Osteoprotegerin (OPG) is a recently discovered member of the TNF receptor superfamily that acts as an important paracrine regulator of bone remodeling. OPG knockout mice develop severe osteoporosis, ...whereas administration of OPG can prevent ovariectomy-induced bone loss. These findings implicate a role for OPG in the development of osteoporosis.
In the present study, we screened the OPG gene promoter for sequence variations and examined their association with bone mineral density (BMD) in 103 osteoporotic postmenopausal women. Single-strand conformation polymorphism analysis followed by DNA sequencing revealed a presence of four nucleotide substitutions: 209 G→A, 245 T→G, 889 C→T, and 950 T→C.
The frequencies of genotypes were as follows: GG (89.3%), GA (10.7%) for 209 G→A polymorphism; TT (89.3%), TG (10.7%) for 245 T→G polymorphism; and TT (25.2%), TC (53.4%), CC (21.4%) for 950 T→C polymorphism. Substitution 889 C→T was found in only two patients.
Statistically significant association of genotypes with BMD at the lumbar spine (P = 0.005) was observed for 209 G→A and 245 T→G polymorphisms. Haplotype GATG was associated with lower BMD as compared with GGTT haplotype.
Our results suggest that 209 G→A and 245 T→G polymorphisms in the OPG gene promoter may contribute to the genetic regulation of BMD.
Aim Incipient cardiovascular autonomic imbalance is not readily diagnosed by conventional methods. Spectral analysis of heart rate variability (HRV) by wavelet transform (WT) was used to measure ...cardiovascular autonomic function in patients with Type 2 diabetes.
Methods Thirty‐two diabetic patients without (D), 26 with cardiovascular autonomic neuropathy (DAN) and 72 control subjects (C) participated. A 30‐min HRV time series was analysed by wavelet transformation and four characteristic frequency intervals were defined: I (0.0095–0.021 Hz), II (0.021–0.052 Hz), III (0.052–0.145 Hz) and IV (0.145–0.6 Hz).
Results When compared with C, in both D and DAN the normalized power and amplitude of interval II were increased and of interval IV decreased, resulting in a significantly higher II/IV ratio. Furthermore, in DAN the normalized power and amplitude of interval I were increased and of interval III decreased when compared with the D and C groups. The diabetic patients were divided in two equal subgroups according to HbA1c < 8.0% and ≥ 8.0%. In the subgroup with HbA1c≥ 8.0%, normalized power in interval II was significantly higher and in interval IV significantly lower than in the subgroup with HbA1c < 8.0%. In D, but not in DAN patients prescribed ACE inhibitors, the absolute amplitude and power of oscillations were significantly higher than in patients not taking ACE inhibitor therapy.
Conclusions Patients with diabetes have increased sympathetic and decreased parasympathetic cardiac activity regardless of the presence of autonomic neuropathy. Glycaemic control and treatment with ACE inhibitors may favourably influence HRV in diabetic patients without autonomic neuropathy.
Abstract
Background and purpose
Amiodarone is commonly use in patients with atrial fibrillation (AF), but the organ toxicity side effects limit its long-term use. We investigated the rates of and ...reasons for permanent amiodarone discontinuation among patients with AF in contemporary clinical practice.
Methods
A single-centre, ongoing, registry-based observational longitudinal study included consecutive AF patients prescribed with amiodarone in our hospital from January 2015 to December 2017. All patients underwent a loading protocol of 400–600 mg of amiodarone daily for 1–2 weeks, followed by 200–400mg daily for 4–8 weeks and 200mg daily or 1000mg weekly thereafter.
Results
Of 657 AF patients taking amiodarone (Mean age 62.2±11.0, female n=215 (32.6%), hypertension n=504 (76.7%), diabetes mellitus n=107 (16.3%), coronary arterial disease n=139 (19.8%), History of Myocardial infarction 86 (13.1%), Stroke/TIA 60 (9.1%), chronic kidney disease 157 (23.9%)), the drug was permanently discontinued in total of 248 patients (37.7%). The reasons for amiodarone discontinuation are shown in Figure. On multivariable Cox-regression analysis, physician's decision (HR 5.6; 95% CI 3.9–7.9, p<0.001) and amiodarone side effects (HR 3.9; 95% CI 2.9–5.1, p<0.001) were significantly associated with permanent amiodarone discontinuation.
The overall time to discontinuation was 23.2±24.1 months. Compared with others, time to discontinuation was shorter in patients post AF ablation (17.3±21.3 vs 24.5±24.5, p=0.05), longer in those with AF progression (29.2±31.0 vs 20.9±20.3, p=0.014) and similar in patients with amiodarone side effects (23.7±17.7 vs 23.0±26.8, p=0.813). Pulmonary toxicity and proarrhythmia were not observed among study patients (Figure).
Chart 1
Conclusion
Our study showed that permanent discontinuation of amiodarone in contemporary clinical practice was due to the drug side effects in 12% of amiodarone-treated AF patients, occurring after a mean 2-year treatment course. The most prevalent side effect was thyroid dysfunction, whereas the prevalence of proarrhythmic effect was low. Notably, physician's fear of complications (which may not always be justified), also was an independent driver of permanent amiodarone discontinuation. More data are needed to inform optimal amiodarone use in AF patients in daily practice.
Abstract
Background and purpose
Amiodarone is the most effective antiarrhythmic drug, but its long-term use is limited by organ toxicity. We studied the rates of and factors associated with permanent ...amiodarone discontinuation in clinical practice.
Methods
An ongoing prospective single-centre registry-based observational study included consecutive amiodarone-naïve patients treated for cardiac arrhythmias in a university hospital between January 2015 and December 2017. Amiodarone was administered in loading doses of 400–800 mg daily for 1–2 weeks, followed by 200–400mg daily for 4–8 weeks and 200mg daily or 1000mg weekly thereafter.
Results
Of 1032 patients (mean age 61.5±11.4 years), 30.0% were females, and amiodarone was used for atrial fibrillation (AF, n=657, 63.7%), atrial flutter (n=187, 18.1%), other supraventricular arrhythmias (n=118, 11.4%), premature ventricular beats (n=239, 23.2%) or ventricular tachycardias (n=236, 22.9%). The most prevalent comorbidities were hypertension (n=761, 73.7%), coronary artery disease (n=283, 27.4%), heart failure (n=197, 19.2%), chronic kidney disease (n=266, 25.8%) and diabetes mellitus (n=196, 19.0%).
Amiodarone was permanently discontinued due to its side effects in 103 patients (10.0%), physician's fear of complications in 73 (7.1%), patient preference in 4 (0.4%) or for miscellaneous reasons in 6 (0.6%). In another 161 patients (15.6%), the discontinuation was due to catheter ablation of index arrhythmia (n=90) or progression to permanent AF (n=71). On multivariable Cox-regression analysis, physician decision was significantly associated with amiodarone discontinuation (HR 4.2; 95% CI 3.3–5.5, p<0.001) along with the drug side effects (HR 3.0; 95% CI 2.4–3.8, p<0.001).
Overall, amiodarone was permanently discontinued 347 patients (33.6%), after mean 21.4±25.2 months of treatment (median 13.0, IQR 203). The mean time to discontinuation was significantly shorter in patients with drug discontinued due to physician's decision (16.5±15.9 vs 22.7±26.9, p=0.013) and slightly longer in those with amiodarone side effects (24.9±25.8 vs 19.9±24.8 months, p=0.093) than in others. Side effects resulting in permanent amiodarone discontinuation were: hyperthyreosis (66, 6.4%), hypothyreosis (19, 1.8%), liver injury (5, 0.5%), bradycardia/AV block (9, 0.9%), QT prolongation (2, 0.2%) and corneal deposits (4, 0.4%). Pulmonary toxicity was not observed among study patients.
Conclusion
Our study showed that permanent amiodarone discontinuation in contemporary practice was due to its side effects in 10% of amiodarone-treated patients, occurring after a mean 2-year treatment course. The most prevalent side effect was thyroid dysfunction, whilst the prevalence of proarrhythmic effect was low. Notably, physician's fear of complications (which may not always be justified), was an independent driver of permanent amiodarone discontinuation. More data are needed to inform optimal amiodarone use in daily practice.
Abstract
Funding Acknowledgements
Type of funding sources: None.
Background
Treatment burden (TB) is defined as the patient’s workload of health care and its impact on patient functioning and ...well-being. High TB can lead to nonadherence, higher risk of adverse outcomes and lower quality of life. We have previously reported a higher TB in patients with atrial fibrillation (AF) vs. those with other chronic conditions. In this analysis, we explored sex-related differences in self-reported TB in AF patients.
Methods
A single-centre, prospective study included consecutive patients with AF under drug treatment for at least six months before enrolment from April to June 2019. Patients were asked to voluntarily and anonymously answer Treatment Burden Questionnaire (TBQ). All patients signed the written consent for participation.
Results
Of 331 patients (mean age 65.4 ±10.3 years, mean total AF history 6.41 ±6.62 years), 127 (38.4%) were females. The mean TB was significantly higher in females compared to males (53.7 vs. 42.6 out of 170 points, p < 0.001), also females more frequently reported TB ≥59 points than males (37.8% vs 20.6%, p = 0.001). Item-specific sex-related differences in self-reported TB questionnaire are showed in Figure. Sex-related differences in TB on multivariable regression analyses of the highest TB quartile (≥59 points) are showed in Table.
Conclusion
Our study was first to explore the sex-specific determinants of TB in AF patients. Females had significantly higher TB compared with males. Approximately 2 in 5 females and 1 in 5 males reported TB ≥59 points, previously shown to be an unacceptable burden of treatment for patients. Using a NOAC rather than VKA in females and a rhythm control strategy in males could decrease TB to acceptable values. Table.Multivariable Logistic Regression analysis of the highest TB quartile (TB ≥59)VariableOR95% CIP valueFemalePPI therapy5.3541.97-14.560.001NOAC0.3190.12-0.830.019Diuretic therapy0.3180.13-0.760.010CHA2DS2-VASc score0.7000.49-0.990.045MaleAblation and/or ECV0.3830.18-0.810.012Supraventricular arrhythmias0.2220.05-0.980.047VKA Vitamin K antagonist; ECV: electrical cardioversion; AF: Atrial fibrillation; PPI: Proton pump inhibitor; PCI: Percutaneous coronary intervention; NOAC: Non-vitamin k antagonist oral anticoagulant.Abstract Figure.
Twenty-four late postmenopausal women with osteoporosis were studied. The patients were separated in three subgroups according to the BsmI polymorphism of the vitamin D receptor (VDR) gene: BB (n = ...8), Bb (n = 10) and bb (n = 6). They did not differ in age (mean ages were 66.0 years, 65.9 years and 63.9 years, respectively), years after menopause (18.7 years, 18.1 years and 18.4 years) or body weight (64.9 kg, 65.3 kg and 63.8 kg), the variables known to be associated with bone mineral density (BMD). The results show that the response to antiresorptive bisphosphonate therapy in combination with calcium supplementation is modified by VDR genotype. The lumbar spine BMD increased significantly faster in the BB and Bb groups (7.3% and 7.0%, respectively) compared with the bb group (2.5%) during 1 year of cyclic etidronate therapy (400 mg/day) and calcium supplementation (1000 mg/day). The biochemical marker of bone resorption (urinary hydroxyproline excretion) as well as the bone formation marker (serum levels of osteocalcin) decreased during the treatment. With respect to VDR genotype, a significantly higher decrease in osteocalcin level was observed in bb as compared with BB subjects. We conclude that the VDR genotype is involved in an individual's response to cyclic etidronate therapy with calcium supplementation.
Microvascular blood flow in the human skin is subject to rhythmic variations reflecting the influence of heartbeat, respiration, intrinsic myogenic activity, neurogenic factors and endothelial ...activity. The aim of our study was to test the hypothesis that basal skin blood flow (BSBF) and its dynamic components differ (1) among diabetic patients without autonomic neuropathy and with it and healthy control subjects, and (2) among the upper and lower extremities.
BSBF at four recording sites with predominantly nutritive capillary circulation (right and left caput ulnae, right and left medial malleolus) was measured by laser Doppler flowmetry in 25 diabetic patients without cardiovascular autonomic neuropathy (D), 18 neuropathic diabetic patients (DAN) and 36 healthy controls (C). Wavelet transform was applied to the laser Doppler signal.
In absolute terms, mean flow, mean amplitude of the total spectrum and mean amplitudes at all frequency intervals were highest in C, followed by DAN and lowest in D. However, these differences were statistically significant only in the left arm. Within all three groups, mean flow and spectral amplitudes were significantly higher in the arms than in the legs, besides there was a significant difference between the two arms in D.
We have confirmed the differences in BSBF among D, DAN and C, and demonstrated differences among the four recording sites which have not been previously described. The latter indicates an uneven progression of autonomic neuropathy and allows for speculation that the left arm is the latest to be affected.
Abstract
Introduction
The MB-LATER score (Male, Bundle brunch block, Left atrium ≥47 mm, Type of AF paroxysmal, persistent or long-standing persistent, and ER-AF=early recurrent AF during first three ...months) was originally developed for prediction of late AF recurrences post AF catheter ablation (CA-AF). Subsequently, the score has been internationally validated in multiple AF cohorts, showing a good prediction ability for recurrent AF post AF-CA. We assessed prediction ability of the MB-LATER score for recurrent AF after successful electrical cardioversion (ECV) of AF.
Methods
The retrospective study included a Serbian and Icelandic centre, enrolling patients post successful ECV of AF in the period between January 2014 and February 2016. Of 580 patients, 136 (23.4%) were excluded because incomplete data needed for the MB-LATER score calculation. AF episodes lasting ≤7 days before ECV were classified as paroxysmal AF, and the ER-AF component of the MB-LATER score was excluded from the analysis because of different clinical implications in the setting of ECV. The study outcome was defined as the time to first recurrence of AF post successful ECV. Patients post successful ECV were seen at 1 and 6 months post ECV and every 12 months thereafter.
Results
Among 444 patients (median age 68 years IQR 60.0–74.6, 289 males 65.2%, 200 45.0% with non-paroxysmal AF. AF re-occurred in 283 patients (63.7%) after a median of 233.5 IQR 44–366) days post successful ECV. Patients with recurrent AF had significantly higher median MB-LATER score than those without (1 IQR 1–2 vs. 2 IQR 1–2, p<0.001). On univariate analysis, the MB-LATER score was significantly associated with time to AF recurrence post ECV (Hazard Ratio 1.20; 95% CI 1.07–1.35, p=0.003), showing modest but statistically significant prediction ability for recurrent AF post successful ECV (c-statistic 0.61; 95% CI 0.56–0.66, p<0.001). The Kaplan-Meyer survival free from AF post successful ECV was significantly better for patients with a MB-LATER score of <2 than for those with a score of ≥2 (log-rank p=0.005) (Fig 1.).
Figure 1
Conclusion
In our analysis of an international cohort of AF patients post successful ECV, the MB-LATER score showed a modest but statistically significant prediction ability for recurrent AF post ECV. Reliable prediction of recurrent AF post ECV could inform patient selection and treatment decision-making. Further prospective validation of the MB-LATER score prediction ability for recurrent AF post ECV is underway.
The cellular mechanisms for the insulin resistance in pregnancy and gestational diabetes mellitus are not known. The membrane protein plasma cell glycoprotein PC-1 has been identified as an inhibitor ...of insulin receptor tyrosine kinase activity and could have a role in insulin resistance. This study aimed to examine the effects of insulin on glucose transport and changes in insulin receptor tyrosine phosphorylation, IRS-1 and PC-1.
Adipocytes were obtained either during elective cesarean section from three groups of subjects (Type II diabetic pregnant women ( n=6) women with gestational diabetes mellitus ( n=10) and pregnant women with normal glucose tolerance ( n=6) as pregnant control subjects) or during elective gynaecological surgery from non-pregnant ( n=6) control subjects.
Insulin stimulated glucose transport was reduced by 50% in women with gestational diabetes mellitus and 70% in pregnant women with Type II diabetes, compared to the non-pregnant control subjects. After maximal insulin stimulation of adipocytes, IRTK phosphorylation was reduced by 29.5% in women with gestational diabetes mellitus and 44.5% in women with Type II diabetes, compared to the non-pregnant control subjects. We also found that IRS-1 phosphorylation was reduced by 32% and 48%, respectively. On the other hand, PC-1 content in adipocytes in women with gestational diabetes mellitus increased by 320% and 668% in Type II diabetic women, compared to the non-pregnant control subjects.
Our results indicate that women with gestational diabetes mellitus and Type II diabetes have increased PC-1 content and suggest that this could contribute to lower phosphorylation levels of IRTK and IRS-1. Furthermore, these postreceptor defects in insulin signalling pathway are greater in both groups compared to the women with normal pregnancy. However, results from women with Type II diabetes show that pre-existing insulin resistance lead to an even greater deterioration of the signalling pathway.
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