Effect of Benidipine Alone and in Combination With Bosentan and Sildenafil in Amelioration of Pulmonary Arterial Hypertension in Experimental Model in Rats.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a persistent condition affecting the pulmonary arteries' endothelium. Benidipine, a calcium channel blocker, possesses vasodilatory, anti-inflammatory activity, reduces oxidative stress, and inhibits the activity of Transforming growth factor-ß (TGF-ß) and α-smooth muscle actin (α-SMA). The present study was designed to investigate the effect of benidipine alone and in combination with bosentan and sildenafil on monocrotaline (MCT)-induced pulmonary hypertension in a rat model. PAH was induced by a single-dose administration of MCT in rats. Animals were randomized into different groups and treated with benidipine alone and in combination with bosentan or sildenafil. Various parameters such as hemodynamic parameters, Fulton's index and oxidative stress parameters were performed. Additionally, histopathology of lung and right ventricular of heart tissue, immunohistochemistry, expression of α-SMA, endothelial nitric oxide synthase (eNOS), TGF-ß, and RT-PCR, and an in vitro study using human umbilical vein endothelial cells (HUVECs) was also carried out. Treatment of benidipine and its combination exhibited better prevention in the elevated right ventricular systolic pressure, right ventricular hypertrophy, rise in oxidative stress, and increase in expression of α-SMA and TGF-ß receptor 1 compared with MCT control group rats. In HUVECs, the expression of α-SMA was increased, whereas that of eNOS decreased after TGF-ß exposure and was substantially reversed after pretreatment with benidipine. We concluded that benidipine and its combination with bosentan and sildenafil exhibit beneficial effects in MCT-induced PAH through the eNOS/TGF-ß/α-SMA signaling pathway.

Secretory carcinoma of salivary gland origin: A recently established masquerader.

Secretory carcinoma (SC) of the salivary gland is considered to be a low-intermediate grade tumor with the potential of locally aggressive behavior. This tumor is similar both genetically (ETV6-NTRK3 fusion) and histologically to secretory carcinoma of the breast. We intent to share our experience of four cases of SC in terms of clinical behavior, pathological features, and treatment outcome. Medical records of four cases of SC were retrieved and analyzed for clinical presentation, surgical treatment, and outcome. Pathological data was reanalyzed along with immunohistochemistry. Out of the four identified SC cases, three were men. Two lesions originated from the parotid gland and two from minor salivary glands. Two of these cases exhibited features of locally aggressive pattern. SC of salivary gland origin has distinct histological and immunohistochemical features apart from the characteristic genetic translocation and fusion. Surgery with or without adjuvant radiotherapy is the treatment of choice. To establish the biological behavior of this tumor, larger case series with long-term follow-up is desirable.

Non-invasive characterization of coronary artery atherosclerotic plaque using dual energy CT: Explanation in ex-vivo samples.

PURPOSE: In this study non-calcified plaque composition is evaluated by Dual Energy CT (DECT). Energy Dispersive X-ray Spectroscopy (EDS) has been used to study the Plaque composition. An attempt has been made to explain the DECT results with EDS analysis. METHODS: Thirty-two ex-vivo human cadaver coronary artery samples were scanned by DECT and data was evaluated to calculate their effective atomic number and electron density (Zeff & ρe) by inversion method. Result of DECT was compared with pathology to assess their differentiating capability. The EDS study was used to explain DECT outcome. RESULTS: DECT study was able to differentiate vulnerable plaque from stable with 87% accuracy (area under the curve (AUC):0.85 [95% confidence interval {CI}:0.73-0.98}] and Kappa Coefficient (KC):0.75 with respect to pathology. EDS revealed significant compositional difference in vulnerable and stable plaque at p < .05. The weight percentage of higher atomic number elements like F, Na, Mg, S, Si, P, Cl, K and Ca was found to be slightly more in vulnerable plaques as compared to a stable plaque. EDS also revealed a significantly increased weight percentage of nitrogen in stable plaques. CONCLUSIONS: The EDS results were able to explain the outcomes of DECT study. This study conclusively explains the physics of DECT as a tool to assess the nature of non-calcified plaques as vulnerable and stable. The method proposed in this study allows for differentiation between vulnerable and stable plaque using DECT.

Clinical significance of intracoronary thrombus aspirated during primary percutaneous intervention: An immunohistopathological study.

BACKGROUND: Manual thrombus aspiration during primary percutaneous intervention provides us with aspirated thrombus sample, that may contain material from the disrupted plaque. Immunohistopathological analysis of thrombus can yield valuable information about the clinical and cardiovascular outcomes and possible mechanisms of myocardial infarction. MATERIAL AND METHODS: We studied and analysed the immunohistopathological features of coronary thrombus aspirated from patients undergoing primary percutaneous coronary angioplasty. Immunohistological staining included markers namely CD68, SMA and CD34 for macrophages, smooth muscle actin and endothelium, respectively. Major adverse cardiac events, angiographic outcome and infarct size were also noted. RESULTS: Fifty-three patients (Mean age - 51.3±13years; males-47) who underwent primary percutaneous coronary intervention with aspiration thrombectomy were enrolled. Thrombus was successfully aspirated in 40 of 53 patients (75.4%). Patients with successful thrombus aspiration had higher ST-segment resolution (≥50%) as compared to patients with failed thrombus aspiration. Presence of RBC-rich thrombus on microscopy was more commonly associated with post-procedure TIMI flow of <2 as compared to patients with fibrin-rich thrombus and a trend towards lower myocardial blush grade<2 (P=0.10), and a significantly higher final infarct size (37.5±5% vs 25±15%; P=0.04 of myocardium) on nuclear scan. Immunohistology revealed presence of plaque material in 72% (26/36) of the samples. CONCLUSIONS: Immunohistopathological evaluation of intracoronary thrombus may be of prognostic importance. High prevalence of plaque material in the aspirated intracoronary thrombus suggests plaque rupture as a possible etiology for vessel occlusion in these patients. SHORT SUMMARY: Immunohistopathological evaluation of intracoronary thrombus reveals high prevalence of plaque material in the aspirated intracoronary thrombus suggesting plaque rupture as a possible etiology for vessel occlusion in Indian STEMI patients.

DECT evaluation of noncalcified coronary artery plaque.

PURPOSE: Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (ρ(e)) and the effective atomic number (Z(eff)) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. METHODS: For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (ρ(e), Z(eff)) lie in the range of (2.65 × 10(23) ≤ ρ(e) ≤ 3.64 × 10(23)/cm(3)) and (6.80 ≤ Z(eff) ≤ 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V1) and HU(V2), with V1,V2 = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (ρ(e), Z(eff)) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (ρ(e), Z(eff)) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. RESULTS: The authors find that the calibration gives ρ(e) with an accuracy of ±3.5% while Z(eff) is found within ±1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques are practically nonexistent, and microcalcification, as observed in histopathology, has to be taken into account to explain the nature of the observed (ρ(e), Z(eff)) data. This also enables us to judge the composition of the plaque in terms of basic model which considers the plaque to be composed of fibres, lipids, and microcalcification. CONCLUSIONS: This simple and reliable method has the potential as an effective modality to investigate the composition of noncalcified coronary artery plaques and thus help in their characterization. In this inversion method, (ρ(e), Z(eff)) of the scanned sample can be found by eliminating the effects of the CT machine and also by ensuring that the determination of the two unknowns (ρ(e), Ze(ff)) does not interfere with each other and the nature of the plaque can be identified in terms of a three component model.

Light and electron microscopic features of surgically excised left atrial appendage in rheumatic heart disease patients with atrial fibrillation and sinus rhythm.

INTRODUCTION: There are few studies comparing the pathology of the remodeled substrate in patients of rheumatic heart disease with atrial fibrillation (AF) and normal sinus rhythm (NSR). METHODS: The study group comprised 30 patients with rheumatic heart disease undergoing mitral valve replacement. Excised left atrial appendages of these patients [17 with persistent AF and 13 NSR (control group)] were subjected to light and electron microscopic examination. RESULTS: The histopathological findings of the myocardium were characterized by cardiomyocyte hypertrophy (CH), nuclear enlargement (NE), perinuclear clearing (PC), sarcoplasmic vacuolation (SV), fibrosis, and inflammation in the patients with AF and NSR. NE (17/17 vs. 4/13; P=.004), PC (17/17 vs. 4/13; P=.004), SV (17/17 vs. 9/13; P=.06), and fibrosis (15/17 vs. 3/13; P=.001) were all significantly more common in patients with AF. Inflammatory cells were observed in 9/17 patients of AF as compared to 1 in NSR patients (9/17 vs. 1/13; P=.02). CH was common in the patients with AF as compared with those in NSR (17/17 vs. 10/13; P=.103). In AF patients, electron microscopy revealed cardiomyocytes with depletion of the contractile elements (Z-bands), glycogen particle accumulation, and an increase in mitochondria. Cells severely affected by AF showed loss of contractile elements with extensive areas of SV, presence of myelin figures, and mitochondrial aggregates. Majority of AF cases showed extensive fibrosis in the form of collagen bundles in the interstitium. CONCLUSION: The left atrial substrate in AF as compared with NSR, in rheumatic heart disease patients, is associated with significant degenerative remodeling and ongoing inflammation that is associated with extensive fibrosis.