Not all obstructive cardiac lesions are created equal: double-chamber right ventricle in pregnancy

Double-chambered right ventricle (DCRV) is a rare form of right ventricular outflow tract (RVOT) obstruction accounting for approximately 1% of patients with congenital heart disease. It consists of an anomalous muscle bundle that divides the right ventricle usually between the sinus (inlet) and the infundibulum (outlet). This division creates a proximal chamber with high pressure and a distal chamber with low pressure. The hemodynamic obstruction of the RVOT is usually an acquired phenomenon, however the substrate for the anomalous muscle bundle is likely congenital. The diagnosis of DCRV should be considered in the young patient with an elevated right ventricular systolic pressure and intracavitary gradient. Echocardiography and cardiac MRI are the principal diagnostic tools for the assessment of DCRV. This entity is often misdiagnosed as pulmonary hypertension in the young patient, and can often go overlooked and untreated for many years. Definitive therapy involves surgical resection of the muscle bundle. This can often be curative and if done in a timely fashion, may prevent right ventricular remodeling. We describe the unique diagnostic dilemma, the course and management of a young adult with DCRV during pregnancy.     

Pioglitazone Acutely Reduces Energy Metabolism and Insulin Secretion in Rats

Our objective was to determine if the insulin-sensitizing drug pioglitazone acutely reduces insulin secretion and causes metabolic deceleration in vivo independently of change in insulin sensitivity. We assessed glucose homeostasis by hyperinsulinemic-euglycemic and hyperglycemic clamp studies and energy expenditure by indirect calorimetry and biotelemetry in male Wistar and obese hyperinsulinemic Zucker diabetic fatty (ZDF) rats 45 min after a single oral dose of pioglitazone (30 mg/kg). In vivo insulin secretion during clamped hyperglycemia was reduced in both Wistar and ZDF rats after pioglitazone administration. Insulin clearance was slightly increased in Wistar but not in ZDF rats. Insulin sensitivity in Wistar rats assessed by the hyperinsulinemic-euglycemic clamp was minimally affected by pioglitazone at this early time point. Pioglitazone also reduced energy expenditure in Wistar rats without altering respiratory exchange ratio or core body temperature. Glucose-induced insulin secretion (GIIS) and oxygen consumption were reduced by pioglitazone in isolated islets and INS832/13 cells. In conclusion, pioglitazone acutely induces whole-body metabolic slowing down and reduces GIIS, the latter being largely independent of the insulin-sensitizing action of the drug. The results suggest that pioglitazone has direct metabolic deceleration effects on the β-cell that may contribute to its capacity to lower insulinemia and antidiabetic action.Major drugs developed to treat type 2 diabetes aim at either increasing insulin secretion or reducing insulin resistance (1–4). Two classes of insulin-sensitizing agents are currently used, the biguanides (metformin) and the thiazolidinediones (TZDs), of which the only one still recommended for use in some countries is pioglitazone (5). TZDs are peroxisome proliferator–activated receptor-γ (PPARγ) agonists. They stimulate adipocyte differentiation, relieving other tissues from fat excess, thereby reducing their resistance to insulin (6,7). The beneficial effects of TZDs are not limited to increased insulin sensitivity and also include preservation of β-cell function (8). It is thought that the beneficial effect of TZDs on β-cell function in vivo is indirect and occurs via a relief of the need for insulin hypersecretion because of their insulin sensitizing action. We should, however, consider the possibility that the classical antidiabetic insulin sensitizers, pioglitazone and metformin, might also have beneficial effects on glucose homeostasis via direct reduction of insulin hypersecretion independently of insulin resistance.We previously demonstrated in vitro that pioglitazone acutely slows down glucose and lipid metabolism in the β cell and inhibits glucose-induced insulin secretion (GIIS) primarily at submaximal and much less at maximal glucose concentrations (right shift in the glucose dose response) via a PPARγ-independent mechanism (9). These acute effects of pioglitazone are likely attributable to complex I inhibition of the electron transport chain (10) and involve reduced glucose oxidation, decreased ATP levels, and increased AMPK activation (9). Interestingly, metformin causes similar effects (J.L. and M.P., unpublished data). Hence, we proposed the novel concept of “metabolic deceleration” as a mode of action of some antidiabetic drugs and suggested that the action of pioglitazone to reduce glucose metabolism and insulin secretion in the β-cell may partly explain its beneficial effects (9). The concept that metabolic deceleration protects the β-cell from both oxidative and endoplasmic reticulum stress has recently been reviewed (11,12).In the current study we performed in vivo experiments in normal Wistar and obese Zucker diabetic fatty (ZDF) rats to better understand how acute treatment with pioglitazone alters glucose homeostasis, with particular focus on how it reduces hyperinsulinemia. The following questions were asked: 1) Can we confirm in vivo our previous in vitro findings in isolated rat islet and β-cell line that pioglitazone acutely reduces insulin secretion? 2) Is this acute effect of pioglitazone on insulin secretion independent of its effects on insulin sensitivity? and 3) Does pioglitazone acutely slow down whole-body energy metabolism?     

Tumor blush: left ventricular cardiac hemangioma with supply from both the left anterior descending and circumflex arteries

A fifty-year-old male had an echocardiogram for an abnormal electrocardiogram; it revealed a left ventricular mass. A cardiac catheterization revealed normal coronary arteries and a fine tumor blush of the cardiac tumor with feeding arteries from the circumflex as well as the second diagonal coronary vessels. Due to increased risk of embolization, he underwent surgery via a transatrial approach and a 1.5 cm cavernous-capillary hemangioma was removed from the base of the posteromedial papillary muscle. Primary tumors of the heart are rare, and the symptoms and signs depend on the location and size of the tumor. Coronary angiography remains an integral part in the evaluation of cardiac tumors and often can reveal a characteristic 'tumor blush.' The natural history of the tumor is unpredictable and excision of the tumor remains the treatment of choice. We present a rare case of characteristic angiographic tumor blush of a left ventricular cardiac hemangioma with feeding arteries from both the left anterior descending as well as the circumflex arteries. This rare two-system supply was due to the intracavitary location of the hemangioma, and fortunately did not pose any excessive difficulty in mobilization and excision during surgery.     

Effects of insulin detemir on balloon catheter injured carotid artery in Zucker fatty rats

ObjectiveWe compared the effect of the long acting basal insulin analog detemir with neutral protamine Hagedorn (NPH) insulin, and normal saline on recovery from vascular injury (balloon catheter mediated) in an animal model of insulin resistance.MethodsFemale Zucker fatty rats were administered NPH/detemir/saline for 7 days following which, they underwent balloon catheter mediated injury of left carotid artery, and were continued on the respective regimen for an additional 21 days when they were sacrificed. We evaluated the injured carotid artery for intimal hyperplasia (Intima/Media ratio) and also, aortic arch protein for markers of oxidative stress and inflammation, in addition to expression and phosphorylation of eNOS using well established methods.ResultsThere was a significant difference in intimal hyperplasia (Intima/Media ratio) between control and detemir treated rats (1.3 ± 0.09, 0.82 ± 0.08; p < 0.001) whereas the IM ratio in NPH treated rats was not significantly different from saline (1.17 ± 0.1). Expression of p-eNOS (ser-1177) in both NPH and insulin detemir (1.3 ± 0.15, 1.11 ± 0.12) was significantly higher than controls (0.56 ± 0.13; p < 0.05). We did not find significant differences in the expression of MnSOD, eNOS and NFκB-p65.ConclusionWe conclude that in insulin resistant states, treatment with Insulin detemir but not NPH is associated with less intimal hyperplasia, although both insulins increased eNOS phosphorylation.     

Retinal manifestations in patients following COVID-19 infection: A consecutive case series

Purpose:To describe retinal manifestations seen in patients associated with COVID-19 infection at a multi-specialty tertiary care hospital in Southern India.Methods:In this retrospective chart review, all consecutive cases presenting to the Retina-Uveitis service from May 2020 to January 2021 with retinal manifestations associated with COVID-19 infection or its sequelae or as a result of treatment given for COVID-19 were included.Results:Of the 7 patients, 3 were female, and 4 were male. Four patients had onset of symptoms during the active phase of COVID-19 infection. Four had bilateral and three had unilateral involvement. The manifestations ranged from mild to vision threatening. Vision threatening manifestations included infections: endogenous endophthalmitis, candida retinitis and tubercular choroidal abscess and bilateral pre-foveal hemorrhages. Milder manifestations included paracentral acute middle maculopathy, central serous chorio-retinopathy and voriconazole induced visual symptoms. Final visual acuity was 6/36 or better in the four severe cases and 6/9 or better in the mild cases.Conclusion:This study highlights the retinal manifestations associated with COVID-19 infection and its sequelae. As these patients presented with an association with COVID-19 (either during or after recovery), ophthalmologists should be vigilant and screen for such entities in case of complaints of visual symptoms or in the presence of systemic sepsis. The outcomes can be good with prompt and aggressive management.     

Hyperactive Transforming Growth Factor‐β1 Signaling Potentiates Skeletal Defects in a Neurofibromatosis Type 1 Mouse Model

Dysregulated transforming growth factor beta (TGF‐β) signaling is associated with a spectrum of osseous defects as seen in Loeys‐Dietz syndrome, Marfan syndrome, and Camurati‐Engelmann disease. Intriguingly, neurofibromatosis type 1 (NF1) patients exhibit many of these characteristic skeletal features, including kyphoscoliosis, osteoporosis, tibial dysplasia, and pseudarthrosis; however, the molecular mechanisms mediating these phenotypes remain unclear. Here, we provide genetic and pharmacologic evidence that hyperactive TGF‐β1 signaling pivotally underpins osseous defects in Nf1^flox/?;Col2.3Cre mice, a model which closely recapitulates the skeletal abnormalities found in the human disease. Compared to controls, we show that serum TGF‐β1 levels are fivefold to sixfold increased both in Nf1^flox/?;Col2.3Cre mice and in a cohort of NF1 patients. Nf1‐deficient osteoblasts, the principal source of TGF‐β1 in bone, overexpress TGF‐β1 in a gene dosage–dependent fashion. Moreover, Nf1‐deficient osteoblasts and osteoclasts are hyperresponsive to TGF‐β1 stimulation, potentiating osteoclast bone resorptive activity while inhibiting osteoblast differentiation. These cellular phenotypes are further accompanied by p21‐Ras–dependent hyperactivation of the canonical TGF‐β1–Smad pathway. Reexpression of the human, full‐length neurofibromin guanosine triphosphatase (GTPase)‐activating protein (GAP)‐related domain (NF1 GRD) in primary Nf1‐deficient osteoblast progenitors, attenuated TGF‐β1 expression levels and reduced Smad phosphorylation in response to TGF‐β1 stimulation. As an in vivo proof of principle, we demonstrate that administration of the TGF‐β receptor 1 (TβRI) kinase inhibitor, SD‐208, can rescue bone mass deficits and prevent tibial fracture nonunion in Nf1^flox/?;Col2.3Cre mice. In sum, these data demonstrate a pivotal role for hyperactive TGF‐β1 signaling in the pathogenesis of NF1‐associated osteoporosis and pseudarthrosis, thus implicating the TGF‐β signaling pathway as a potential therapeutic target in the treatment of NF1 osseous defects that are refractory to current therapies. © 2013 American Society for Bone and Mineral Research.