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Objective
To investigate the biological mechanism of the effect of different intensity exercises on diabetic cardiomyopathy.
Methods
87 raise specific pathogen SPF healthy 6-week-old male Sprague–Dawley rats, fed 6 weeks with high-fat diet for rats were used, and a diabetic model was established by intraperitoneal injection of streptozotocin – randomly selected 43 rats were divided into Diabetic control group (DCG, n = 10), Diabetic exercise group 1 (DEG1, n = 11), Diabetic exercise group 2 (DEG2, n = 11) and Diabetic exercise group 3 (DEG3, n = 11). The rats in DEG1 were forced to run on a motorized treadmill, the exercise load consisted of running at a speed of 10 m/min, the exercise load of the rats in DEG2 were running at a speed of 15 m/min, the exercise load of the rats in DEG3 were running at a speed of 20 m/min, for one hour once a day for 6 weeks. After 6 weeks of exercise intervention, glucose metabolism-related indexes in rats such as blood glucose (FBG), glycosylated serum protein (GSP) and insulin (FINS); cardiac fibrinolytic system parameters such as PAI-1 (plasminogen activator inhibitor 1), Von Willebrand factor (vWF), protein kinase C (PKC) and diacylglycerol (DAG); and serum level of NO, eNOS and T-NOS were measured.
Result
Compared with DCG, fasting blood glucose and GSP were decreased, while insulin sensitivity index and insulin level were increased in all rats of the three exercise groups. FBG decrease was statistically significant (P < 0.01), only GSP decrease was statistically significant (P < 0.05) in DEG1 and DEG2, PAI-1 in three exercise groups were significantly reduced (P < 0.05), plasma vWF levels in the three exercise groups were significantly lower than those in the DCG group (P < 0.01); PKC levels decreased dramatically in the three exercise groups and DAG levels decrease slightly (P < 0.05), but with no significant difference. Compared with DCG, the serum level of NO was significantly higher (P < 0.05), and eNOS level was significantly elevated (P < 0.05). T-NOS elevation was statistically significant in DEG1 (P < 0.05).
Conclusions
Low- and moderate-intensity exercise can better control blood glucose level in diabetic rats; myocardial PAI-1 in DEG1, DEG2 and DEG3 rats decreased significantly (P < 0.05), serum NO increased (P < 0.05) and eNOS increased (P < 0.05) significantly. Therefore, it is inferred that exercise improves the biological mechanism of diabetic cardiomyopathy by affecting the levels of PAI-1 and eNOS, and there is a dependence on intensity.
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Steno Diabetes Centre Odense, Odense University Hospital, Odense, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus, Denmark
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Objective
Physiologically, pregnancy-associated plasma protein-A (PAPP-A) serves to liberate bound IGF1 by enzymatic cleavage of IGF-binding proteins (IGFBPs), IGFBP4 in particular. Clinically, PAPP-A has been linked to cardiovascular disease (CVD). Stanniocalcin-2 (STC2) is a natural inhibitor of PAPP-A enzymatic activity, but its association with CVD is unsettled. Therefore, we examined associations between the STC2–PAPP-A–IGFBP4–IGF1 axis and all-cause mortality and CVD in patients with type 2 diabetes (T2D).
Design
We followed 1284 participants with T2D from the ADDITION trial for 5 years.
Methods
Circulating concentrations of STC2, PAPP-A, total and intact IGFBP4 and IGF1 and -2 were measured at inclusion. End-points were all-cause mortality and a composite CVD event: death from CVD, myocardial infarction, stroke, revascularisation or amputation. Survival analysis was performed by Cox proportional hazards model.
Results
During follow-up, 179 subjects presented with an event. After multivariable adjustment, higher levels of STC2, PAPP-A, as well as intact and total IGFBP4, were associated with all-cause mortality; STC2: hazard ratio (HR) = 1.84 (1.09–3.12) (95% CI); P = 0.023, PAPP-A: HR = 2.81 (1.98–3.98); P < 0.001, intact IGFBP4: HR = 1.43 (1.11–1.85); P = 0.006 and total IGFBP4: HR = 3.06 (1.91–4.91); P < 0.001. Higher PAPP-A levels were also associated with CVD events: HR = 1.74 (1.16–2.62); P = 0.008, whereas lower IGF1 levels were associated with all-cause mortality: HR = 0.51 (0.34–0.76); P = 0.001.
Conclusions
This study supports that PAPP-A promotes CVD and increases mortality. However, STC2 is also associated with mortality. Given that STC2 inhibits the enzymatic effects of PAPP-A, we speculate that STC2 either serves to counteract harmful PAPP-A actions or possesses effects independently of the PAPP-A–IGF1 axis.
Significance statement
PAPP-A has pro-atherosclerotic effects and exerts these most likely through IGF1. IGF1 is regulated by the STC2–PAPP-A–IGFBP4–IGF1 axis, where STC2, an irreversible inhibitor of PAPP-A, has been shown to reduce the development of atherosclerotic lesions in mice. We examined the association of this axis to mortality and CVD in T2D. We demonstrated an association between PAPP-A and CVD. All components of the STC2–PAPP-A–IGFBP4–IGF1 axis were associated with mortality and it is novel that STC2 was associated with mortality in T2D. Our study supports that inhibition of PAPP-A may be a new approach to reducing mortality and CVD. Whether modification of STC2 could serve as potential intervention warrants further investigation.
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The concept of the heart as an endocrine organ arises from the observation that the atrial cardiomyocytes in the mammalian heart display a phenotype that is partly that of endocrine cells. Investigations carried out between 1971 and 1983 characterised, by virtue of its natriuretic properties, a polypeptide referred to atrial natriuretic factor (ANF). Another polypeptide isolated from brain in 1988, brain natriuretic peptide (BNP), was subsequently characterised as a second hormone produced by the mammalian heart atria. These peptides were associated with the maintenance of extracellular fluid volume and blood pressure. Later work demonstrated a plethora of other properties for ANF and BNP, now designated cardiac natriuretic peptides (cNPs). In addition to the cNPs, other polypeptide hormones are expressed in the heart that likely act upon the myocardium in a paracrine or autocrine fashion. These include the C-type natriuretic peptide, adrenomedullin, proadrenomedullin N-terminal peptide and endothelin-1. Expression and secretion of ANF and BNP are increased in various cardiovascular pathologies and their levels in blood are used in the diagnosis and prognosis of cardiovascular disease. In addition, therapeutic uses for these peptides or related substances have been found. In all, the discovery of the endocrine heart provided a shift from the classical functional paradigm of the heart that regarded this organ solely as a blood pump to one that regards this organ as self-regulating its workload humorally and that also influences the function of several other organs that control cardiovascular function.
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Objective
Real-world-based population data about the optimal low-density lipoprotein cholesterol (LDL-C) level for preventing cardiovascular disease in very high-risk populations is scarce.
Methods
From 2009 to 2012, 26,922 people aged ≥ 40 years with type 2 diabetes mellitus (T2DM) who had a history of percutaneous coronary intervention (PCI) were analyzed. Data from the Korean National Health Insurance System were used. They were followed up to the date of a cardiovascular event or the time to death, or until December 31, 2018. Endpoints were recurrent PCI, newly stroke or heart failure, cardiovascular death, and all-cause death. Participants were divided into the following categories according to LDL-C level: <55 mg/dL, 55–69 mg/dL, 70–99 mg/dL, 100–129 mg/dL, 130–159 mg/dL, and ≥ 160 mg/dL.
Results
Compared to LDL-C < 55 mg/dL, the hazard ratios (HR) for re-PCI and stroke increased linearly with increasing LDL-C level in the population < 65 years. However, in ≥ 65 years old, HRs for re-PCI and stroke in LDL-C = 55–69 mg/dL were 0.97 (95% CI: 0.85–1.11) and 0.96 (95% CI: 0.79–2.23), respectively. The optimal range with the lowest HR for heart failure and all-cause mortality were LDL-C = 70–99 mg/dL and LDL-C = 55–69 mg/dL, respectively, in all age groups (HR: 0.99, 95% CI: 0.91–1.08 and HR: 0.91, 95% CI: 0.81–1.01).
Conclusion
LDL-C level below 55 mg/dL appears to be optimal in T2DM patients with established cardiovascular disease aged < 65 years, while an LDL-C level of 55–69 mg/dL may be optimal for preventing recurrent PCI and stroke in patients over 65 years old.
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Department of Internal Medicine, Section of Metabolic Vascular Medicine, Division of Diabetes and Nutritional Sciences, Cardiovascular Endocrinology Laboratory, Faculty of Medicine, Hospital de Urgencias, National University of Córdoba, X5000 Córdoba, Argentina
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Since their discovery in 1981, the cardiac natriuretic peptides (cNP) atrial natriuretic peptide (also referred to as atrial natriuretic factor) and brain natriuretic peptide have been well characterised in terms of their renal and cardiovascular actions. In addition, it has been shown that cNP plasma levels are strong predictors of cardiovascular events and mortality in populations with no apparent heart disease as well as in patients with established cardiac pathology. cNP secretion from the heart is increased by humoral and mechanical stimuli. The clinical significance of cNP plasma levels has been shown to differ in obese and non-obese subjects. Recent lines of evidence suggest important metabolic effects of the cNP system, which has been shown to activate lipolysis, enhance lipid oxidation and mitochondrial respiration. Clinically, these properties lead to browning of white adipose tissue and to increased muscular oxidative capacity. In human association studies in patients without heart disease higher cNP concentrations were observed in lean, insulin-sensitive subjects. Highly elevated cNP levels are generally observed in patients with systolic heart failure or high blood pressure, while obese and type-2 diabetics display reduced cNP levels. Together, these observations suggest that the cNP system plays a role in the pathophysiology of metabolic vascular disease. Understanding this role should help define novel principles in the treatment of cardiometabolic disease.
Section of Pacing and Electrophysiology, Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Dalian Medical University, Dalian, Liaoning, China
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Dalian Medical University, Dalian, Liaoning, China
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Objective
Post-treatment contrast-induced acute kidney injury (CI-AKI) is associated with poor outcomes in patients with acute myocardial infarction (AMI). A lower free triiodothyronine (FT3) level predicts a poor prognosis of AMI patients. This study evaluated the effect of plasma FT3 level in predicting CI-AKI and short-term survival among AMI patients.
Methods
Coronary arteriography or percutaneous coronary intervention was performed in patients with AMI. A 1:3 propensity score (PS) was used to match patients in the CI-AKI group and the non-CI-AKI group.
Results
Of 1480 patients enrolled in the study, 224 (15.1%) patients developed CI-AKI. The FT3 level was lower in CI-AKI patients than in non-CI-AKI patients (3.72 ± 0.88 pmol/L vs 4.01 ± 0.80 pmol/L, P < 0.001). Compared with those at the lowest quartile of FT3, the patients at quartiles 2–4 had a higher risk of CI-AKI respectively (P for trend = 0.005). The risk of CI-AKI increased by 17.7% as FT3 level decreased by one unit after PS-matching analysis (odds ratio: 0.823; 95% CI: 0.685–0.988, P = 0.036). After a median of 31 days of follow-up (interquartile range: 30–35 days), 78 patients died, including 72 cardiogenic deaths and 6 non-cardiogenic deaths, with more deaths in the CI-AKI group than in the non-CI-AKI group (53 vs 25, P < 0.001). Kaplan–Meier survival analysis showed that patients at a lower FT3 quartile achieved a worse survival before and after matching.
Conclusion
Lower FT3 may increase the risk of CI-AKI and 1-month mortality in AMI patients.
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Thyroid hormone stimulates cardiac inotropy and chronotropy via direct genomic and non-genomic mechanisms. Hyperthyroidism magnifies these effects, resulting in an increase in heart rate, ejection fraction and blood volume. Hyperthyroidism also affects thrombogenesis and this may be linked to a probable tendency toward thrombosis in patients with hyperthyroidism. Patients with hyperthyroidism are therefore at higher risk for atrial fibrillation, heart failure and cardiovascular mortality. Similarly, TSH suppressive therapy for differentiated thyroid cancer is associated with increased cardiovascular risk. In this review, we present the latest insights on the cardiac effects of thyroid suppression therapy for the treatment of thyroid cancer. Finally, we will show new clinical data on how to implement this knowledge into the clinical practice of preventive medicine.
Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
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Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
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Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA
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Research conducted across phylogeny on cardiac regenerative responses following heart injury implicates endocrine signaling as a pivotal regulator of both cardiomyocyte proliferation and heart regeneration. Three prominently studied endocrine factors are thyroid hormone, vitamin D, and glucocorticoids, which canonically regulate gene expression through their respective nuclear receptors thyroid hormone receptor, vitamin D receptor, and glucocorticoid receptor. The main animal model systems of interest include humans, mice, and zebrafish, which vary in cardiac regenerative responses possibly due to the differential onsets and intensities of endocrine signaling levels throughout their embryonic to postnatal organismal development. Zebrafish and lower vertebrates tend to retain robust cardiac regenerative capacity into adulthood while mice and other higher vertebrates experience greatly diminished cardiac regenerative potential in their initial postnatal period that is sustained throughout adulthood. Here, we review recent progress in understanding how these three endocrine signaling pathways regulate cardiomyocyte proliferation and heart regeneration with a particular focus on the controversial findings that may arise from different assays, cellular-context, age, and species. Further investigating the role of each endocrine nuclear receptor in cardiac regeneration from an evolutionary perspective enables comparative studies between species in hopes of extrapolating the findings to novel therapies for human cardiovascular disease.
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The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.
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Department of Medicine O, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Physiology, Faculty of Health Sciences, Center for Functional and Diagnostic Imaging and Research, Centre of Endocrinology and Metabolism, Herlev University Hospital, Herlev Ringvej 75, Herlev DK‐2730, Denmark
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Department of Medicine O, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Physiology, Faculty of Health Sciences, Center for Functional and Diagnostic Imaging and Research, Centre of Endocrinology and Metabolism, Herlev University Hospital, Herlev Ringvej 75, Herlev DK‐2730, Denmark
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Department of Medicine O, Department of Clinical Physiology and Nuclear Medicine, Department of Clinical Physiology, Faculty of Health Sciences, Center for Functional and Diagnostic Imaging and Research, Centre of Endocrinology and Metabolism, Herlev University Hospital, Herlev Ringvej 75, Herlev DK‐2730, Denmark
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Purpose
The aim of this study was to investigate structure and function of the heart in subclinical hyperthyroidism (SH) before and after obtaining euthyroidism by radioactive iodine treatment, using high precision and observer-independent magnetic resonance imaging (MRI) technology.
Methods
Cardiac MRI was performed before and after euthyroidism was obtained by radioactive iodine treatment in 12 otherwise healthy patients (11 women and one man, mean age 59 years, range 44–71 years) with a nodular goiter and SH, and compared with eight healthy controls investigated at baseline. Cardiac data were expressed as an index, as per body surface area, except for heart rate (HR) and ejection fraction.
Results
Post-treatment cardiac MRI was performed in median 139 days after a normalized serum TSH value had been recorded. During treatment, serum TSH increased from (median (range)) 0.01 (0.01–0.09) to 0.88 (0.27–3.99) mU/l. Patients with untreated SH had increased resting HR (P<0.01) as well as cardiac index (cardiac output as per body surface area) (P<0.01) compared with controls. Obtaining euthyroidism resulted in a significant decrease in left ventricular mass index (LVMI) of 2.7 g/m2 (P=0.034), in HR of 8 bpm (P=0.001), and in cardiac index of 0.24 l/min per m2 (P=0.017).
Conclusions
Normalization of thyroid function by radioactive iodine treatment of SH resulted in significant reductions in clinically important heart parameters such as LVMI, HR, and cardiac index. SH should be regarded as a condition in which aggressive treatment should be considered to protect cardiac function.
