The effects of antidiabetic agents on heart failure.

In the Netherlands, approximately 250,000 people are living with heart failure. About one-third of them have comorbid diabetes mellitus type 2. Until recently, the effects of antidiabetic agents on heart failure were largely unknown. This changed after an observed increased risk of heart failure and ischaemic heart disease associated with thiazolidinediones that prompted the requirement for cardiovascular outcome trials for new glucose-lowering drugs. In the past decade, three new classes of antidiabetic agents have become available (i.e. dipeptidyl peptidase­4 inhibitors, glucagon-like peptide­1 receptor agonists and sodium-glucose cotransporter­2 (SGLT2) inhibitors). Although the first two classes demonstrated no beneficial effects on heart failure compared to placebo in patients with diabetes mellitus type 2, SGLT2 inhibitors significantly and consistently lowered the risk of incident and worsening heart failure. Two recent trials indicated that these favourable effects were also present in non-diabetic patients with heart failure with reduced ejection fraction, resulting in significantly lower risks of hospitalisation for heart failure and presumably also cardiovascular and all-cause mortality. SGLT2 inhibitors have been shown to be benefit on top of recommended heart failure therapy including sacubitril/valsartan and may also prove beneficial for heart failure with preserved ejection fraction. In this review, we discuss the effects of antidiabetic agents on heart failure.

Thyrotoxic periodic paralysis: an unusual presentation of hyperthyroidism.

Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism among Asians, characterised by sudden onset of hypokalaemia and muscle paralysis. Several factors may contribute to a delay in diagnosis, including the subtlety of hyperthyroidism, the transient nature of the events and the rarity of this disease in the West. As life-threatening arrhythmias may occur during an attack, awareness among physicians is necessary for early recognition and treatment. Advances have been made in understanding the pathophysiological mechanism leading to hypokalaemia, which include recently identified mutations of the inwardly rectifying potassium channel Kir2.6. Treatment includes the supplementation of potassium, a nonselective beta-blocker, and ultimately treatment of the underlying hyperthyroidism. Here we report three cases of TPP in the Netherlands, and review the literature on clinical features, pathophysiological hypothesis and treatment.

Intra-operative parathyroid hormone measurements - experience of a non-academic hospital.

BACKGROUND: Surgery is the treatment of choice for symptomatic primary hyperparathyroidism. The majority of research concerning intra-operative parathyroid hormone (ioPTH) measurements is conducted in university hospitals. Whether ioPTH measurements are feasible and useful in predicting the presence of remaining hyperfunctioning parathyroid tissue in a non-academic hospital remains uncertain. METHODS: Data were collected on all patients with biochemically proven and surgically treated primary hyperparathyroidism treated at the Reinier de Graaf Hospital from August 2002 to December 2007. RESULTS: Sixty-five patients were included. The mean pre-operative serum calcium level was 2.78 mmol/l (range 2.28 - 3.80 mmol/l, normal range 2.20 - 2.65 mmol/l) and the mean serum parathyroid hormone level 17.0 pmol/l (range 4.0 - 90.3 pmol/l, normal range 1.0 - 5.5 pmol/l). All patients were operated on for primary hyperparathyroidism, using ioPTH measurements during their first operation. Sensitivity and specificity rates of ioPTH measurements were 98% and 89%, respectively. The ioPTH test accurately indicated incomplete removal of all hyperfunctioning parathyroid tissue in 8 patients (12%). Five patients (8%) were re-explored immediately, of whom 4 were successfully treated in this single operative session. One patient was operated on successfully the next day. Two patients were operated on with a successful result during a second admission. In all the ioPTH measurements there was 1 false-positive result (1.5%) and 1 false-negative result (1.5%). The mean postoperative calcium value for the successfully treated patients was 2.34 mmol/l (range 2.14 - 2.71 mmol/l, normal range 2.20 - 2.65 mmol/l). The mean postoperative PTH level for the successfully treated patients was 3.76 pmol/l (range 0.40 - 7.1 pmol/l). CONCLUSION: Our data suggest that ioPTH measurements are feasible and useful in a non-academic hospital.

Raloxifene exposure enhances brain activation during memory performance in healthy elderly males; its possible relevance to behavior.

Raloxifene is a selective estrogen receptor modulator (SERM) that is prescribed in females only, but its use in male subjects is increasingly considered. With a growing number of patients having potential benefit from raloxifene, the need for an assessment of its effects on brain function is growing. Effects of estrogens on brain function are very subtle and difficult to detect by neuropsychological assessment. Functional imaging techniques, however, have been relatively successful in detecting such changes. This study used functional magnetic resonance imaging (fMRI) to examine effects of raloxifene treatment on memory function. Healthy elderly males (n = 28; mean age 63.6 years, SD 2.4) were scanned during performance on a face encoding paradigm. Scans were made at baseline and after 3 months of treatment with either raloxifene (n = 14) or placebo (n = 14). Treatment effects were analyzed using mixed-effects statistical analysis (FSL). Activation during task performance involved bilateral parietal and prefrontal areas, anterior cingulate gyrus, and inferior prefrontal, occipital, and mediotemporal areas bilaterally. When compared to placebo, raloxifene treatment significantly enhanced activation in these structures (Z > 3.1), except for mediotemporal areas. Task performance accuracy diminished in the placebo group (P = 0.02), but remained constant in the raloxifene group (P = 0.60). In conclusion, raloxifene treatment enhanced brain activation in areas spanning a number of different cognitive domains, suggesting an effect on cortical arousal. Such effects may translate into small effects on behavior, including effects on attention and working memory performance, executive functions, verbal skills, and episodic memory. Further neuropsychological assessment is necessary to test the validity of these predictions.

Interindividual differences of medial temporal lobe activation during encoding in an elderly population studied by fMRI.

Functional MRI (fMRI) is used to study medial temporal lobe (MTL) activation during encoding of new information into memory. In most studies, fMRI data of different subjects are averaged in standard coordinate space. However, interindividual differences in activation can be extensive, reflecting functional heterogeneity. Further, anatomical differences in brain structure cause additional variance and loss of registration accuracy. Such differences in structural and functional MTL characteristics may interfere with the efficiency of averaging data across subjects, and may become more significant with aging and dementia. The current study concerns the analysis of individual differences in MTL activation associated with episodic encoding.Twenty-nine healthy elderly men between 60 and 70 years old performed a simple face encoding task during fMRI scanning. Individual data were analyzed in native space, and compared to the group average in standard space (Talairach and Tournoux).MTL volumes between subjects varied between 6.34 and 11.27 cm(3), and had considerable variation when mapped to standard space. Eighteen of the 29 subjects showed MTL activity and activation patterns varied both in location and size (ranging from 0.11 to 1.78 cm(3)), with the strongest activation in the left posterior part of the MTL. In standard space, no region was significantly activated on a group level at a comparable alpha level. We conclude that while the majority of elderly subjects show MTL activation during episodic encoding of faces, there is considerable structural and functional variability between subjects. Group analysis in standard space may not be appropriate for studies of a complex structure such as the MTL, particularly not in aging and dementia.

Raloxifene, conjugated oestrogen and endothelial function in postmenopausal women.

OBJECTIVES: To study the long-term effects of raloxifene, a potential designer oestrogen, and oestrogen monotherapy on endothelial function in healthy postmenopausal women. DESIGN: A 2-year double-blind, randomized and placebo-controlled study in an Academic Medical Center. Fifty-six hysterectomized but otherwise healthy postmenopausal women randomly received raloxifene hydrochloride 60 mg day-1 (n = 15) or 150 mg day-1 (n = 13), conjugated equine oestrogen (CEE) 0.625 mg day-1 (n = 15), or placebo (n = 13). MAIN OUTCOME MEASURES: Endothelial function as estimated from brachial artery flow-mediated, endothelium-dependent vasodilation and nitroglycerine-induced endothelium-independent vasodilation, and plasma levels of the endothelium-derived regulatory proteins, von Willebrand factor (vWF) and endothelin (ET). RESULTS: Raloxifene 60 mg did not significantly affect endothelial function. As compared with placebo, at 6 months of therapy, raloxifene 150 mg and CEE were associated with a mean increase in vWF of 25.5% point (95% CI 3.6-47.3) and 26.6% point (95% CI 6.9-46.3), respectively. At 24 months of therapy, raloxifene 150 mg was associated with a mean decrease in ET of 0.96 pg mL-1 (95% CI -1.57 to -0.36). Raloxifene nor CEE significantly affected endothelium-dependent and/or -independent vasodilation. CONCLUSIONS: Our results suggest that long-term therapy with raloxifene or oral CEE does not affect endothelium-dependent vasodilation in healthy postmenopausal women. Raloxifene 150 mg day-1 might have both positive and negative effects on endothelium. The clinical significance of these findings remains to be investigated.