Jonathan McGavock

Cardiac Steatosis in Diabetes Mellitus A 1H-Magnetic Resonance Spectroscopy Study

Background— The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. Methods and Results— To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45±12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized 1H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. Conclusions— In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

Adiposity of the Heart*, Revisited

The unrelenting obesity epidemic is one likely explanation for the recent adverse secular trends in cardiovascular morbidity and mortality rates in the United States (1, 2). Hospitalizations for congestive heart failure have increased, and the steady decline in coronary heart diseaserelated deaths since the 1950s has leveled off (3). The recent obesity epidemic poses a major threat to human health in the United States because these persons will be predisposed to a burden of major chronic disease (1, 2). Obesity has both metabolic and cardiovascular health consequences; in particular, obese individuals are at much greater risk for type 2 diabetes and cardiovascular disease (3, 4). Obesity is traditionally considered to be an indirect cause of heart disease. Obese persons typically present with several Framingham risk factors, including hypertension, dyslipidemia, and diabetes mellitus. These risk factors predispose the patient to myocardial infarction that, in severe cases, results in ischemic cardiomyopathy (4). In addition to an elevated Framingham risk score, the hemodynamic hallmarks of obesity are increased heart rate and stroke volume (5). This hyperdynamic circulation is thought to be a compensatory adaptation to increased adipose tissue mass at the expense of eccentric left ventricular remodeling. In extreme obesity, this condition can progress to nonischemic dilated cardiomyopathy (2, 6). In contrast to these 2 rather traditional concepts, an emerging body of basic research is revisiting a previous hypothesis (7, 8): that fat is a direct cardiotoxin (9, 10). In 1933, the original autopsy studies of Smith and Willius (8) suggested that fatty degeneration of the heart is a common consequence of obesity and a possible cause of dilated cardiomyopathy in humans. After Alexander and colleagues (11) called this theory into question in the 1960s, the issue lay dormant for the next several decades (9). Now a growing body of evidence is revisiting the hypothesis that excessive deposits of lipids within myocardial tissue (that is, cardiac lipotoxicity) is an important but forgotten cause of nonischemic dilated cardiomyopathy in humans (12, 13). Under healthy conditions, most triglyceride is stored in adipocytes; the amount of triglyceride stored in nonadipocyte tissues (such as the pancreas, liver, and myocardium) is minimal and very tightly regulated. Various genetic rodent models of obesity have shown that cytosolic triglyceride accumulates excessively in these organs (termed steatosis) when this regulation is disrupted. This accumulation has been implicated in activating adverse signaling cascades that culminate in irreversible cell death (termed lipotoxicity) and lead to several well-recognized clinical syndromes (13). These include nonalcoholic hepatic steatosis; pancreatic -cell failure in type 2 diabetes; and most recently, dilated cardiomyopathy (Figure 1). Figure 1. Concept of lipotoxicity. bottom The purposes of this article are to review recent basic animal research that demonstrates direct toxic effects of lipid accumulation on the myocardium and to highlight emerging efforts to translate this work into the clinical setting by using novel cardiac magnetic resonance imaging and spectroscopy technology. The results of this research could provide insight into the pathogenesis of heart disease in obese humans and guide the development of a novel biomarker and drug target for the prevention of heart failure in these persons. Steatosis in Rodents The seminal research that showed a role for steatosis in obesity-related organ dysfunction was performed with the Zucker diabetic fatty rat, which is a genetic model of progressive type 2 diabetes (14-16). In this obese rodent, type 2 diabetes developed secondary to a loss-of-function mutation in tissue receptors for leptin, the adipocyte-derived hormone that regulates appetite and body weight (17). This model of genetic obesity is more extreme than the milder leptin resistance that commonly accompanies dietary obesity in humans (17). Initial studies demonstrated that pancreatic steatosis directly caused islet cell failure and the subsequent hyperglycemia that characterized this model (14-16). Although leptin was generally thought to act centrally to regulate caloric intake and energy expenditure (17), a series of studies provided experimental evidence that leptin also acts directly on the pancreatic islet cells to stimulate fatty acid oxidation, thereby limiting cellular triglyceride accumulation (18). These findings suggested that leptin signaling is also essential in regulating peripheral lipid stores. Furthermore, the investigators described a pathway whereby failure of the leptin receptor led to excessive cytosolic accumulation of triglyceride and its by-product, ceramide, within islet cells. This accumulation activated the inducible form of nitric oxide synthase, which accelerated cell death (apoptosis) and failure of the -cell (14, 15). Interventions that stimulated free-fatty acid oxidation, like restoration of leptin signaling or thiazolidinedione therapy, effectively attenuated triglyceride accumulation in islet cells and prevented the onset of type 2 diabetes (19). These findings provided evidence that steatosis is an integral determinant of -cell failure in the pathogenesis of obesity-associated type 2 diabetes. In addition to pancreatic -cell failure, the Zucker diabetic fatty rat experienced age-related cardiac dysfunction that was characterized by eccentric left ventricular remodeling, increased left ventricular pressure, and decreased systolic performance (9, 20). The abnormalities in cardiac structure and function are accompanied by a 2-fold increase in myocardial triglyceride content and ceramide that is similar to the accumulation seen in islet cells. Myocardial DNA laddering, which is a marker of apoptosis, is also increased (9). Of note, early administration of thiazolidinedione therapy is effective in attenuating myocardial triglyceride accumulation and normalizing left ventricular contractile performance (9, 20), as shown in Figure 2. Because reduced myocardial lipid content and improved cardiac structure and function were observed independent of changes in body weight, they strongly suggest a role for myocardial steatosis in obesity-related cardiomyopathy. Figure 2. Myocardial lipotoxicity in the Zucker diabetic fatty rat. Top panel. white bars light gray bars dark gray bars Bottom panel. The extreme obesity in the Zucker rat model makes it difficult to determine whether the cardiac maladaptations are related to excessive myocardial lipid accumulation or to increased expression of conventional risk factors for cardiovascular disease. To address this limitation, various lean genetic mouse models of cardiac-restricted steatosis have recently been developed (10, 21-29). These animals display diffuse myocardial lipid content in the absence of obesity or any other traditional cardiovascular risk factors, thereby allowing researchers to study the acute effects of myocardial steatosis on left ventricular structure and function. Overexpression of long-chain acyl-CoA synthetase, a key enzyme involved in triglyceride synthesis, produces an example of cardiac-restricted steatosis. Increased protein expression of acyl-CoA synthetase in the myocardium disrupts the balance between lipid import and export in the myocardium (Figure 3), which results in diffuse lipid accumulation and a greater than 2-fold increase in heart mass (10). The severe myocardial steatosis that is observed in this animal is associated with substantial left ventricular hypertrophy by 4 weeks of age that coincides with left ventricular dilatation and eventually progresses to heart failure. Of importance, the changes in cardiac lipid content, structure, and function develop without any change in lipid profile or body weight of the animal. This pattern of steatosis-induced heart failure has been reproduced by targeted overexpression of genes that are involved in lipid delivery (24, 26) and synthesis (10, 25) and by targeted deletion of genes that are involved in lipoprotein secretion (21) from the myocardium. Taken together, these data demonstrate that cardiac-specific steatosis, independent of systemic obesity, is a direct cause of dilated cardiomyopathy. Figure 3. Myocardial-specific lipotoxicity. Top panel. Middle panel. gray bars white bars Bottom panel. The development of cardiac-restricted transgenic murine models have also shown the therapeutic potential of several countermeasures, including adenoviral administration of leptin (Figure 3) and apolipoprotein B (26, 28), dietary replacement of long-chain triglycerides with medium-chain triglycerides (22), and blockade of production of reactive oxygen species (29). Each of these interventions has effectively ameliorated the myocardial steatosis in these mouse models and has rescued the myocardium from progression to dilated cardiomyopathy. These data reinforce the observations in the Zucker diabetic fatty rat that lipid accumulation is toxic in the myocardium. It is important to note that current thinking suggests that the cardiomyopathy is not a direct consequence of triglyceride accumulation alone, but that cardiomyopathy develops secondary to an accumulation of by-products of lipid metabolism, such as ceramide or other fatty acid derivatives that are known to interfere with intracellular signaling pathways (9, 30). This research provides convincing evidence for an acute role of steatosis in the development of left ventricular hypertrophy and dysfunction in animal models of obesity; until recently, however, few data from human research were available to support this theory. Quantification of Lipids in Human Tissues To study the role of steatosis in the clinical setting, we and others have developed a magnetic resonance imaging and spectroscopy technique that permits the precise and reproducible quantification of intracellular trig

Blood Volume Expansion and Cardiorespiratory Function: Effects of Training Modality

PURPOSE To evaluate the effects of different modalities of aerobic (i.e., interval (INT) and continuous (CONT)) training on cardiorespiratory function and the importance of training-induced blood volume (BV) expansion on aerobic power and LV function. We hypothesized that if modality-mediated differences in cardiorespiratory function exist after INT and CONT, they would be related directly to differences in training-induced hypervolemia. METHODS We examined the effects of 12 wk of CONT and INT on BV, volume-regulatory hormones (angiotensin II, aldosterone, atrial natriuretic peptide), and cardiorespiratory function in 20 untrained males (mean age 30 +/- 4 (SD)). Participants were stratified (mass and VO2max) and randomly assigned to control, CONT, or INT. RESULTS There were no significant changes in cardiorespiratory function or BV in the control group. Twelve weeks of continuous and interval training, respectively, resulted in significant changes in VO2max (23 +/- 18 vs 21 +/- 10%), peak stroke volume (20 +/- 18 vs 11 +/- 18%), and BV (12 +/- 9 vs 10 +/- 6%). Changes in VO2max were directly related to changes in BV (r = 0.47). Angiotensin II significantly increased after 1 wk of CONT and INT and thereafter returned to baseline values. There was no significant difference between the CONT and INT groups with regard to changes in vascular volumes, volume-regulatory hormones, and/or cardiorespiratory function. CONCLUSIONS These data indicate that: 1) 12 wk of CONT and INT result in similar improvements in VO2max, and LV function and 2) training-induced hypervolemia accounts for approximately 47% of the changes in VO2max after CONT and INT.

Vigorous physical activity and longitudinal associations with cardiometabolic risk factors in youth.

Objective:To examine the longitudinal associations between different physical activity (PA) intensities and cardiometabolic risk factors among a sample of Canadian youth.Methods:The findings are based on a 2-year prospective cohort study in a convenience sample of 315 youth aged 9–15 years at baseline from rural and urban schools in Alberta, Canada. Different intensities (light, moderate and vigorous) of PA were objectively assessed with Actical accelerometers. The main outcome measures were body mass index (BMI) z-score, waist circumference, cardiorespiratory fitness and systolic blood pressure at 2-year-follow-up and conditional BMI z-score velocity. A series of linear regression models were conducted to investigate the associations after adjusting for potential confounders.Results:At follow-up, cardiorespiratory fitness increased (quartile 1 vs quartile 4=43.3 vs 50.2; Ptrend<0.01) and waist circumference decreased (quartile 1 vs quartile 4=79.0 vs 72.6; Ptrend=0.04; boys only) in a dose-response manner across quartiles of baseline vigorous-intensity PA. A similar trend was observed for systolic blood pressure (quartile 1 vs quartile 4=121.8 vs 115.3; Ptrend=0.07; boys only). Compared with quartile 1 of vigorous-intensity PA, BMI z-score at follow-up and conditional BMI z-score velocity were significantly lower in the quartile 2 and 3 (P<0.05). Waist circumference at follow-up also decreased (quartile 1 vs quartile 4=75.3 vs 73.8; Ptrend=0.04) across quartiles of baseline moderate-intensity PA.Conclusions:Time spent in vigorous-intensity PA was associated with several positive health outcomes 2 years later. These findings suggest that high-intensity activities in youth help to reduce the risk for several chronic diseases.

Physical activity intensity and cardiometabolic risk in youth.

OBJECTIVE To determine the association between physical activity (PA) intensities and cardiometabolic risk factors in youth. DESIGN Cross-sectional study using data from the 2008 Healthy Hearts Prospective Cohort Study of Physical Activity and Cardiometabolic Health in Youth. SETTING Rural and urban communities in Alberta, Canada. PARTICIPANTS A convenience sample of 605 youth aged 9 to 17 years. Youth were on average aged 12.1 years, 248 were boys (41%), and 157 were overweight or obese (26%). MAIN EXPOSURE Actical accelerometer-measured PA intensity. MAIN OUTCOMES MEASURES The primary outcome was body mass index (calculated as weight in kilograms divided by height in meters squared) z score. Secondary outcome measures included waist circumference, systolic blood pressure, and cardiorespiratory fitness (maximal oxygen consumption [[Vdot]O2max]). RESULTS Body mass index z score, waist circumference, and systolic blood pressure decreased and [Vdot]O2max increased in a dose-response manner across tertiles of vigorous PA (adjusted P < .001). No significant differences in cardiometabolic risk factors were seen across tertiles of moderate or light PA in multivariable analyses. Achieving more than 7 minutes of vigorous PA daily was associated with a reduced adjusted odds ratio of overweight status (0.56; 95% CI, 0.33-0.95) and elevated systolic blood pressure (0.36; 95% CI, 0.16-0.79). The odds of overweight status and elevated blood pressure decreased with increasing time and intensity of PA. CONCLUSIONS Only vigorous PA was consistently associated with lower levels of waist circumference, body mass index z score, systolic blood pressure, and increased cardiorespiratory fitness in youth. These findings underscore the importance of vigorous PA in guidelines for children and adolescents.

Arterial compliance in young children: the role of aerobic fitness:

Background Reduced arterial compliance is reflective of vascular dysfunction, which promotes the atherosclerotic process, and is therefore an important predictor of vascular disease. In adults, obesity, age, aerobic fitness, oestrogens and race influence arterial compliance. Although stature and blood pressure are known to influence compliance in children, other determinants are less established. This investigation sought to determine the predictors of arterial compliance in children, assess the extent to which aerobic fitness is related to compliance, and compare compliance between girls and boys. Methods Participants (99 children aged 9-11 years, 55 boys) were assessed for aerobic fitness, physical activity level, blood pressure, body mass, percentage fat mass, height, maturity and arterial compliance (large and small). Predictors of compliance were determined using stepwise regression. Second, children were divided into quartiles according to fitness, and arterial compliance was compared using analysis of covariance (ANCOVA). Finally, differences in compliance between girls and boys were assessed using ANCOVA. Results We found that fitness, blood pressure and height accounted for 37% of the variance in large artery compliance. Mass, fitness, maturity and blood pressure accounted for 44% of the variance in small artery compliance. Children in the highest fitness quartile had greater compliance than children in the two lowest quartiles, by as much as 34%. There were no differences in compliance between girls and boys after adjusting for covariates. Discussion These data show that aerobic fitness is associated with arterial compliance in 9-11-year-old children, supporting the concept that physical fitness may exert a protective effect on the cardiovascular system.

Effect of Pioglitazone Therapy on Myocardial and Hepatic Steatosis in Insulin-Treated Patients with Type 2 Diabetes

High levels of myocardial and hepatic triglyceride are common in obesity and type 2 diabetes. Monotherapy with thiazolidinedione agents reduces hepatic steatosis by up to 50% in patients with type 2 diabetes. It is not known if treatment with a thiazolidinedione added to insulin has a similar beneficial antisteatotic effect. The aim of our study was to determine whether the addition of pioglitazone to insulin treatment in patients with type 2 diabetes has antisteatotic action in the heart and the liver. Thirty-two patients were randomized to 6 months of treatment with insulin or insulin plus pioglitazone. In addition to blood tests, we evaluated myocardial and hepatic triglyceride content, as well as subcutaneous and visceral fat mass at the L2 level, by magnetic resonance spectroscopy and imaging, respectively. Despite weight and subcutaneous fat mass gain, hemoglobin A1c was significantly reduced by both treatments. Myocardial and hepatic triglyceride contents were reduced by the treatment with pioglitazone plus insulin (p = .02 and .03, respectively) but not by the treatment with insulin. Systolic and diastolic blood pressure and heart function remained unchanged in both groups. The addition of pioglitazone to insulin therapy reduced myocardial and hepatic steatosis, consistent with the reported ability of the thiazolidinedione agents to redistribute fat from nonadipose to subcutaneous adipose depots.

Cardiorespiratory fitness and the risk of overweight in youth: the Healthy Hearts Longitudinal Study of Cardiometabolic Health.

The primary objective of this longitudinal study was to determine the association between cardiorespiratory fitness and the risk of overweight status in youth. To accomplish this aim we analyzed data from annual school‐based surveys of cardiorespiratory fitness and anthropometry conducted between 2004 and 2006. The first analysis was performed on a cohort of 902 youth aged 6–15 years followed for 12 months to assess the association between cardiorespiratory fitness levels determined from a graded maximal field test and the risk of becoming overweight. The second analysis was conducted on a cohort of 222 youth followed for 2 years to assess the continuous association between annual changes fitness and weight gain. Children with low cardiorespiratory fitness were characterized by higher waist circumference and disproportionate weight gain over the 12‐month follow‐up period (P < 0.05). Within the entire cohort, the 12‐month risk of overweight classification was 3.5‐fold (95% confidence = 2.0–6.0, P < 0.001) higher in youth with low cardiorespiratory fitness, relative to fit peers. A time series mixed effects regression model revealed that reductions in cardiorespiratory fitness were significantly and independently associated with increasing BMI (r = −0.18, P < 0.05) in youth. Accordingly, low cardiorespiratory fitness and reductions in fitness over time are significantly associated with weight gain and the risk of overweight in children 6–15 years old. An assessment of cardiorespiratory fitness using a common field test may prove useful for the identification of youth at risk of overweight and serve as a potential target for obesity prevention.

Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus: focus on cardiovascular complications

With the growing prevalence of childhood obesity and type 2 diabetes mellitus (T2DM) in youth, the challenge of cardiovascular disease risk management has entered the paediatric realm, affecting specialists, family physicians and allied healthcare professionals alike. Currently, there is little evidence to support optimal strategies for management of T2DM in youth and the associated cardiovascular complications. Physical activity plays a powerful role in the prevention and management of T2DM and cardiovascular disease in adults. This review will focus on the role of physical activity for the prevention of T2DM in youth and its associated cardiovascular complications. The first part describes the prevalence of cardiovascular risk factors in this cohort. The second part focuses on the role of physical activity in the prevention and management of T2DM in youth. Collectively, the limited intervention and observation studies published to date suggest that daily targets of 60–90 minutes of physical activity and less than 60 minutes of screen time (i.e. time spent in front of a television, computer or video games) are required for the prevention and management of T2DM in youth. Large-scale intervention studies are needed to determine the most effective physical activity strategies for the prevention and management of T2DM in youth.

Metabolic Consequences of Hepatic Steatosis in Overweight and Obese Adolescents

OBJECTIVE To test the hypothesis that hepatic steatosis is associated with risk factors for type 2 diabetes in overweight and obese youth, mediated by cardiorespiratory fitness. RESEARCH DESIGN AND METHODS This was a cross-sectional study comparing insulin sensitivity between 30 overweight and obese adolescents with hepatic steatosis, 68 overweight and obese adolescents without hepatic steatosis, and 11 healthy weight adolescents without hepatic steatosis. Cardiorespiratory fitness was determined by a graded maximal exercise test on a cycle ergometer. Secondary outcomes included presence of metabolic syndrome and glucose response to a 75-g oral glucose challenge. RESULTS The presence of hepatic steatosis was associated with 55% lower insulin sensitivity (P = 0.02) and a twofold greater prevalence of metabolic syndrome (P = 0.001). Differences in insulin sensitivity (3.5 vs. 4.5 mU ⋅ kg−1 ⋅ min−1, P = 0.03), prevalence of metabolic syndrome (48 vs. 20%, P = 0.03), and glucose area under the curve (816 vs. 710, P = 0.04) remained between groups after matching for age, sex, and visceral fat. The association between hepatic steatosis and insulin sensitivity (β = −0.24, t = −2.29, P < 0.025), metabolic syndrome (β = −0.54, t = −5.8, P < 0.001), and glucose area under the curve (β = 0.33, t = 3.3, P < 0.001) was independent of visceral and whole-body adiposity. Cardiorespiratory fitness was not associated with hepatic steatosis, insulin sensitivity, or presence of metabolic syndrome. CONCLUSIONS Hepatic steatosis is associated with type 2 diabetes risk factors independent of cardiorespiratory fitness, whole-body adiposity, and visceral fat mass.