B-type natriuretic peptide and acute coronary syndromes.
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Angina, Unstable↗
Biomedical subjects
Rakesh Sharma
Publications and source records attributed to Rakesh Sharma.
Insulin resistance in moderate chronic heart failure is related to hyperleptinaemia, but not to norepinephrine or TNF-alpha.
OBJECTIVES: Chronic heart failure (CHF) has emerged as an insulin-resistant state, independently of ischaemic aetiology. The underlying mechanisms of this finding are not known. Catecholamines, tumor necrosis factor alpha (TNFalpha) and leptin, the adipocyte specific hormone, have all been implicated as mediators of impaired insulin sensitivity. The purpose of this study was to examine in patients with CHF and in comparison to healthy controls subjects whether norepinephrine, TNFalpha or leptin relate to insulin sensitivity. DESIGN: 41 patients with CHF (age 60+/-2 years, NYHA I/II/III/IV 4/12/22/3, peak oxygen consumption 17.6+/-1.0 ml/kg per min) and 21 healthy controls of similar age and total and regional fat distribution were studied in a cross-sectional study. Insulin sensitivity was assessed by intravenous glucose tolerance testing using the minimal model approach; catecholamines, TNFalpha and soluble TNF receptors 1 and 2 were also measured. Total and regional body fat mass was assessed by dual energy X-ray absorptiometry. RESULTS: Insulin sensitivity was reduced in CHF patients compared to controls by 31% (P<0.01) and fasting insulin was higher in patients than in controls (79.1+/-9.7 vs. 41.4+/-6.0 pmol/l, P<0.01). Patients had, compared to healthy controls, elevated serum leptin levels (8.28+/-0.84 vs. 4.83+/-0.68 ng/ml), norepinephrine (3.45+/-0.34 vs. 1.87+/-0.16 nmol/l, both P<0.01) and soluble TNF-receptors 1 (1280+/-141 vs. 639+/-52 pg/ml) and 2 (2605+/-184 vs. 1758+/-221 pg/ml, both P<0.01). Leptin levels corrected for total body fat mass were higher in CHF patients than in controls (41.3+/-3 vs. 24.3+/-2 pg/ml per 100 g, P<0.001). TNFalpha was not significantly different between the groups. In both groups there was an inverse correlation between insulin sensitivity and serum leptin (r=-0.65, P<0.0001 for pooled subjects); in contrast, no significant relation was found between insulin sensitivity and norepinephrine or TNFalpha. In multivariate regression analysis, leptin emerged as the only significant predictor of insulin sensitivity (standardised coefficient=-0.59, P<0.001), independent of body fat mass, age and peak VO2. CONCLUSION: In moderate CHF, elevated leptin levels directly and independently predict insulin resistance. Elevated serum leptin levels could play a role in the impaired regulation of energy metabolism in CHF. In contrast to observations in other conditions, TNFalpha and norepinephrine are not related to insulin resistance in moderate CHF.
Adipose Tissue↗
The syndrome of cardiac cachexia.
Cachexia, i.e. body wasting, has long been recognised as a serious complication of chronic illness. The occurrence of wasting in chronic heart failure (CHF) has been known for many centuries, but it has not been investigated extensively until recently. Cardiac cachexia is a common complication of CHF which is associated with poor prognosis, independently of functional disease severity, age, measures of exercise capacity, and left ventricular ejection fraction. Patients with cardiac cachexia suffer from generalised loss of lean tissue, fat tissue, as well as bone tissue. Cachectic CHF patients are weaker and fatigue earlier. This is due to both reduced skeletal muscle mass and impaired skeletal muscle quality. Concerning the pathophysiology of cardiac cachexia, there is increasing evidence that neurohormonal and immune abnormalities may play a crucial role. Cachectic CHF patients have raised plasma levels of norepinephrine, epinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone levels. A number of studies have also shown that cardiac cachexia is linked to raised plasma levels of inflammatory cytokines, such as tumor necrosis factor alpha. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems, termed catabolic/anabolic imbalance, is likely to be responsible for the development of the wasting process. It is hoped that a better understanding of the pathophysiological mechanisms involved in cardiac cachexia will lead to novel therapeutic strategies in the (near) future.
Cachexia↗
Cytokines, apoptosis and cachexia: the potential for TNF antagonism.
The cachexia syndrome is characterised by progressive weight loss and depletion of lean body mass and has long been recognised as a poor prognostic sign. Whilst the clinical features of the wasting process are readily apparent, its pathogenesis is complex and poorly understood. There is increasing evidence that the immune system, in particular inflammatory cytokines, may play an important role in the development of cachexia. The cytokine considered to be the most relevant to this process is tumor necrosis factor alpha (TNF), although other mediators such as interleukin (IL) 1, IL-6 and interferon gamma have also been implicated. Apoptosis represents a potential pathway by which wasting can occur in chronic diseases. Cytokines and their corresponding receptors are known to be important regulators of cell death. Apoptosis has been demonstrated in the skeletal muscle of patients with chronic heart failure (CHF) and is thought to be partly responsible for the significant impairment of functional work capacity associated with this condition. An understanding of the mechanisms that regulate muscle protein breakdown is essential for the development of strategies for treating or even preventing muscle cachexia in patients. It is the aim of this article to review the role of inflammatory cytokines, particularly TNF, in the pathogenesis of wasting and also the potential for anti-cytokine therapy. Although this review will concentrate predominantly on the syndrome of CHF, other chronic illnesses such as liver disease, cancer, and sepsis will also be discussed.
Apoptosis↗
Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration.
BACKGROUND: Abnormal prolongation of QRS duration is a common finding in patients with chronic heart failure, and is associated with an impaired prognosis. The optimum QRS duration for separating chronic heart failure patients with respect to prognosis has not been determined. Whilst resynchronisation of ventricular conduction may benefit patients with QRS>150 ms, this has yet to be determined for patients with moderate QRS prolongation. METHODS: We evaluated 155 patients with chronic heart failure (New York Heart Association class 2.6+/-0.8, mean+/-S.D.). The mean follow-up period was 838+/-748 days. Patients were sub-grouped according to QRS duration: <120 ms (normal QRS, n=82), 120-150 ms (moderate prolongation, n=44) and >150 ms (severe prolongation, n=29). RESULTS: The optimal QRS duration for stratifying patients for 2-year event free survival was 120 ms (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64-0.81). Moderate prolongation of QRS duration was associated with a worse New York Heart Association class, peak oxygen consumption and left ventricular ejection fraction when compared to patients with normal QRS duration (all P<0.05). Patients with moderate prolongation of QRS duration had similar impairment of New York Heart Association class and peak oxygen consumption as compared with patients with QRS duration >150 ms (all P>0.05). CONCLUSIONS: The optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms. Heart failure patients with moderate QRS prolongation share similar impairment of exercise capacity and functional class to those with severe prolongation.
Aged↗
Beta-blocker therapy for dynamic left-ventricular outflow tract obstruction.
BACKGROUND: In a small but significant group of elderly patients who present with breathlessness, dynamic left-ventricular outflow tract obstruction (DLVOTO) may be responsible for symptom generation. The aim of our study was to investigate the effect of beta-blockade on ventricular physiology and symptoms in patients with DLVOTO. METHODS: We performed a pilot study in 15 patients (age 76+/-10 years, mean+/-S.D., 14 female) with symptoms of exercise intolerance (New York Heart Association, NYHA, class 2.7+/-0.5). All patients had normal resting left ventricular (LV) systolic function together with DLVOTO based on the presence of basal septal hypertrophy and the development of high outflow tract velocities on stress echocardiography. All were commenced on oral atenolol (mean dose 45+/-19 mg), but this could not be tolerated in four patients due to a deterioration in clinical status. RESULTS: In the remaining 11 patients who could tolerate atenolol therapy, the rate pressure product was significantly lower (23%, P=0.028) and there was a marked reduction in LV outflow tract velocity (23%, P=0.001) following beta-blockade. Patient symptoms improved significantly following atenolol therapy, with a reduction in mean NYHA class from 2.8+/-0.4 to 1.5+/-0.5 (P<0.0001). CONCLUSIONS: Beta-blockade may represent a beneficial therapeutic approach in selected patients with DLVOTO as identified by stress echocardiography.
Adrenergic beta-Antagonists↗
The cardiac component of cardiac cachexia.
BACKGROUND: Recent evidence suggests the importance of noncardiac mechanisms in the genesis of the syndrome of cardiac cachexia. This raises the question of the relative role of the heart itself in this syndrome. This study sought to assess the cardiac dimensions, mass, and function and changes in these parameters over time in patients with chronic heart failure with and without cachexia. METHODS: Doppler echocardiography was performed in 28 patients with nonedematous weight loss (>7.5% over a period of >6 months) compared with 56 matched patients without weight loss in a ratio of 1:2 (age 71 +/- 13 vs 67 +/- 8 years, P =.07; New York Heart Association class 2.9 +/- 0.7 vs 2.6 +/- 0.6, P =.08). In 18 cachectic and 35 noncachectic patients with previous echocardiographic recordings, we analyzed the changes in left ventricular (LV) dimensions and mass over time. RESULTS: Cardiac dimensions including LV diastolic (69 +/- 9 mm vs 67 +/- 13 mm) and systolic cavity diameter (58 +/- 11 mm vs 55 +/- 15 mm), LV mass (480 +/- 180 g vs 495 +/- 190 g), and LV systolic and diastolic function including fractional shortening (16% +/- 10% vs 18% +/- 10%), isovolumic relaxation time (29 +/- 22 ms vs 36 +/- 27 ms), and E/A ratio (2.7 +/- 1.6 vs 3.3 +/- 2.9) did not differ between cachectic and noncachectic patients (all P >.1). By analyzing changes in LV mass over time, we found an increase (>20%) in 2 (11%) cachectic and 14 (40%) noncachectic patients and a decrease in LV mass (>20%) in 9 (50%) cachectic and 8 (23%) noncachectic patients (chi2 test, P <.05). CONCLUSIONS: Although no specific cardiac abnormality could be detected echocardiographically in cachectic patients compared with patients with noncachectic chronic heart failure in a cross-sectional study, over time a significant loss of LV mass (>20%) occurs more frequently in patients with cardiac cachexia.
Cachexia↗
Relationship between oxidative stress and embryotoxicity of hydrosalpingeal fluid.
BACKGROUND: Oxidative stress mechanisms are involved in the pathophysiology of many reproductive disorders. The objective of this study was to characterize oxidative stress parameters in hydrosalpingeal fluid (HSF) and examine their possible role in early embryo development. METHODS AND RESULTS: HSF was aspirated at laparoscopic salpingectomy in 11 infertile women. Reactive oxygen species (ROS), total (non-enzymatic) antioxidant capacity (TAC) and lipid peroxidation (LPO) were assayed. Two-cell mouse embryos were incubated with 25, 50 or 75% HSF and the blastocyst development rate was observed. ROS was detected in five of 11 (45%) HSF samples with a mean of 4.2 x 10(4) c.p.m. LPO was detected in all samples at a mean (+/- SD) value of 5575.4 +/- 6091.9 micromol/l malonaldehyde. The mean blastocyst development rate at 25, 5+/- 0 and 75% HSF and in the control group was 88.9 +/- 9.4, 65.7 +/- 19.1, 45.7 +/- 5.7 and 96.7% respectively (P < 0.0001). The blastocyst development rate was positively correlated to ROS concentrations (P < 0.02) but was not significantly related to LPO. CONCLUSIONS: The blastocyst development rate decreased with increasing concentrations of HSF. For the first time, the presence of ROS, LPO and TAC activity in human HSF was characterized. A possible role of oxidative stress in the embryotoxicity of HSF is suggested.
Animals↗
Radioisotopes and airport security.
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Aerospace Medicine↗
Immune and neurohormonal pathways in chronic heart failure.
Chronic heart failure is a complex disorder with interactions among the cardiovascular, immune, and neurohormonal systems. The concept that the progression of heart failure is due to neurohormonal abnormalities has received the greatest attention to date, leading to substantial therapeutic benefits. Although many current therapies are also thought to exert a variety of immunologic effects, this has been much less studied. In this review, the authors discuss a number of interactions among immune pathways and neurohormonal abnormalities relevant to heart failure. Cytokines, in particular tumor necrosis factor-alpha, have tremendous interactive opportunities within a regulatory network of energy metabolism, immune function, and neuroendocrine and hormonal function. Inflammatory cytokines are known to contribute to the progression of heart failure, and have been related to patients' prognosis. Advanced heart failure can be considered a state of chronic (low-grade) inflammation, and there are many reasons to suggest that anticytokine therapy could be successful in these patients. These novel approaches are certainly not without some risk, and many of them are very expensive, which may limit their application to certain subgroups of patients. In the future, it may not be enough to monitor cardiac function alone. Rather, the immune and neurohormonal status of patients may also need to be included in the performance of a complete assessment.
Chronic Disease↗