Serum adiponectin concentrations as a risk factor for cardiovascular complications in type 1 diabetes.

AIM: By analyzing data from DCCT/EDIC study, we investigated the associations of serum adiponectin concentrations with macrovascular complications and cardiovascular events in T1D. MATERIALS AND METHODS: Adiponectin concentrations were measured in EDIC year 8. The participants (n = 1040) were divided into four groups by quartiles of adiponectin concentrations. The association of macrovascular complications and cardiovascular events were analyzed by using multivariable regression and Cox proportional hazards models. RESULTS: High adiponectin concentrations were associated with decreased risk of peripheral artery disease represented by ankle brachial index (ORs (95% CI): 0.22 (0.07-0.72), 0.48 (0.18-1.25), and 0.38 (0.14-0.99) in fourth, third, and second quartiles compared with first quartile), with reduced carotid intima-media thickness, and with increased LVEDV index. Moreover, high adiponectin concentrations were also associated with increased risk of any cardiovascular events (HRs (95% CI): 2.59 (1.10-6.06), 2.03 (0.90-4.59), and 1.22 (0.52-2.85)) and major atherosclerotic cardiovascular events (HRs (95% CI): 11.37 (2.04-63.43), 5.68 (1.04-31.07), and 3.76 (0.65-21.77) in fourth, third, and second quartiles compared with first quartile), however, after adjustments with LVEDV index, these associations were diminished. CONCLUSIONS: Adiponectin may protect carotid atherosclerosis and peripheral artery disease in T1D. It may be associated with increased cardiovascular events, depending on cardiac structural changes.

HbA1c Variability as an Independent Risk Factor for Microvascular Complications in Type 1 Diabetes.

BACKGROUND: There are few studies on the role of long-term glycemic variability in complications of type 1 diabetes (T1D). This study was aimed to investigate the associations of HbA1c variability represented by the coefficient of variation of HbA1c with incident microvascular complications in T1D by analyzing the data set from the DCCT/EDIC study. METHODS: Patients (n = 1240) were divided into four groups by HbA1c variability quartiles. Incident microvascular complications were assessed for a duration of an average of 20.5 years. Multivariable models were performed to examine the associations between HbA1c variability and incident microvascular complications. RESULTS: All incident microvascular complications were higher in the fourth quartile of the HbA1c variability group. After adjusting for clinical risk factors, HbA1c variability was positively associated with a higher risk of all diabetic microvascular complications (P < .05). Specifically, it had 1.125 (1.082-1.170), 1.114 (1.074-1.154), 1.061 (1.024-1.099), or 1.088 (1.052-1.125) times higher odds (95% confidence interval [CI]) of having retinopathy, nephropathy, clinical neuropathy, or autonomic neuropathy, independent of mean HbA1c values (P < .05). Furthermore, there were higher incident microvascular complications with higher HbA1c variability when HbA1c value was above the group median of 7.9%, while only higher incident autonomic neuropathy with higher HbA1c variability when HbA1c was below the group median. CONCLUSIONS: Our results showed a significant independent association between HbA1c variability and the risk of microvascular complications in T1D. HbA1c variability might be a supplemental risk stratification tool to mean HbA1c for microvascular complications in T1D.

Endothelial Natriuretic Peptide Receptor 1 Play Crucial Role for Acute and Chronic Blood Pressure Regulation by Atrial Natriuretic Peptide.

BACKGROUND: ANP (atrial natriuretic peptide), acting through NPR1 (natriuretic peptide receptor 1), provokes hypotension. Such hypotension is thought to be due to ANP inducing vasodilation via NPR1 in the vasculature; however, the underlying mechanism remains unclear. Here, we investigated the mechanisms of acute and chronic blood pressure regulation by ANP. METHODS AND RESULTS: Immunohistochemical analysis of rat tissues revealed that NPR1 was abundantly expressed in endothelial cells and smooth muscle cells of small arteries and arterioles. Intravenous infusion of ANP significantly lowered systolic blood pressure in wild-type mice. ANP also significantly lowered systolic blood pressure in smooth muscle cell-specific Npr1-knockout mice but not in endothelial cell-specific Npr1-knockout mice. Moreover, ANP significantly lowered systolic blood pressure in Nos3-knockout mice. In human umbilical vein endothelial cells, treatment with ANP did not influence nitric oxide production or intracellular Ca2+ concentration, but it did hyperpolarize the cells. ANP-induced hyperpolarization of human umbilical vein endothelial cells was inhibited by several potassium channel blockers and was also abolished under knockdown of RGS2 (regulator of G-protein signaling 2), an GTPase activating protein in G-protein α-subunit. ANP increased Rgs2 mRNA expression in human umbilical vein endothelial cells but failed to lower systolic blood pressure in Rgs2-knockout mice. Endothelial cell-specific Npr1-overexpressing mice exhibited lower blood pressure than did wild-type mice independent of RGS2, and showed dilation of arterial vessels on synchrotron radiation microangiography. CONCLUSIONS: Together, these results indicate that vascular endothelial NPR1 plays a crucial role in ANP-mediated blood pressure regulation, presumably by a mechanism that is RGS2-dependent in the acute phase and RGS2-independent in the chronic phase.

Changes of insulin resistance status and development of complications in type 1 diabetes mellitus: Analysis of DCCT/EDIC study.

AIM: There is no longitudinal study regarding the changes of insulin resistance (IR) status and the development of complications in type 1 diabetes (T1D). By analyzing data sets from DCCT/EDIC study, we investigated the associations of IR status changes and diabetic complications in T1D. MATERIALS AND METHODS: Estimated glucose disposal rate (eGDR) was calculated at entry of DCCT and in EDIC year 12 (average 18.5 years later) to represent IR. The participants (n = 957) were divided into four groups based on IR changes from baseline: RR group (stayed resistant; n = 49), RS group (became sensitive; n = 42), SR group (became resistant; n = 197), and SS group (stayed sensitive; n = 669). The association of diabetic complications were analyzed by using multivariable logistic regression models. RESULTS: The improved IR decreased the risk of peripheral neuropathy, whereas the deteriorated IR increased the risk of diabetic complications including hypertension, peripheral artery disease, coronary artery calcification, retinopathy, albuminuria, peripheral neuropathy, and cardiac autonomic neuropathy (P < 0.05). Moreover, RR group (HR = 3.59, 95% CI (2.05-6.32)), RS group (HR = 2.27, 95% CI (1.11-4.64)) and SR group (HR = 1.90, 95% CI (1.24-2.92)) had higher risk of cardiovascular events compared to SS group (P < 0.05). CONCLUSIONS: This study highlights the importance of IR changes represented by eGDR in the development of diabetic complications. Patients with T1D and IR may require intensive therapy.

Association of Thyroid Function with Suicidal Behavior: A Systematic Review and Meta-Analysis.

Thyroid disease is a very common condition that influences the entire human body, including cognitive function and mental health. As a result, thyroid disease has been associated with multiple neuropsychiatric conditions. However, the relationship between thyroid dysfunction and suicide is still controversial. We conducted a systematic review and meta-analysis to describe the association of thyroid function with suicidal behavior in adults. We searched four data bases (MEDLINE, EMBASE, PsycINFO, and Scopus) from their inception to 20 July 2018. Studies that reported mean values and standard deviation (SD) of thyroid hormone levels [Thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3)] in patients with suicidal behavior compared with controls were included in this meta-analysis. The abstracts and papers retrieved with our search strategies were reviewed independently and in duplicate by four reviewers for assessment of inclusion criteria and data extraction, as well as for evaluation of risk of bias. Random-effects models were used in this meta-analysis to establish the mean difference on thyroid function tests between groups. Overall, 2278 articles were identified, and 13 studies met the inclusion criteria. These studies involved 2807 participants, including 826 participants identified with suicidal behavior. We found that patients with suicide behavior had lower levels of FT3 (-0.20 pg/mL; p = 0.02) and TT4 (-0.23 µg/dL; p = 0.045) compared to controls. We found no differences in either TSH, FT4, or TT3 levels among groups. With our search strategy, we did not identify studies with a comparison of overt/subclinical thyroid disease prevalence between patients with and without suicide behavior. The studies included in this meta-analysis had a low-to-moderate risk of bias. In the available literature, the evidence regarding the association of thyroid disorders and suicidal behavior is limited. We found that patients with suicidal behavior have significantly lower mean FT3 and TT4 levels when compared to patients without suicidal behavior. The clinical implications and pathophysiologic mechanisms of these differences remain unknown and further research is needed.

Association of Thyroid Function with Posttraumatic Stress Disorder: a Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis describing the association of thyroid function with posttraumatic stress disorder (PTSD) in adults. METHODS: The authors conducted a comprehensive search from databases' inception to July 20, 2018. The meta-analysis included studies that reported mean values and standard deviation (SD) of thyroid hormone levels (thyroid-stimulating hormone [TSH], free thyroxine [FT4], free triiodothyronine [FT3], total T4 [TT4], and total T3 [TT3]) in patients with PTSD compared with controls. Five reviewers worked independently, in duplicate, to determine study inclusion, extract data, and assess risk of bias. The mean value and SD of the thyroid function tests were used to calculate the mean difference for each variable. Random-effects models for meta-analyses were applied. RESULTS: The meta-analysis included 10 observational studies at low-to-moderate risk of bias. Studies included 674 adults (373 PTSD, 301 controls). The meta-analytic estimates showed higher levels of FT3 (+0.28 pg/mL; P = .001) and TT3 (+18.90 ng/dL; P = .005) in patients with PTSD compared to controls. There were no differences in TSH, FT4, or TT4 levels between groups. In the subgroup analysis, patients with combat-related PTSD still had higher FT3 (+0.36 pg/mL; P = .0004) and higher TT3 (+31.62 ng/dL; P<.00001) compared with controls. Conversely, patients with non-combat-related PTSD did not have differences in FT3 or TT3 levels compared with controls. CONCLUSION: There is scarce evidence regarding the association of thyroid disorders with PTSD. These findings add to the growing literature suggesting that thyroid function changes may be associated with PTSD.

Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart.

BACKGROUND: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood. METHODS: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function. RESULTS: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy-lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin-nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti-interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice. CONCLUSIONS: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide-NPR1 system plays an important role in protecting the maternal heart from interleukin-6-induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.

Hormone treatments in congestive heart failure.

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Total flavonoids from Astragalus alleviate endothelial dysfunction by activating the Akt/eNOS pathway.

Objective To investigate the vasodilative and endothelial-protective effects and the underlying mechanisms of total flavonoids from Astragalus (TFA). Methods The vasodilative activities of TFA were measured with a myograph ex vivo using rat superior mesenteric arterial rings. The primary human umbilical vein endothelial cell (HUVEC) viabilities were assayed using the cell counting kit-8 after hypoxia or normoxia treatment with or without TFA. Akt, P-Akt, eNOS, P-eNOS, Erk, P-Erk, Bcl-2 and Bax expression were analyzed using western blotting. Results TFA showed concentration-dependent vasodilative effects on rat superior mesenteric arterial rings, but had no effects on normal or potassium chloride precontracted arterial rings. TFA did not affect HUVEC viabilities in normoxia, but dramatically promoted cell proliferation in the concentration range of 1 to 30 µg/mL under hypoxia. Moreover, TFA significantly increased the ratios of P-Akt/Akt and P-eNOS/eNOS in vascular endothelial cells under hypoxic conditions, but did not change the P-Erk/Erk or Bcl-2/Bax ratios. Conclusions TFA might exhibit vasorelaxant and endothelial-protective effects via the Akt/eNOS signaling pathway.

The Correlated Factors of Serum CA19-9 Levels in Diabetic Patients.

BACKGROUND: Serum CA19-9 level is a sensitive marker for pancreatic tissue damage; however, its correlation factors are still unclear in diabetic patients. This study was aimed to investigate the correlation factors of serum CA 19-9 levels in these patients. METHODS AND RESULTS: Based on their serum CA19-9 levels, 412 diabetic patients (57 type 1 and 355 type 2) were divided into the negative group (432 cases, CA19-9 37 U /ml) and the positive group (31 cases, CA19-9 ≥ 37 U /ml). The two groups were compared with age, sex, duration of diabetic history, hemoglobin A1c, blood lipid, fasting C-peptide level, and area under the curve C-peptide. The difference was significant between 2 groups in age, hemoglobin A1c, total cholesterol, highdensity lipoprotein cholesterol, fasting C-peptide level, and area under the curve C-peptide (P < 0.05). A multivariate linear regression model found that the type of diabetes, hemoglobin A1c, area under the curve C-peptide, and high-density lipoprotein cholesterol are the independent contributors to CA19-9 levels. CONCLUSION: The results indicated that CA19-9 levels in patients with diabetes mellitus were related to not only age and sex but also diabetic type, hemoglobin A1c, lipid metabolism, and pancreatic beta cell function.

Ghrelin and Blood Pressure Regulation.

Ghrelin is a growth hormone-releasing polypeptide that was first isolated from the rat stomach in 1999. High expression of growth hormone secretagogue receptor, the ghrelin receptor, in the heart, kidney, and blood vessels provides evidence of ghrelin activity in blood pressure regulation. Circulating ghrelin concentrations are reported to be inversely correlated with blood pressure, and the acute and chronic effects of ghrelin in decreasing blood pressure have been reported in animals with normal blood pressure, healthy individuals, animals and patients with heart failure, and animals with hypertension. The mechanism by which ghrelin regulates blood pressure appears to be related to modulation of the autonomic nervous system, direct vasodilatory activities, and kidney diuresis. Thus, modulation of the signaling pathway through ghrelin may provide a novel concept for treating hypertension. In this review, we discuss the current evidence and potential mechanisms of ghrelin activity in blood pressure regulation.

Endogenous ghrelin attenuates pressure overload-induced cardiac hypertrophy via a cholinergic anti-inflammatory pathway.

Cardiac hypertrophy, which is commonly caused by hypertension, is a major risk factor for heart failure and sudden death. Endogenous ghrelin has been shown to exert a beneficial effect on cardiac dysfunction and postinfarction remodeling via modulation of the autonomic nervous system. However, ghrelin's ability to attenuate cardiac hypertrophy and its potential mechanism of action are unknown. In this study, cardiac hypertrophy was induced by transverse aortic constriction in ghrelin knockout mice and their wild-type littermates. After 12 weeks, the ghrelin knockout mice showed significantly increased cardiac hypertrophy compared with wild-type mice, as evidenced by their significantly greater heart weight/tibial length ratios (9.2±1.9 versus 7.9±0.8 mg/mm), left ventricular anterior wall thickness (1.3±0.2 versus 1.0±0.2 mm), and posterior wall thickness (1.1±0.3 versus 0.9±0.1 mm). Furthermore, compared with wild-type mice, ghrelin knockout mice showed suppression of the cholinergic anti-inflammatory pathway, as indicated by reduced parasympathetic nerve activity and higher plasma interleukin-1ß and interleukin-6 levels. The administration of either nicotine or ghrelin activated the cholinergic anti-inflammatory pathway and attenuated cardiac hypertrophy in ghrelin knockout mice. In conclusion, our results show that endogenous ghrelin plays a crucial role in the progression of pressure overload-induced cardiac hypertrophy via a mechanism that involves the activation of the cholinergic anti-inflammatory pathway.

The cardiovascular action of hexarelin.

Hexarelin, a synthetic growth hormone-releasing peptide, can bind to and activate the growth hormone secretagogue receptor (GHSR) in the brain similar to its natural analog ghrelin. However, the peripheral distribution of GHSR in the heart and blood vessels suggests that hexarelin might have direct cardiovascular actions beyond growth hormone release and neuroendocrine effects. Furthermore, the non-GHSR CD36 had been demonstrated to be a specific cardiac receptor for hexarelin and to mediate its cardioprotective effects. When compared with ghrelin, hexarelin is chemically more stable and functionally more potent. Therefore, it may be a promising therapeutic agent for some cardiovascular conditions. In this concise review, we discuss the current evidence for the cardiovascular action of hexarelin.