Ian I. Joffe

Abnormal cardiac function in the streptozotocin-induced, non–insulin-dependent diabetic rat: Noninvasive assessment with Doppler echocardiography and contribution of the nitric oxide pathway☆

OBJECTIVES We sought to evaluate in vivo and in vitro left ventricular (LV) geometry and function in streptozotocin-induced diabetic rats and the possible role of the nitric oxide (NO) pathway. BACKGROUND Diabetes results in cardiac dysfunction; however, the specific abnormalities are unknown. Because decreased NO contributes to abnormal vascular function in diabetics, we hypothesized that NO pathway abnormalities may contribute to diabetic cardiomyopathy. METHODS Control rats and those with non-insulin-dependent diabetes mellitus (NIDDM) underwent echocardiography, hemodynamic assessment, isolated heart perfusion and measurement of exhaled NO and LV endothelial constitutive nitric oxide synthase (ecNOS). RESULTS Diabetic rats had increased LV mass (3.3 +/- 0.6 vs. 2.6 +/- 0.3 g/g body weight [BW], p < 0.001) and cavity dimensions (diastolic 2.0 +/- 0.1 vs. 1.8 +/- 0.2 cm/cm tibial length [TL], p < 0.05). Diabetic rats had prolonged isovolumic relaxation time (IVRT) (40 +/- 8 vs. 26 +/- 6 ms, p < 0.0001), increased atrial contribution to diastolic filling (0.47 +/- 0.09 vs. 0.30 +/- 0.08 m/s, p < 0.0001), and elevated in vivo LV end-diastolic pressure (7 +/- 6 vs. 2 +/- 1 mm Hg, p = 0.04). Diabetic rats had increased chamber stiffness. Shortening was similar in both groups, despite reduced meridional wall stress in diabetics, suggesting impaired systolic contractility. Exhaled NO was lower in diabetic rats (1.8 +/- 0.2 vs. 3.3 +/- 0.3 parts per billion, p < 0.01) and correlated with Doppler LV filling. The ecNOS was similar between the groups. CONCLUSIONS Diabetic cardiomyopathy is characterized by LV systolic and diastolic dysfunction, the latter correlating with decreased exhaled NO. The NO pathway is intact, suggesting impaired availability of NO as contributor to cardiomyopathy.

Osteoporosis associated with rheumatoid arthritis : pathogenesis and management

Rheumatoid arthritis is associated with both localized and generalized osteoporosis. Localized osteoporosis can be considered to be caused by local disease mechanisms, including the generation of factors from activation of the cytokine pathway. The etiology of generalized osteoporosis has been difficult to elucidate, particularly because of the lack of sensitive techniques to measure bone mineral density. The introduction of single- and dual-photon absorptiometry and quantitative computed tomography has allowed more accurate assessment of bone mineral density. In general, bone mineral density loss at appendicular sites does not correlate well with axial bone density loss. Corticosteroid treatment exaggerates the development of osteoporosis in up to 40% of patients with rheumatoid arthritis. Sex hormone status, physical activity, disease duration, and functional class are all significant predictors for the development of osteoporosis. Current therapy for prevention and treatment is based largely on theoretical considerations. Physical activity should be encouraged once acute joint inflammation has settled. Postmenopausal women and amenorrheic premenopausal women will benefit from cyclical estrogen replacement. Patients with low serum 1,25-dihydroxy vitamin D3 levels, and males with low serum testosterone levels, are candidates for replacement therapy with the appropriate hormones. In patients who are receiving corticosteroids the dose should be limited, and oral calcium supplements are of benefit. The use of the newer corticosteroid deflazacort, and disease-modifying immunosuppressive drugs, are discussed. Other therapeutic options which should be considered, although published trials are scarce, are calcitonin and the diphosphonates. Further studies are awaited concerning the optimum prevention and treatment of osteoporosis associated with rheumatoid arthritis.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of change of cancellous bone volume with short-term use of the new immunosuppressant rapamycin in rats

SummaryImmunosuppressants have adverse effects on bone mineral metabolism in animal and human studies, with corticosteroids producing low-turnover osteopenia, and cyclosporin-A (CsA) producing high-turnover osteopenia. Rapamycin (RAPA) is a new immunosuppressant reported to be at least 10 times more potent than CsA, and acts via a different pathway to CsA and the other new immunosuppressant FK506. This study investigated the effects of RAPA on bone mineral metabolism in the rat. Forty-two, 10-week-old, male Sprague Dawley rats were divided into three groups, and treated according to the following protocol: group A (control) received RAPA vehicle by daily gavage for 14 days (n = 12); group B (high dose RAPA) received RAPA 2.5 mg/kg/day by daily gavage for 14 days (n = 15); group C (low dose RAPA) received RAPA 1.25 mg/kg/day by daily gavage for 14 days (n = 15). Rats were weighed and bled on days 0, 7, and 14 for measurement of blood ionized calcium, bone Gla protein (BGP), parathyroid hormone (PTH), and 1,25(OH)2D. Tibial bone histomorphometry was determined on day 14 after double-calcein labeling. Weight gain was similar in the two groups treated with RAPA compared with control animals. High-dose RAPA (group B) transiently depressed serum BGP levels on day 7, with elevated blood ionized calcium levels on day 7, and lowered 1,25(OH)2D levels on day 14. Serum PTH levels were unchanged. Low dose RAPA (group C) did not affect calciotropic hormones. Histomorphometric analyses of tibial metaphyses revealed that parameters of bone formation and resorption were not significantly different in the groups treated with RAPA (group B and C) compared with control animals (group A). Trabecular bone volume (BV/TV) in group B (high-dose RAPA) (15.39 ± 1.01%) and C (low-dose RAPA) (15.38 ±0.57%) was not significantly altered compared with group A (control) (16.42 ± 0.86%). Short-term treatment with RAPA, unlike CsA, does not result in excess resorption and loss of bone volume. The depressed serum 1,25(OH)2D levels seen with high-dose RAPA therapy may adversely effect bone mineral metabolism in the long term.

Acquired dynamic left ventricular outflow tract obstruction complicating acute anterior myocardial infarction: Serial echocardiographic and clinical evaluation

We describe three cases of dynamic outflow obstruction complicating acute anterior myocardial infarction. Serial echocardiography suggests the intraventricular gradient results from basal hyperkinesis, the latter being a reciprocal response to the apical wall motion abnormality.

Rapid Development of a Papillary Fibroelastoma with Associated Thrombus: The Role of Transthoracic and Transesophageal Echocardiography

Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are frequently utilized in patients with suspected cerebral vascular ischemia. We describe a patient with suspected cerebral vascular ischemic event whom was found to have a mobile valvular mass by TTE and TEE. The lesion was unusual due to its rapid development over a period 6 months, which was documented on serial echocardiography. The mass was excised surgically and pathology showed a papillary fibroelastoma with extensive thrombus. The differential diagnosis of a cardiac valvular mass and the treatment of cardiac fibroelastomas are reviewed. In this case, both TTE and TEE were valuable in diagnosis and facilitating surgical management of a cardiac fibroelastoma.

Mycotic aneurysm of the descending thoracic aorta: The role of transesophageal echocardiography

Mycotic aneurysms of the aorta are prone to rupture. Thus rapid and accurate diagnosis is essential so that surgical repair can be undertaken. We report a case of mycotic aortic aneurysm caused by mitral valve endocarditis. The aneurysm situated at the junction of the thoracoabdominal aorta was readily detected by transesophageal echocardiography. Computed tomography and aortography were complementary to transesophageal echocardiography in establishing the diagnosis. The patient underwent successful repair and acute inflammation of the aneurysm was present at histologic examination.

Cardiac tamponade in association with an atrial septal defect: Echocardiographic Doppler and hemodynamic observations

We describe a case of cardiac tamponade in association with an atrial septal defect, in which pulsus paradoxus and respiratory variations in right and left ventricular filling were absent. Doppler echocardiography of the flow across the atrial septal defect showed bidirectional shunting, explaining the absence of pulsus paradoxus and respiratory variations in chamber filling.