Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia

Secular trends in echocardiographic left ventricular mass in the community: the Framingham Heart Study

Objective: To investigate secular trends in echocardiographically determined left ventricular mass (LVM). Design, setting and participants: Longitudinal community-based cohort study in Framingham, Massachussetts. LVM was calculated from routine echocardiography in 4320 participants (52% women) of the Framingham offspring cohort at examination cycles 4 (1987–1991), 5 (1991–1995), 6 (1995–1998) and 8 (2005–2008), totalling 13 971 person-observations. Main outcome measures: Sex-specific trends in mean LVM (and its components, LV diastolic diameter (LVDD) and LV wall thickness (LVWT)), and LVM indexed to body surface area (BSA). Results: In men, age-adjusted LVM modestly increased from examination 4 to 8 (192 g to 198 g, p-trend=0.0005), whereas, in women it decreased from 147 g at examination 4 to 140 g at examination 8 (p-trend<0.0001). The trend for increasing LVM in men tracked with an increasing LVDD (p-trend=0.0002), whereas the decline in LVM in women was accompanied by a decrease in LVWT (p-trend<0.0001). Indexing LVM to BSA abolished the increasing trend in men (p-trend=0.49), whereas, the decreasing trend in women was maintained. Conclusions: In our longitudinal analysis of a large community-based sample spanning two decades, we observed sex-related differences in trends in LVM, with a modest increase of LVM in men (likely attributable to increasing body size), but a decrease in women. Additional studies are warranted to elucidate the basis for these sex-related differences

Successful up-scaled population interventions to reduce risk factors for non-communicable disease in adults: Results from the International Community Interventions for Health (CIH) project in China, India and Mexico

Background: Non-communicable disease (NCD) is increasing rapidly in low and middle-income countries (LMIC), and is associated with tobacco use, unhealthy diet and physical inactivity. There is little evidence for up-scaled interventions at the population level to reduce risk in LMIC. Methods: The Community Interventions for Health (CIH) program was a population-scale community intervention study with comparator population group undertaken in communities in China, India, and Mexico, each with populations between 150,000-250,000. Culturally appropriate interventions were delivered over 18-24 months. Two independent cross-sectional surveys of a stratified sample of adults aged 18-64 years were conducted at baseline and follow-up. Results: A total of 6,194 adults completed surveys at baseline, and 6,022 at follow-up. The proportion meeting physical activity recommendations decreased significantly in the control group (C) (44.1 to 30.2%), but not in the intervention group (I) (38.0 to 36.1%), p<0.001. Those eating ≥5 portions of fruit and vegetables daily decreased significantly in C (19.2 to 17.2%), but did not change in I (20.0 to 19.6%,), p=0.013. The proportion adding salt to food was unchanged in C (24.9 to 25.3%) and decreased in I (25.9 to 19.6%), p<0.001. Prevalence of obesity increased in C (8.3 to 11.2%), with no change in I (8.6 to 9.7%,) p=0.092. Concerning tobacco, for men the difference-in-difference analysis showed that the reduction in use was significantly greater in I compared to C (p=0.014) Conclusions: Up-scaling known health promoting interventions designed to reduce the incidence of NCD in whole communities in LMIC is feasible, and has measurable beneficial outcomes on risk factors for NCD, namely tobacco use, diet, and physical inactivity

The obesity paradox in men with coronary heart disease and heart failure: the role of muscle mass and leptin.

AIMS: We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox. BACKGROUND: The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF). METHODS: Prospective study of 4046 men aged 60-79 years followed up for a mean period of 11 years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF. RESULTS: Overweight (BMI 25-9.9 kg/m(2)) and obesity (BMI ≥ 30 kg/m(2)) were associated with lower mortality risk compared to men with normal weight (BMI 18.5-24.9 kg/m(2)) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p=0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p=0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p=0.60 for trend) but made minor differences to those with HF [p=0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p=0.98 for trend]. CONCLUSION: The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse associatio

Immigrant status and increased risk of heart failure: the role of hypertension and life-style risk factors

<p>Abstract</p> <p>Background</p> <p>Studies from Sweden have reported association between immigrant status and incidence of cardiovascular diseases. The nature of this relationship is unclear. We investigated the relationship between immigrant status and risk of heart failure (HF) hospitalization in a population-based cohort, and to what extent this is mediated by hypertension and life-style risk factors. We also explored whether immigrant status was related to case-fatality after HF.</p> <p>Methods</p> <p>26,559 subjects without history of myocardial infarction (MI), stroke or HF from the community-based Malmö Diet and Cancer (MDC) cohort underwent a baseline examination during 1991-1996. Incidence of HF hospitalizations was monitored during a mean follow-up of 15 years.</p> <p>Results</p> <p>3,129 (11.8%) subjects were born outside Sweden. During follow-up, 764 subjects were hospitalized with HF as primary diagnosis, of whom 166 had an MI before or concurrent with the HF. After adjustment for potential confounding factors, the hazard ratios (HR) for foreign-born were 1.37 (95% CI: 1.08-1.73, <it>p </it>= 0.009) compared to native Swedes, for HF without previous MI. The results were similar in a secondary analysis without censoring at incident MI. There was a significant interaction (<it>p </it>< 0.001) between immigrant status and waist circumference (WC), and the increased HF risk was limited to immigrants with high WC. Although not significant foreign-born tended to have lower one-month and one-year mortality after HF.</p> <p>Conclusions</p> <p>Immigrant status was associated with long-term risk of HF hospitalization, independently of hypertension and several life-style risk factors. A significant interaction between WC and immigrant status on incident HF was observed.</p

Body surface area and baseline blood pressure predict subclinical anthracycline cardiotoxicity in women treated for early breast cancer.

BACKGROUND AND AIMS: Anthracyclines are highly effective chemotherapeutic agents which may cause long-term cardiac damage (chronic anthracycline cardiotoxicity) and heart failure. The pathogenesis of anthracycline cardiotoxicity remains incompletely understood and individual susceptibility difficult to predict. We sought clinical features which might contribute to improved risk assessment. METHODS: Subjects were women with early breast cancer, free of pre-existing cardiac disease. Left ventricular ejection fraction was measured using cardiovascular magnetic resonance before and >12 months after anthracycline-based chemotherapy (>3 months post-Trastuzumab). Variables associated with subclinical cardiotoxicity (defined as a fall in left ventricular ejection fraction of ≥5%) were identified by logistic regression. RESULTS: One hundred and sixty-five women (mean age 48.3 years at enrollment) completed the study 21.7 months [IQR 18.0-26.8] after starting chemotherapy. All received anthracyclines (98.8% epirubicin, cumulative dose 400 [300-450] mg/m2); 18% Trastuzumab. Baseline blood pressure was elevated (≥140/90mmHg, mean 147.3/86.1mmHg) in 18 subjects. Thirty-four subjects (20.7%) were identified with subclinical cardiotoxicity, independent predictors of which were the number of anthracycline cycles (odds ratio, OR 1.64 [1.17-2.30] per cycle), blood pressure ≥140/90mmHg (OR 5.36 [1.73-17.61]), body surface area (OR 2.08 [1.36-3.20] per standard deviation (0.16m2) increase), and Trastuzumab therapy (OR 3.35 [1.18-9.51]). The resultant predictive-model had an area under the receiver operating characteristics curve of 0.78 [0.70-0.86]. CONCLUSIONS: We found subclinical cardiotoxicity to be common even within this low risk cohort. Risk of cardiotoxicity was associated with modestly elevated baseline blood pressure-indicating that close attention should be paid to blood pressure in patients considered for anthracycline based chemotherapy. The association with higher body surface area suggests that indexing of anthracycline doses to surface area may not be appropriate for all, and points to the need for additional research in this area

A mathematical model for the burden of diabetes and its complications

BACKGROUND: The incidence and prevalence of diabetes are increasing all over the world. Complications of diabetes constitute a burden for the individuals and the whole society. METHODS: In the present paper, ordinary differential equations and numerical approximations are used to monitor the size of populations of diabetes with and without complications. RESULTS: Different scenarios are discussed according to a set of parameters and the dynamical evolution of the population from the stage of diabetes to the stage of diabetes with complications is clearly illustrated. CONCLUSIONS: The model shows how efficient and cost-effective strategies can be obtained by acting on diabetes incidence and/or controlling the evolution to the stage of complications

The PPARGC1A Gly482Ser polymorphism is associated with left ventricular diastolic dysfunction in men

<p>Abstract</p> <p>Background</p> <p>The Gly482Ser polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 alpha (<it>PPARGC1A</it>) has been demonstrated to be associated with diabetes, obesity and hypertension, all of which are important risk factors for left ventricular diastolic dysfunction.</p> <p>Methods</p> <p>The <it>PPARGC1A </it>Gly482Ser polymorphism was genotyped in a community-based cohort of 499 men and 533 women, who also underwent an echocardiographic examination to determine their left ventricular diastolic function. The association between the polymorphism and the presence of diastolic dysfunction was evaluated using logistic regression models.</p> <p>Results</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was significantly associated with a lower risk of diastolic dysfunction in men, but not in women. In a model adjusting for potential confounders (age, body mass index, leisure time physical activity, hypertension and diabetes) the results were still significant and substantial (odds ratio 0.13, 95% confidence interval 0.03–0.54, p for trend = 0.004). The results were consistent in a series of models, and they imply a multiplicative, protective effect of the Ser allele, with lower risk of diastolic dysfunction for each copy of the allele.</p> <p>Conclusion</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was associated with decreased risk of diastolic left ventricular dysfunction in men, but not in women, in our large community-based sample. It was associated with a substantially decreased risk, even after adjustment for potential confounders. The clinical importance of the findings has to be established in further studies.</p