using dual-energy X-ray absorptiometry and abdominal computed tomography scans. Participants gained ∼5% of weight in 8 wk and lost ∼80% of gained fat in 8 wk. We measured abdominal subcutaneous and femoral adipocyte sizes and numbers after weight gain and loss. RESULTS Volunteers gained 3.1 ± 2.1 (mean ± SD) kg body fat with overfeeding and lost 2.4 ± 1.7 kg body fat with underfeeding. Although UBSQ and visceral fat gains were completely reversed after 8 wk of underfeeding, lower-body fat had not yet returned to baseline values. Abdominal and femoral adipocyte sizes, but not numbers, decreased with weight loss. Decreases in abdominal adipocyte size and UBSQ fat mass were correlated (ρ = 0.76, P = 0.001), as were decreases in femoral adipocyte size and lower-body fat (ρ = 0.49, P = 0.05). CONCLUSIONS UBSQ and visceral fat increase and decrease proportionately with a short-term weight gain and loss, whereas a gain of lower-body fat does not relate to the loss of lower-body fat. The loss of lower-body fat is attributed to a reduced fat cell size, but not number, which may result in long-term increases in fat cell numbers.

Leptin Signaling in Adipose Tissue: Role in Lipid Accumulation and Weight Gain

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1–dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P =0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain. # Novelty and Significance {#article-title-18}Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1–dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.

Effect of Weight Gain on Cardiac Autonomic Control During Wakefulness and Sleep

Obesity has been associated with increased cardiac sympathetic activation during wakefulness, but the effect on sleep-related sympathetic modulation is not known. The aim of this study was to investigate the effect of fat gain on cardiac autonomic control during wakefulness and sleep in humans. We performed a randomized, controlled study to assess the effects of fat gain on heart rate variability. We recruited 36 healthy volunteers, who were randomized to either a standardized diet to gain ≈4 kg over 8 weeks followed by an 8-week weight loss period (n=20) or to serve as a weight-maintainer control (n=16). An overnight polysomnogram with power spectral analysis of heart rate variability was performed at baseline, after weight gain, and after weight loss to determine the ratio of low-frequency to high-frequency power and to examine the relationship between changes in heart rate variability and changes in insulin, leptin, and adiponectin levels. Mean weight gain was 3.9 kg in the fat gain group versus 0.1 kg in the maintainer group. Low frequency/high frequency increased both during wakefulness and sleep after fat gain and returned to baseline after fat loss in the fat gain group and did not change in the control group. Insulin, leptin, and adiponectin also increased after fat gain and fell after fat loss, but no clear pattern of changes was seen that correlated consistently with changes in heart rate variability. Short-term fat gain in healthy subjects is associated with increased cardiac sympathetic activation during wakefulness and sleep, but the mechanisms remain unclear.

Screening for obstructive sleep apnea in early outpatient cardiac rehabilitation: Feasibility and results

BACKGROUND Obstructive sleep apnea (OSA) has been recognized as a risk factor for cardiovascular disease and mortality. The aim of this study was to determine the feasibility and efficacy of implementing a screening program for OSA in early outpatient cardiac rehabilitation (CR) and to estimate the risk for OSA in this population. METHODS From 535 consecutive patients enrolled in early outpatient CR we screened 383 (72%) patients and classified them as low- vs. high-risk for OSA using the Berlin questionnaire. Those considered at high-risk for OSA were referred for further evaluation. We assessed the yield and feasibility of the screening program, patient compliance with referral, and the percentage of patients diagnosed with OSA after polysomnography. RESULTS Mean age was 63 ± 12 years, 70% were men, 20% had diabetes, 65% had hypertension, and 58% had experienced a recent myocardial infarction. Two hundred and one patients (52%) had a high risk for OSA based on the questionnaire. Of the 169 who completed the CR program, only 111 (78%) were referred for further evaluation (Fig. 1). Of the 74 patients who completed their OSA work-up, 39 were found to have OSA with an apnea-hypopnea index of ≥ 5 events/h. CONCLUSIONS Implementation of a simple screening program for OSA in early outpatient CR is feasible with minimal incremental resources. A significant percentage of patients at high-risk decline further evaluation, suggesting that their perceived risk for OSA and its consequences may be low.

Sleep quality in temporomandibular disorder cases

OBJECTIVE The aim of this study was to characterize self-reported sleep quality (SQ) in cases with temporomandibular disorder (TMD) and to compare their results with those of healthy controls. METHODS The Pittsburgh Sleep Quality Index (PSQI) was used to measure SQ in a convenience sample of 609 TMD cases and 88 controls. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I diagnostic nomenclature was used, but Axis I diagnoses were based on the consensus of two reliable criterion examiners and not the RDC/TMD algorithms. The PSQI scores for TMD cases were calculated also for the RDC/TMD Axis II measures assessing chronic pain and disability, depression, and nonspecific physical symptoms. PSQI scores of the TMD cases were compared with those from controls. RESULTS TMD cases with one to five TMD diagnoses (n = 609) had a mean PSQI score of 7.0 [95% confidence interval (CI) = 6.7-7.4]. In comparison, the mean score was 5.2 (95% CI = 4.6-5.9) for control subjects. For the subset of TMD cases with pain-free diagnoses (n = 113), the PSQI score was similar to controls with 5.1 (95% CI = 4.5-5.6), whereas it was significantly different for cases with pain-related diagnoses 7.5 (95% CI = 6.6-8.3; n = 87). Although the number of TMD diagnoses and participant age had some influence on SQ, psychosocial status, and pain-related impairment assessed with RDC/TMD Axis II measures had the strongest association with SQ, in particular, dysfunctional chronic pain. CONCLUSION SQ is impaired in TMD patients with pain-related diagnoses, and even more in those with dysfunctional pain. This relationship between sleep and pain suggests that SQ should be assessed in TMD pain patients, especially in those with significant Axis II involvement.

Periodic Limb Movements in Complex Sleep Apnea Syndrome

Introduction: The development of repetitive central apneas during application of CPAP in patients initially showing obstructive apneas, a condition called complex sleep apnea syndrome (CompSAS), implies respiratory control instability. Respiratory control is known to be transiently destabilized by arousals. We hypothesized that PLMS and PLM- related arousals would be more frequent in patients with CompSAS compared to those with obstructive sleep apnea (OSA) and could account for some of the respiratory instability. Methodology: Comparative retrospective review of patients studied in our Sleep Disorders Center. Results: 88 patients with CompSAS were compared with 112 patients with OSA. Total arousal index (TAI), respiratory- related arousal index (RRAI), and PLM-related arousal index (PLMAI) were similar during the diagnostic polysomnogra- phy of CompSAS and OSA patients. Following CPAP application, patients with CompSAS had a higher TAI (27.2 (15.5 - 39.9) vs. 16.6 (10.7 - 26.5); p� 0.001; median (interquartile range)), but a lower PLMI (0 (0 - 21.1) vs. 12.6 (0 - 36.2); p=0.009) and PLMAI (0 (0 - 1.3) vs. 0.8 (0 - 4.2); p=0.004) than patients with OSA. Conclusion: PLMS and PLM-related arousals are not more common in CompSAS than in OSA patients and do not appear to play a significant role in destabilizing respiratory control in CompSAS patients.

Comparison of Endothelial Function in Asian Indians Versus Caucasians

BACKGROUND Asian Indians have markedly increased mortality due to coronary artery disease (CAD). Impaired endothelial function has been linked to an increased risk of acute cardiovascular events. We tested the hypothesis that endothelial function was attenuated in Asian Indians and Caucasians. METHODS We studied 14 Asian Indians [mean age: 30 ± 6 years; mean body mass index (BMI): 25 ± 3 kg/m(2)] and 11 Caucasians (mean age: 30 ± 5 years; mean BMI: 26 ± 2 kg/m(2)). All 25 subjects were healthy men and nonsmokers without any history of CAD or diabetes and were not taking medications. Endothelial function was evaluated by ultrasound measures of flow-mediated dilatation (FMD) and endothelium-independent nonflow mediated vasodilatation (NFMD) of the brachial artery, in the morning immediately after awakening (6 a.m.) in a fasting state. RESULTS Mean age, BMI, apnea-hypopnea index, heart rate, and blood pressure were similar in both groups (P = >0.05). When correcting for body surface area, brachial artery diameter was not different between the two groups (2.1% ± 0.3% vs. 2.2% ± 0.4%; P = 0.29). FMD and NFMD were similar in Asian Indians and Caucasians (5.9% ± 4.1% vs. 5.7% ± 2.6%, P = 0.70; 16.4% ± 8% vs. 14.8% ± 4.1%, P = 0.58, respectively). CONCLUSION Endothelial function in Asian Indian men is not attenuated in comparison to Caucasian men.