Javaid Iqbal

Quality of life in patients with chronic heart failure and their carers: a 3-year follow-up study assessing hospitalization and mortality

Chronic heart failure (CHF) due to left ventricular systolic dysfunction is associated with poor quality of life (QoL). This study aimed to assess factors affecting health‐related QoL in CHF patients and their carers and the impact of QoL on clinical outcomes.

Therapeutic manipulation of glucocorticoid metabolism in cardiovascular disease.

The therapeutic potential for manipulation of glucocorticoid metabolism in cardiovascular disease was revolutionized by the recognition that access of glucocorticoids to their receptors is regulated in a tissue‐specific manner by the isozymes of 11β‐hydroxysteroid dehydrogenase. Selective inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 have been shown recently to ameliorate cardiovascular risk factors and inhibit the development of atherosclerosis. This article addresses the possibility that inhibition of 11β‐hydroxsteroid dehydrogenase type 1 activity in cells of the cardiovascular system contributes to this beneficial action. The link between glucocorticoids and cardiovascular disease is complex as glucocorticoid excess is linked with increased cardiovascular events but glucocorticoid administration can reduce atherogenesis and restenosis in animal models. There is considerable evidence that glucocorticoids can interact directly with cells of the cardiovascular system to alter their function and structure and the inflammatory response to injury. These actions may be regulated by glucocorticoid and/or mineralocorticoid receptors but are also dependent on the 11β‐hydroxysteroid dehydrogenases which may be expressed in cardiac, vascular (endothelial, smooth muscle) and inflammatory (macrophages, neutrophils) cells. The activity of 11β‐hydroxysteroid dehydrogenases in these cells is dependent upon differentiation state, the action of pro‐inflammaotory cytokines and the influence of endogenous inhibitors (oxysterols, bile acids). Further investigations are required to clarify the link between glucocorticoid excess and cardiovascular events and to determine the mechanism through which glucocorticoid treatment inhibits atherosclerosis/restenosis. This will provide greater insights into the potential benefit of selective 11β‐hydroxysteroid dehydrogenase inhibitors in treatment of cardiovascular disease.

Congenital absence of inferior vena cava and thrombosis: a case report

IntroductionA congenitally absent Inferior Vena Cava (IVC) is a rare anomaly that is recognised to be associated with idiopathic Deep Venous Thrombosis (DVT), particularly in the young. It may not be apparent until later in life. Retrospectively, as discussed in this case, there can be clues indicating the presence of such an anomaly from a young age. However, it is not clear whether early recognition of this condition would affect the prognosis and treatment.Case presentationA 54 year old gentleman was admitted with 3 weeks of abdominal pain and localised swelling over the right flank. Examination revealed palpable snake-like tortuous, tender lumps on the abdominal wall. Past history revealed chronic non-healing venous leg ulcers, and varicose veins necessitating varicose vein ligation at a very young age. The ulcers eventually needed skin grafting.During this, current admission he was investigated and diagnosed with Deep Vein Thrombosis (DVT). CT scan, performed to search for intra-abdominal cancer, revealed absence of the Inferior Vena Cava with extensive thrombosed collaterals of the superficial abdominal and azygous veins and a congenitally atrophic left kidney.ConclusionThis is a case of one of the oldest patient described in the literature to be diagnosed with absence of the IVC. It is thought that IVC anomalies are under-diagnosed, and may be commoner than once believed. However there were vital clues in his previous medical history suspicious for an underlying venous anomaly. Idiopathic DVT in a relatively young person with a past history of chronic leg ulceration or varicose veins should be investigated for congenital anomalies of the IVC. This is best achieved by CT scan of the abdomen.

Contribution of Endogenous Glucocorticoids and Their Intravascular Metabolism by 11β-HSDs to Postangioplasty Neointimal Proliferation in Mice

Exogenous glucocorticoids inhibit neointimal proliferation in animals. We aimed to test the hypothesis that endogenous glucocorticoids influence neointimal proliferation; this may be mediated by effects on systemic risk factors or locally in vessels and modulated by either adrenal secretion or enzymes expressed in vessels that mediate local inactivation [11β-hydroxysteroid dehydrogenase type II (11β-HSD2) in endothelium] or regeneration [11β-hydroxysteroid dehydrogenase type I (11β-HSD1) in smooth muscle] of glucocorticoids. Femoral artery wire angioplasty was conducted in C57BL/6J, Apo-E(-/-), 11β-HSD1(-/-), Apo-E, 11β-HSD1(-/-) (double knockout), and 11β-HSD2(-/-) mice after glucocorticoid administration, adrenalectomy, glucocorticoid or mineralocorticoid receptor antagonism, or selective 11β-HSD1 inhibition. In C57BL/6J mice, neointimal proliferation was reduced by systemic or local glucocorticoid administration, unaffected by adrenalectomy, reduced by the mineralocorticoid receptor antagonist eplerenone, and increased by the glucocorticoid receptor antagonist RU38486. 11β-HSD2 deletion had no effect on neointimal proliferation, with or without eplerenone. 11β-HSD1 inhibition or deletion had no effect in chow-fed C57BL/6J mice but reduced neointimal proliferation in Apo-E(-/-) mice on Western diet. Reductions in neointimal size were accompanied by reduced macrophage and increased collagen content. We conclude that pharmacological administration of glucocorticoid receptor agonists or of mineralocorticoid receptor antagonists may be useful in reducing neointimal proliferation. Endogenous corticosteroids induce beneficial glucocorticoid receptor activation and adverse mineralocorticoid receptor activation. However, manipulation of glucocorticoid metabolism has beneficial effects only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose rather than intravascular glucocorticoid signaling. Reducing glucocorticoid action with 11β-HSD1 inhibitors that are being developed for type 2 diabetes appears not to risk enhanced neointimal proliferation.

Displacement of Cortisol From Human Heart by Acute Administration of a Mineralocorticoid Receptor Antagonist

CONTEXTnMineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified.nnnOBJECTIVEnThis study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart.nnnPARTICIPANTS AND INTERVENTIONSnNine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire.nnnRESULTSnThere was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration.nnnCONCLUSIONSnHuman cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart.

Malignant peritoneal mesothelioma as a rare cause of ascites: a case report

IntroductionPeritoneal mesothelioma is a rare tumor with diagnostic and therapeutic problems. The peritoneum is the second most common site for development of mesothelioma, which in 30–45% of cases is associated with a synchronous pleural mesothelioma. Clinical symptoms and findings may be confusing and diagnosis can be easily overlooked especially in cases where there is no previous asbestos exposure.Case presentationWe report a case of malignant peritoneal mesothelioma in a 75-year-old woman who presented with ascites which, in the absence of inhalational exposure to asbestos, caused diagnostic confusion, and evaded radiological detection.ConclusionWe concluded from this case that Peritoneal Mesothelioma although rare but should be considered among the differential diagnosis of Ascites.

Metastatic myocardial abscess on the posterior wall of the left ventricle: a case report

IntroductionMyocardial abscess is a rare and potentially fatal condition. Metastatic myocardial abscess in the setting of infective endocarditis has been infrequently reported in the medical literature. To the best of the authors knowledge no case of myocardial abscess affecting the free wall of the left ventricle secondary to infective endocarditis of a right-sided heart valve has been reported previously.Case presentationWe report a case of tricuspid valve endocarditis caused by Staphylococcus aureus and resulting in a myocardial abscess on the posterior wall of the left ventricle, far from the active valvular infection. We also briefly discuss the role of different investigation modalities including cardiac magnetic resonance imaging in diagnosing myocardial abscess.ConclusionMyocardial abscess is a life-threatening illness. A high index of clinical suspicion is required to make a prompt diagnosis. Final diagnosis may need multi-modality imaging. An early diagnosis, aggressive medical therapy, multidisciplinary care and timely surgical intervention may save life in this otherwise fatal condition.

YIA 3 Effect of intracellular glucocorticoid metabolism on neointimal proliferation in a mouse model of wire angioplasty

Rationale Glucocorticoid administration increases cardiovascular risk but inhibits neointimal proliferation in animal models. Glucocorticoid activity in target tissues is regulated by the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD); type-1 regenerates active glucocorticoids and type-2 inactivates glucocorticoids. Both 11β-HSD isozymes are expressed in vessel wall as well as in liver and adipose tissue; they may modulate vascular remodelling by acting locally or by influencing systemic risk factors. This study investigated effects of these isozymes on post-angioplasty neointimal proliferation. Methodology Wire angioplasty was conducted in femoral arteries of C57Bl/6J, Apo-E knockout, 11β-HSD1 knockout, Apo-E/11β-HSD1 double-knockout and 11β-HSD2 knockout mice. Effects of pharmacological inhibition of 11β-HSD1 (Compound 544, 30u2005mg/kg/day) were also studied. Vascular lesions were assessed using novel optical projection tomography and standard histology. Results 11β-HSD1 deletion or inhibition resulted in ∼35% reduction in neointimal volume with corresponding increase in lumen size in western-diet fed Apo-E knockout mice but had no significant effect in chow-fed C57Bl/6J mice. Reduced neointimal proliferation was associated with reduction in weight gain, insulin resistance, systolic blood pressure and macrophage content of neointimal lesions. 11β-HSD2 knockout mice had substantially higher blood pressure than C57Bl/6J mice. Neointimal proliferation, however, was similar in both groups, albeit 11β-HSD2 knockout mice having higher neointimal macrophage content. Conclusion 11β-HSD1 inhibition ameliorates multiple cardiovascular risk factors and reduces neointimal proliferation only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose. Any local amplification (with disruption of 11β-HSD2) or reduction (with disruption of 11β-HSD1) in glucocorticoid concentration within the vessel wall is likely to be insufficient to overcome the effect of systemic risk factors on neointimal proliferation.

071 Quality of life in patients with chronic heart failure and their carers: a 3-year follow-up study assessing hospitalisation and mortality

Introduction Chronic Heart Failure (CHF) due to left ventricular systolic dysfunction is associated with poor quality of life (QoL) and survival. This study aimed to assess the effects of a wide range of clinical, social, psychological and demographic factors on QoL in an unselected cohort of CHF patients and their carers and to investigate the impact of QoL on subsequent hospitalisation and mortality. Methods Demographic, social and clinical data were collected for consecutive CHF patients in an academic hospital setting. All patients (n=179) and informal carers (n=131) completed a generic QoL questionnaire (EQ-5D) and patients also completed CHF specific QoL questionnaire (Minnesota Living with Heart Failure, MLHF). Patients were then followed up for 3u2005years to assess subsequent hospitalisations and mortality. Data were analysed employing step-wise multiple regression and Cox proportional-hazards survival model. Results CHF patients had poor QoL with a mean QoL score of 50±2 on MLHF questionnaire and 0.57±0.03 on EQ-5D questionnaire. QoL score was independently predicted by NYHA class (p<0.001), socioeconomic deprivation (p<0.001) and lack of an informal carer (p=0.05). QoL of carers was associated with QoL of patients and was particularly low in female carers compared to male carers (0.74±0.02 vs 0.86±0.05, p=0.03). Moreover, carer QoL was also affected by patient related factors including NYHA class, presence of anaemia or a cancer. During the follow-up period of 3u2005years (range 33–40u2005months), 67 patients (37%) died. CHF patients in lowest QoL quartile were at significantly increased risk of hospital admissions (HR 7.3, 95%CI 3.6 to 9.1, p<0.001) and death (HR 1.7, 95%CI 1.1 to to 2.9, p=0.03). Mortality was also independently associated with multiple hospitalisations (HR 6.0, CI 3.3 to to 10.0, p<0.001) and lack of β-blocker therapy (HR 1.8, CI 1.1 to 2.8, p=0.03). Conclusion Severe heart failure, poor socioeconomic status and lack of social support results in poor QoL in CHF patients which in turn leads to an increased risk of hospital admissions and death. Clinical Implications QoL assessment may complement clinical prognostic markers to identify CHF patients at high risk of adverse events. Serial assessment of QoL may also provide additional valuable information about disease progression, effect of interventions and prognosis. Abstract 71 Figure 1 Baseline QOL (MLHF score) correlates with subsequent mortality (A) and hospital admissions (B).