Blood pressure circadian rhythms and adverse outcomes in type 2 diabetes patients diagnosed with orthostatic hypotension.

AIMS/INTRODUCTION: Patients with diabetes frequently develop orthostatic hypotension (OH). The present study was designed to examine the relationship of blood pressure (BP) circadian rhythms and outcomes in diabetes with OH. MATERIALS AND METHODS: In the present study, 173 inpatients with type 2 diabetes were enrolled. Patients were divided into an OH group and a non-OH group according to the BP changes detected in the supine and standing position. Then, 24-h ambulatory BP was monitored. Patients were followed up for an average of 45 ± 10 months post-discharge. Outcomes - death and major adverse cardiac and cerebrovascular events, including heart failure, myocardial infarction and stroke - were recorded. RESULTS: There were 61 patients (35.26%) in the OH group and 112 patients (64.74%) in the non-OH group. In the OH group, the night-time systolic BP and night-time diastolic BP were higher, the blood BP rhythms were predominantly of the riser type (67.21%). OH was as an independent marker of riser type circadian rhythm (adjusted odds ratio 4.532, 95% confidence interval 2.579-7.966). In the OH group, the incidence rates of mortality, and major adverse cardiac and cerebrovascular events were increased significantly compared with those in the non-OH group (11.48 vs 2.68%, P = 0.014; 37.70 vs 8.93%, P < 0.01). CONCLUSIONS: In patients who had type 2 diabetes diagnosed with OH, the BP circadian rhythm usually showed riser patterns, and they had increased rates of mortality, and major adverse cardiac and cerebrovascular events.

Relationship between the autoantibody and expression of ß3-adrenoceptor in lung and heart.

BACKGROUND: Evidences suggest that ß3 -adrenoceptor (ß3-AR) plays an important role in heart failure (HF), although no data is reported indicating how these effects may change with the increasing age. Pulmonary congestion and edema are the major life-threatening complications associated with HF. The purpose of this study is to explore the relationship between the anti-ß3-AR autoantibody and the expression of ß3-AR in the lungs and heart for both aged patients and rats with HF. METHODS: Synthetic ß3-AR peptides served as the target antigens in ELISA were used to screen the anti-ß3-AR autoantibody in aged patients and rats. Two aged rat models were constructed based on aortic banding and sham-operation. The expression of ß3-AR mRNA and protein in the lung and heart was measured in intervention and non-intervention groups by Western blot analysis at the baseline, 5(th), 7(th), 9(th) and 11(th) week, respectively. RESULTS: The frequency and titer of anti-ß3-AR autoantibody in aged patients and rats with HF were higher than those in the control group (p<0.05). The expression of ß3-AR mRNA and protein in pulmonary tissues decreased continually from the 7(th) week (p<0.05), followed by HF observed during the 9(th) week. The expression of ß3-AR in myocardial tissues continued to increase after the 9(th) week (p<0.05), and the expression of both ß3-AR mRNA and protein in the BRL group [HF group with BRL37344 (4-[-[2-hydroxy-(3-chlorophenyl)ethyl-amino] phenoxyacetic acid) (a ß3-AR agonist) injection] was positively correlated with BRL37344 when compared with non-BRL group (HF group without BRL37344 injection) (p<0.05). CONCLUSION: Anti-ß3-AR autoantibody was detected in aged patients and rats with HF. The expression of ß3-AR mRNA and protein in pulmonary tissues decreased continually, and began earlier than in the heart, but its expression in myocardial tissues increased continually and could be further promoted by ß3-AR agonist.

Aging might augment reactive oxygen species (ROS) formation and affect reactive nitrogen species (RNS) level after myocardial ischemia/reperfusion in both humans and rats.

Previous studies indicate aging results in significantly decreased cardiac function and increased myocardial apoptosis after myocardial ischemia/reperfusion (MI/R) in humans or rats. The underlying mechanisms of aging-exacerbated effects remain unknown. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are known to play vital roles in aging-related MI/R injury. Heretofore, the effects of aging upon ROS and RNS formation were not investigated in humans, which is the focus of the current study. Due to experimental limitations with clinical trials, an additional animal experiment was performed. All enrolled acute myocardial infarction (AMI) patients received percutaneous coronary intervention (PCI) therapy. AMI patients were assigned into two groups: adult (age <65, n = 34) and elderly (age ≥65, n = 45) AMI patients. Blood samples were obtained from all study participants at 24 h and 3 days post-PCI. Plasma/white blood cell (WBC) ROS and RNS markers (malondialdehyde (MDA), myeloperoxidase (MPO), reduced glutathione (GSH), inducible nitric oxide synthase (iNOS) activity, NOx, and nitrotyrosine) were determined. The same markers were determined in rat cardiac tissue after 24 h MI/R. Compared to the adult group, elderly patients manifested increased plasma MDA and MPO and decreased plasma GSH concentrations. No significant differences in plasma NOx or nitrotyrosine concentration existed between adult and elderly patients. Furthermore, WBC iNOS activity in elderly patients was significantly decreased compared to the adult group. The measurement of ROS markers in the rat experiments was consistent and supported human study data. Surprisingly, RNS markers (NOx and nitrotyrosine) in blood and heart tissue increased from young to middle-aged rats but decreased from middle age to old age. Aging augments ROS, which might exacerbate MI/R injury. Additionally, our data support aging-induced changes of RNS levels in humans and rats in vivo.

Aging might increase myocardial ischemia / reperfusion-induced apoptosis in humans and rats.

Previous studies indicated aging results in the significant cardiac function decreasing and myocardial apoptosis increasing in normal humans or rats. Additionally, animal experiments demonstrated aging increased myocardial ischemia / reperfusion (MI/R)-induced apoptosis. However, whether more myocardial apoptosis happen in the old acute myocardial infarction (AMI) patients is unclear. Reperfusion injury-induced apoptosis is an important cause of heart failure. This study determined the effect of aging upon myocardial apoptosis and cardiac function in patients suffering AMI. All enrolled AMI patients received percutaneous coronary intervention therapy. Volunteers and AMI patients were assigned to four groups: adult (age <65, n = 24) volunteers, elderly (age ≥65, n = 21) volunteers, adult (age <65, n = 29) AMI patients, and elderly (age ≥65, n = 36) AMI patients. Blood samples were obtained from all study participants. Plasma apoptotic markers (soluble form of Fas, tumor necrosis factor alpha, and interleukin 6) levels were determined. Cardiac function was evaluated with echocardiogram and Killip class. Due to lack of a direct apoptotic assay method in live human subjects, an additional animal experiment was performed. Both young (2 months) and old (24 months) rats were subjected to 30-min myocardial ischemia and 3 (for TUNEL/caspase activity apoptotic assay) or 24-h (for cardiac function determination) reperfusion. Compared to adult patients, the elderly patients manifested decreased cardiac function and increased plasma apoptotic marker levels significantly. The animal experiment results (cardiac function and plasma apoptotic markers assays) were consistent with the human result data. Animal TUNEL staining and caspase activity measurement revealed a higher myocardial apoptotic ratio in the older rat group. Aging exacerbated MI/R injury in humans and rats. Differential myocardial apoptosis may play a vital role in mediating the observed effects.

Age-related up-regulation of beta3-adrenergic receptor in heart-failure rats.

Stimulation of beta1- and beta2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta3-AR is also expressed in the heart and that its stimulation leads to negative inotropic effects. The aim of this study was to investigate the expression of beta3-AR in age-related heart-failure rats and its relevance to left ventricular dysfunction. Aging male Wistar rats were divided into young and aging groups according to age, and each group included sham-operation and heart-failure subgroups. Left ventricular end-diastolic pressure (LVEDP) and the ratio of left ventricular weight to body weight (LV/BW) were significantly higher for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). However, the left ventricular end-systolic pressure (LVESP) and the maximal rate of rise or fall of left ventricular pressure were all significantly lower for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). beta3-AR protein levels increased significantly when heart failure worsened in aging rats. These results suggest that beta3-AR expression in age-related heart-failure rats and left ventricular function were highly correlated.

Plasma concentration of Fas/Fas ligand and left ventricular function in response to metoprolol in conjunction with standard treatment.

Recent studies suggest that cardiac myocyte apoptosis contributes to the progress of CHF (congestive heart failure). In the present study, we tested the hypothesis that metoprolol in conjunction with the standard treatment regime for CHF [an ACE (angiotensin-converting enzyme) inhibitor, diuretics and digoxin] may significantly reduce the plasma concentrations of the apoptotic mediators sFas (soluble Fas) and sFasL (soluble Fas ligand) in patients with CHF. An ELISA was used to determine the plasma concentrations of sFas and sFasL in 106 patients with stable CHF at recruitment. Echocardiography was performed at baseline and after 1 year of treatment with metoprolol in conjunction with the standard treatment regime for CHF (i.e. an ACE inhibitor, diuretics and digoxin). The dose of metoprolol was doubled on a biweekly basis up to 50 mg twice a day or maintained at the maximum tolerated dose. Data after 1 year were available for 92 patients and were analysed. The plasma concentrations of sFas and sFasL in patients with CHF decreased significantly (P<0.01) after 1 year of treatment with metoprolol in conjunction with the standard treatment regime compared with at baseline (5.4+/-0.2 compared with 3.2+/-0.1 ng/ml respectively for sFas, and 52.1+/-2.3 compared with 26.7+/-1.0 pg/ml respectively for sFasL). Compared with baseline, after 1 year of treatment with metoprolol in conjunction with the standard treatment regime there were significant improvements in LV (left ventricular) ejection fraction (from 32.6+/-0.9 to 51.5+/-0.8%; P<0.01), LV end-diastolic dimension (from 69.8+/-0.6 to 57.7+/-0.3 mm; P<0.01), LV end-systolic dimension (from 53.9+/-0.6 to 40.5+/-0.5 mm; P<0.01), LV end-diastolic volume (from 254.7+/-5.0 to 164.1+/-2.2 ml; P<0.01) and LV end-systolic volume (from 142.0+/-4.2 to 72.2+/-2.0 ml; P<0.01). In addition, the distance walked in a 6-min walk test increased markedly (P<0.01) from 260.3+/-5.2 m at baseline to 440.9+/-5.7 m after 1 year of treatment. In conclusion, we have demonstrated that metoprolol in conjunction with an ACE inhibitor, diuretics and digoxin in patients with CHF can lead to a reverse in LV remodelling potentially through its anti-apoptotic effects.