Endothelial function does not relate to haemoglobin or serum erythropoietin concentrations and these do not explain the gender difference in endothelial function in healthy middle-aged men and women.

BACKGROUND: Haemoglobin scavenges nitric oxide, and a previous study has shown a negative association between flow-mediated vasodilation (FMD), a measure of nitric oxide (NO)-dependent vasomotor function and haemoglobin concentrations [Hb]. Circulating erythropoietin (EPO) is also negatively associated with [Hb] and could influence availability of NO. The purpose of this study was to examine the association of FMD with [Hb] and EPO concentrations and to determine whether these contribute to the sex difference in FMD. FMD (by high-resolution ultrasound), [Hb], circulating immunoreactive EPO and cardiovascular risk factors were measured in 317 healthy middle-aged men and women (183 women, 33 premenopausal, mean age ± SD, 55 ± 6·8 years) participating in a dietary study. RESULTS: In the whole mixed-sex group, FMD was negatively correlated with [Hb] (R = -0·23, P < 0·001). However, in a multivariable model, incorporating sex and other confounding factors, FMD was independently negatively correlated only with age, male sex and systolic blood pressure: standardized regression coefficients -0·21 (P < 0·01), -0·17 (P < 0·05) and -0·20 (P < 0·05) respectively and not with [Hb]. Similarly, when the analysis was restricted to men or to postmenopausal women, there was no significant relationship between FMD and Hb. There was no significant correlation between FMD and EPO on either univariate analysis in the whole group, in each sex, or in multivariate analysis. CONCLUSION: These results suggest that in healthy middle-aged subjects, FMD is not influenced by [Hb] or EPO and these do not contribute to the gender difference in FMD.

Erythropoietin: a future therapy for failing hearts?

Recently, it has been suggested that erythropoietin may be useful in the treatment of cardiovascular disease, particularly heart failure. This may be by improving microvascular blood supply and ventricular function through prevention of apoptosis and angiogenesis. Promising results were seen in animals but the few, limited clinical trials have shown modest benefits. Additionally, concerns exist regarding potential serious adverse effects of erythropoietin. Our current understanding of the non-haematopoietic mechanisms of erythropoietin is presented here, with a review of trials to date, and a discussion of the questions that remain over the use of this drug in heart failure.

Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion.

Vasoprotective effects of erythropoietin in animal models are mediated by endothelium-derived NO and/or mobilization of EPCs (endothelial progenitor cells) and may be enhanced by ischaemia: whether they are present in humans is unknown. We examined whether the erythropoietin analogue darbepoetin improves FMD (flow-mediated dilatation), a measure of endothelium-derived NO, and whether this is influenced by preceding I/R (ischaemia/reperfusion). A total of 36 patients (50-75 years) with stable coronary artery disease were randomized to receive a single dose of darbepoetin (300 µg) or saline placebo. FMD was measured at the brachial artery using high-resolution ultrasound. CD133⁺/CD34⁺/VEGFR2⁺ (vascular endothelial growth factor receptor 2) circulating EPCs were enumerated by flow cytometry. Measurements were made immediately before darbepoetin/placebo and at 24 h, 72 h and 7 days. At 24 h, FMD was repeated after 20 min of I/R of the upper limb. A further group of 11 patients was studied according to the same protocol, all receiving darbepoetin, with omission of forearm I/R at 24 h. Immunoreactive erythropoietin peaked at 24 h and remained elevated at approximately 50-fold of baseline at 72 h. FMD did not differ significantly between groups at 24 h (before I/R). At 72 h (48 h after I/R), FMD was greater (by 2.3±0.5% in the darbepoetin compared with the placebo group, a 66% increase over baseline; P<0.001) and greater than FMD at the same time point without preceding I/R (P<0.01). Increases in CD133⁺/CD34⁺/VEGFR2⁺ cells after darbepoetin did not differ according to the presence or absence of preceding I/R. Preceding I/R is required for darbepoetin to enhance endothelial function, possibly by increasing expression of the erythropoietin receptor and by a mechanism likely to involve Akt/NO rather than circulating EPCs.

Myopericarditis and myositis in a patient with COVID-19: a case report.

BACKGROUND: Concurrent myopericarditis and myositis can present in patients with pre-existing systemic inflammatory diseases. Here we present a case of myopericarditis and myositis associated with COVID-19, in the absence of respiratory symptoms. CASE SUMMARY: We present a middle-aged female with a history of hypertension and previous myopericarditis. The patient was admitted with symptoms of central chest pain, and ECG and echocardiographic features of myopericarditis. Her symptoms did not improve, and CT thorax suggested possible SARS-CoV-2 infection for which she tested positive, despite no respiratory symptoms. Whilst on the ward, she developed bilateral leg weakness and a raised creatine kinase (CK), and magnetic resonance imaging (MRI) of her thighs confirmed myositis. A cardiac MRI confirmed myopericarditis. She was treated with colchicine 500 µg twice daily, ibuprofen 400 mg three times day, and prednisolone 30 mg per day, and her symptoms and weakness improved. DISCUSSION: We describe the first reported case of concurrent myopericarditis, and myositis associated with COVID-19. Conventional therapy with colchicine, non-steroidal anti-inflammatory drugs, and glucocorticoids improved her symptoms, and reduced biochemical markers of myocardial and skeletal muscle inflammation.

Progenitors in motion: mechanisms of mobilization of endothelial progenitor cells.

Endothelial progenitor cells are a population of bone marrow-derived mononuclear cells thought to engage in endothelial repair and hence are considered potential therapeutic agents in many pathological conditions. The mechanism of their exit from the bone marrow to the circulation and damaged tissues, termed mobilization, has not been fully elucidated. Despite this, several pharmacological interventions have been shown to influence mobilization of these specialized cells. Here we review the current understanding of their mobilization.

Twiddler's syndrome with a subcutaneous implantable cardioverter-defibrillator presenting with an inappropriate shock: a case report.

BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (S-ICDs) are increasingly used in patients at risk of fatal cardiac arrhythmias. Twiddler's syndrome is a condition in which a device is manipulated by the patient after implantation leading to lead twisting and retraction. Device manipulation has been reported multiple times in transvenous pacing systems and occasionally leads to inappropriate discharges from implanted defibrillators. However, little has been reported about device manipulation in S-ICD devices. CASE SUMMARY: We present the case of a 16-year-old who underwent insertion of an S-ICD for idiopathic dilated cardiomyopathy. He represented for a pacing check following a discharge from the device. This showed a significant change in the sensed vectors. Chest radiographs confirmed lead retraction and suggested device manipulation. The device was turned off to prevent further inappropriate shocks. The patient underwent successful reimplantation of a S-ICD device. DISCUSSION: This case highlights that twiddler's syndrome can occur in those with an S-ICD and lead to an inappropriate device discharge. The patient in this case had a number of risk factors that have been previously associated with twiddler's syndrome.

Cinacalcet-associated cardiogenic shock in a patient with cardiomyopathy.

INTRODUCTION: Cinacalcet is a calcimimtic agent used to treat secondary hyperparathyroidism in patients with end-stage renal disease on dialysis or hypercalcemia related to parathyroid carcinoma. This report describes recurring circulatory collapse in a patient treated with cinacalcet for unrelated refractory primary hyperparathyroidism. CASE SUMMARY: A white man, aged 54 years and weighing 68 kg, was admitted to the hospital with lethargy, dyspnea, and twitching in the extremities. He was diagnosed previously with primary hyperparathyroidism and nonischemic dilated cardiomyopathy. Surgical parathyroidectomy had been unsuccessful. His serum calcium concentration was 3.15 micromol/L and was refractory to bisphosphonate therapy. Therapy with cinacalcet 30 mg/d was reinitiated, resulting in a reduction in serum calcium concentration and greatly increased heart failure requiring inotropic drug therapy and hemofiltration. After 13 days of treatment, cinacalcet was withdrawn, and the patient's condition unproved. On reintroduction of cinacalcet 30 mg/d, the patient decompensated and required emergency circulatory support. Decompensation resolved 5 days after discontinuation of cinacalcet. DISCUSSION: Based on a score of 7 on the Naranjo adverse drug reaction probability scale, cinacalcet was the probable cause of cardiogenic shock in this patient. Calcium-channel antagonist poisoning is associated with hypotension and bradycardia, whereas the calcium sensitizer levosimendan has been reported to improve low-output heart failure, suggesting that calcium may have inotropic properties. CONCLUSIONS: It appears that cardiac function in this patient had adapted to hypercalcemia and became destabilized after introduction of cinacalcet. Caution should be exercised when considering treatment with cinacalcet in patients with heart failure.

Falls as a complication of diabetes mellitus in older people.

OBJECTIVES: The aims of this study were to determine the incidence of falls in a group of elderly patients with diabetes and to assess for the prevalence of risk factors for falls in this population. DESIGN: This is a population-based study with questionnaire-based interviews. SETTING: The setting for this study was the London District General Hospital outpatient department. PARTICIPANTS: Seventy-seven patients with diabetes, aged over 65 years, randomly selected whilst attending for general diabetic annual review. Patients with dementia, blindness, and immobility and those who were unable to give informed consent were excluded from this study. MEASUREMENTS: The incidence of falls in the last 12 months was used. Information was collected on the incidence of hypoglycaemic episodes, the presence of other medical conditions, visual impairment, and peripheral neuropathy, the use of medications and walking aids, and HbA1C and blood pressure control. RESULTS: The incidence of falls was 39%. Falls occurred more frequently in female patients and patients of increasing age. Falls occurred more frequently in patients with poor diabetic control [risk ratio (RR)=7.83 (2.948-20.799), chi2 value=6.422]; patients requiring assistance with mobility: for those mobile with a stick [RR=1.839 (1.048-3.227), chi2=4.619]; and those who had previously suffered a stroke [RR=1.929 (1.143-3.257), chi2=4.615]. CONCLUSION: We provide evidence that poorly controlled diabetes and conditions associated with complications of diabetes are associated with an increased risk of falling in older people. We recommend early recognition of the multiple causes of falls in the older diabetic patient and prompt referral of this group of patients to a specialist falls clinic.

Imaging of pericardial tumours: a case report.

BACKGROUND: Pericardial tumours are unusual and may be difficult to characterise with imaging. They manifest as large, non-contractile, solid masses within the pericardium. Presenting symptoms include heart failure, arrythmias, sudden death, cyanosis and chest pain. CASE PRESENTATION: We describe a case of massive pericardial fibroma in a 52 year old woman, who presented with palpitations only. CONCLUSION: We illustrate the different imaging modalities available to image this tumour prior to surgical resection, and indicate the strengths and weaknesses of each.

Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis.

BACKGROUND: We set out in this study to demonstrate the adverse effect profile of methotrexate when used in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in a district general hospital population, and to investigate the effect of alcohol consumption in these patients. METHODS: A prospective evaluation of 550 RA patients and 69 PsA patients was undertaken, controlling for confounding factors. Systematically randomised patients were further analysed regarding alcohol consumption. A transaminase level of three times the upper limit of normal on two or more occasions was taken to indicate hepatic injury. RESULTS: Gastrointestinal disturbance was the predominant adverse effect in RA patients (9.8%); hepatic disturbance was the most frequent in PsA patients (14.5%). Both groups had hepatic enzyme elevation; PsA patients were at significantly greater risk of elevated transaminases than RA patients (14.5% vs 7.5%, respectively, chi2 = 4.017). Alcohol consumption did not correlate with hepatic injury (mean 5.15 vs 6.6 alcohol units/week consumed by RA and PsA patients, respectively). CONCLUSION: Our data show methotrexate-treated PsA patients have a higher incidence of hepatotoxicity compared with methotrexate-treated patients with RA. It is proposed that psoriatic patients may be inherently more susceptible to methotrexate hepatotoxicity than are rheumatoid patients.

Arterial injury and endothelial repair: rapid recovery of function after mechanical injury in healthy volunteers.

Objective. Previous studies suggest a protracted course of recovery after mechanical endothelial injury; confounders may include degree of injury and concomitant endothelial dysfunction. We sought to define the time course of endothelial function recovery using flow-mediated dilation (FMD), after ischaemia-reperfusion (IR) and mechanical injury in patients and healthy volunteers. The contribution of circulating CD133(+)/CD34(+)/VEGFR2(+) "endothelial progenitor" (EPC) or repair cells to endothelial repair was also examined. Methods. 28 healthy volunteers aged 18-35 years underwent transient forearm ischaemia induced by cuff inflation around the proximal biceps and radial artery mechanical injury induced by inserting a wire through a cannula. A more severe mechanical injury was induced using an arterial sheath and catheter inserted into the radial artery of 18 patients undergoing angiography. Results. IR and mechanical injury produced immediate impairment of FMD (from 6.5 ± 1.2% to 2.9 ± 2.2% and from 7.4 ± 2.3% to 1.5 ± 1.6% for IR and injury, resp., each P < 0.001) but recovered within 6 hours and 2 days, respectively. FMD took up to 4 months to recover in patients. Circulating EPC did not change significantly during the injury/recovery period in all subjects. Conclusions. Recovery of endothelial function after IR and mechanical injury is rapid and not associated with a change in circulating EPC.

Prospective study on circulating MicroRNAs and risk of myocardial infarction.

OBJECTIVES: This study sought to explore the association between baseline levels of microRNAs (miRNAs) (1995) and incident myocardial infarction (1995 to 2005) in the Bruneck cohort and determine their cellular origin. BACKGROUND: Circulating miRNAs are emerging as potential biomarkers. We previously identified an miRNA signature for type 2 diabetes in the general population. METHODS: A total of 19 candidate miRNAs were quantified by real-time polymerase chain reactions in 820 participants. RESULTS: In multivariable Cox regression analysis, 3 miRNAs were consistently and significantly related to incident myocardial infarction: miR-126 showed a positive association (multivariable hazard ratio: 2.69 [95% confidence interval: 1.45 to 5.01], p = 0.002), whereas miR-223 and miR-197 were inversely associated with disease risk (multivariable hazard ratio: 0.47 [95% confidence interval: 0.29 to 0.75], p = 0.002, and 0.56 [95% confidence interval: 0.32 to 0.96], p = 0.036). To determine their cellular origin, healthy volunteers underwent limb ischemia-reperfusion generated by thigh cuff inflation, and plasma miRNA changes were analyzed at baseline, 10 min, 1 h, 5 h, 2 days, and 7 days. Computational analysis using the temporal clustering by affinity propagation algorithm identified 6 distinct miRNA clusters. One cluster included all miRNAs associated with the risk of future myocardial infarction. It was characterized by early (1 h) and sustained activation (7 days) post-ischemia-reperfusion injury and consisted of miRNAs predominantly expressed in platelets. CONCLUSIONS: In subjects with subsequent myocardial infarction, differential co-expression patterns of circulating miRNAs occur around endothelium-enriched miR-126, with platelets being a major contributor to this miRNA signature.

The vanishing vast ventricular thrombus.

A 54-year old man presented with multiple pulmonary emboli and an incidental finding of a huge left ventricular thrombus. Transthoracic echo images demonstrated a globally dilated heart with very poor left ventricular function. It was elected to manage the patient medically, and he was commenced on warfarin therapy, resulting in completed resolution of the thrombus over 10 weeks. No underlying cause was found and he did not experience any further embolic events. This illustrates a rare case of a large ventricular thrombus in a patient with no underlying risk factors.