PGC-1α Agonist Rescues Doxorubicin-Induced Cardiomyopathy by Mitigating the Oxidative Stress and Necroptosis.

Cardiomyopathy (particularly dilated cardiomyopathy (DCM)) significantly contributes to development and progression of heart failure (HF), and inflammatory factors further deteriorate the symptoms. Morphological and functional defects of the heart in doxorubicin (DOX)-induced cardiomyopathy (cardiotoxicity) are similar to those of DCM. We used anagonist of PGC-1α (PPAR (peroxisome proliferator-activated receptor-gamma)-γ coactivator-1α) that is considered as the 'master regulator' of mitochondrial biogenesis with an aim to rescue the DOX-induced deleterious effects on the heart. Forty male C57BL/6J mice (8 weeks old) were divided in four groups, Control, DOX, ZLN005, and ZLN005 + DOX (n = 10 each group). The DOX-induced (10 mg/kg, single dose) cardiomyopathy mimics a DCM-like phenotype with marked morphologic alteration in cardiac tissue and functional derangements. Significant increased staining was observed for Masson Trichrome/Picrosirius red and α-Smooth Muscle Actinin (α-SMA) that indicated enhanced fibrosis in the DOX group compared to the control that was attenuated by (peroxisome proliferator-activated receptor-gamma (PPAR-γ) coactivator) (PGC)-1α (alpha) agonist (four doses of 2.5 mg/kg/dose; cumulative dose = 10 mg/kg). Similarly, elevated expression of necroptosis markers along with enhanced oxidative stress in the DOX group were alleviated by PGC-1α agonist. These data collectively suggested the potent therapeutic efficacy of PGC-1α agonist in mitigating the deleterious effects of DOX-induced cardiomyopathy, and it may be targeted in developing the future therapeutics for the management of DCM/HF.

Posttransplant lymphoproliferative disorder in a heart transplant recipient: a case report.

Malignancy in heart transplant recipients is a grave complication. Post-transplant lymphoproliferative disorder (PTLD) is the second most common tumour in adults and commonest in children. The incidence varies with the transplanted organ from 1 to 2% following kidney transplantation to as high as 10% following thoracic organ transplantation due to different immunosuppression intensity. PTLD include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissue to frank malignancy with aggressive behaviour (lymphoma). Epstein-Barr virus (EBV) infection and prolonged immunosuppressant therapy are implicated in the pathogenesis of PTLD. The incidence of PTLD varies from 2.6% at 1 year to 28% at 10 years post-transplant. Seronegativity for EBV in recipients with seropositive donors increases the risk of PTLD in recipients. The majority of early-onset PTLDs (85%) are of B-cell origin and associated with EBV. Timely and accurate diagnosis with histological examination of lymphoid tissue is essential for early intervention. Reduction of immunosuppressive therapy (IST) and rituximab usually are effective in remission of PTLD. In resistant cases, chemotherapy is given with or without rituximab. Adoptive T-cell transfer represents a promising therapeutic approach. Early PTLD respond well to lowering immunosuppression and has a favourable prognosis compared to late PTLD. Five-year survival is 30% for high-grade lymphomas. The prognosis of EBV-negative lymphomas is worse. One out of 40 heart transplant recipients followed up in our centre developed PTLD. He was treated to remission and we describe this case here.

Interleukin-33 Induces Neutrophil Extracellular Trap (NET) Formation and Macrophage Necroptosis via Enhancing Oxidative Stress and Secretion of Proatherogenic Factors in Advanced Atherosclerosis.

Interleukin-33 (IL-33) acts as an 'alarmin', and its role has been demonstrated in driving immune regulation and inflammation in many human diseases. However, the precise mechanism of action of IL-33 in regulating neutrophil and macrophage functioning is not defined in advanced atherosclerosis (aAT) patients. Further, the role of IL-33 in neutrophil extracellular trap (NET) formation in aAT and its consequent effect on macrophage function is not known. In the present study, we recruited n = 52 aAT patients and n = 52 control subjects. The neutrophils were isolated from both groups via ficoll/percoll-based density gradient centrifugation. The effect of IL-33 on the NET formation ability of the neutrophils was determined in both groups. Monocytes, isolated via a positive selection method, were used to differentiate them into macrophages from each of the study subjects and were challenged by IL-33-primed NETs, followed by the measurement of oxidative stress by calorimetric assay and the expression of the proinflammatory molecules by quantitative PCR (qPCR). Transcript and protein expression was determined by qPCR and immunofluorescence/ELISA, respectively. The increased expression of IL-33R (ST-2) was observed in the neutrophils, along with an increased serum concentration of IL-33 in aAT compared to the controls. IL-33 exacerbates NET formation via specifically upregulating CD16 expression in aAT. IL-33-primed NETs/neutrophils increased the cellular oxidative stress levels in the macrophages, leading to enhanced macrophage necroptosis and the release of atherogenic factors and matrix metalloproteinases (MMPs) in aAT compared to the controls. These findings suggested a pathogenic effect of the IL-33/ST-2 pathway in aAT patients by exacerbating NET formation and macrophage necroptosis, thereby facilitating the release of inflammatory factors and the release of MMPs that may be critical for the destabilization/rupture of atherosclerotic plaques in aAT. Targeting the IL-33/ST-2-NETs axis may be a promising therapeutic target for preventing plaque instability/rupture and its adverse complications in aAT.

Incidence and predictors of de novo late-onset persistent atrial fibrillation in postoperative rheumatic heart disease patients (LOAF-RHD study).

PURPOSE: Late-onset atrial fibrillation (LOAF) after valve surgery for degenerative mitral valve disease often with underlying mitral valve prolapse is a known phenomenon. However, there is no similar data for postoperative rheumatic heart disease (RHD) patients. We sought to assess the incidence and predictors of LOAF during postoperative follow-up in RHD patients. METHODS: This single-center retrospective case-control study included a total of 384 RHD patients with normal sinus rhythm (NSR) who underwent rheumatic valve surgery between 1st July 2008 and 30th June 2013. Patients detected with de novo persistent atrial fibrillation (AF) after 2 months of valve surgery were diagnosed as having LOAF. Presurgical demographic and echocardiographic parameters were compared between the LOAF and NSR groups to identify risk factors for LOAF. RESULTS: The incidence of de novo LOAF after rheumatic valve surgery was 9.63% at an average of 2.67 ± 1.32 years follow-up. Age ≥ 32 years [OR 2.4 (95% CI 1.2-5.1); P = 0.01] and left atrial (LA) size ≥ 51 mm [OR 5.9 (95% CI 2.8-12.4); P < 0.0001] were the most significant and independent predictors of LOAF. Moreover, significant mitral valve disease was associated with a higher risk of LOAF than significant aortic valve disease (P = 0.037). LA size ≥ 51 mm at surgery showed a fair discriminative power [AUC = 0.75; sensitivity = 68%, specificity = 70%] to identify patients at high risk for LOAF. CONCLUSIONS: Late-onset AF develops in almost a tenth of the RHD patients postoperatively following corrective valve surgery. Preoperative LA size can be used to identify patients at high risk for LOAF.

Concomitant Transthyretin Amyloidosis and Severe Aortic Stenosis in Elderly Indian Population: A Pilot Study.

BACKGROUND: Prevalence of both degenerative severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR-CA) increases with age. Dual disease (AS+myocardial ATTR-CA) occurs in significant proportion of patients undergoing surgical aortic valve replacement (SAVR). OBJECTIVES: This study aimed to determine the prevalence of ATTR-CA in severe AS in the Indian population, identify noninvasive predictors of its diagnosis, and understand its impact on prognosis. METHODS: Symptomatic severe AS patients aged ≥65 years undergoing SAVR were enrolled. ATTR-CA diagnosis was based on preoperative 99m-technetium pyrophosphate (PYP) scan and intraoperatively obtained basal interventricular septum biopsy for myocardial ATTR-CA, and excised native aortic valve for isolated valvular ATTR-CA. Primary amyloidosis was excluded by serum/urine protein electrophoresis with serum immunofixation. RESULTS: SAVR was performed in 46 AS patients (age 70 ± 5 years, 70% men). PYP scan was performed for 32 patients, with significant PYP uptake in 3 (n = 3 of 32, 9.4%), suggestive of myocardial ATTR-CA. On histopathological examination, none of the interventricular septum biopsy specimens had amyloid deposits, whereas 33 (71.7%) native aortic valves showed amyloid deposits, of which 19 (57.6%) had transthyretin deposition suggestive of isolated valvular amyloidosis. Noninvasive markers of dual disease included low myocardial contraction fraction (median [interquartile range], 28.8% [23.8% to 39.1%] vs 15.3% [9.3% to 16.1%]; P = 0.006), deceleration time (215 [144 to 236] ms vs 88 [60 to 106] ms; P = 0.009) and global longitudinal strain (-18.7% [-21.1% to -16.9%] vs -14.2% [-17.0% to -9.7%]; P = 0.030). At 1-year follow-up, 2 patients died (4.3%); 1 each in myocardial ATTR-CA negative and positive groups (3.4% vs 33.3%; P = 0.477). CONCLUSIONS: Dual disease is not uncommon in India. Isolated valvular amyloidosis in severe AS is much more common.

Role of 3D reconstructed images in primary pulmonary vein stenosis.

Primary pulmonary vein stenosis (PPVS) is a rare congenital cardiac anomaly. The surgical management of PPVS requires anatomical delineation of pulmonary venous drainage along with exact localization of the stenosis. Since echocardiography cannot visualize the whole length of pulmonary veins (PV), computed tomography (CT) pulmonary venography becomes necessary. Three-dimensional (3D) reconstruction helps in planning PV augmentation and for prognostication. Here, we present 3D reconstructed CT pulmonary venography images of a 3-month-old child who presented to us with PPVS.

Dextroversion due to giant left atrium in a child.

Giant left atrium is extremely rare in pediatric population. We hereby report a case of 4-year-old child with giant left atrium (LA) due to "non-rheumatic" mitral regurgitation (MR). The giant LA caused dextro-rotation of the heart, which immediately reverted to normal cardiac position after surgical repair. The case is reported for the unusual manifestation of giant LA as dextroversion.

Detecting sub-clinical disease activity in patients with chronic rheumatic valvular heart disease.

OBJECTIVE: Valve disease progression in rheumatic heart disease(RHD) is generally attributed to recurrent attacks of acute rheumatic fever(ARF). However, persistence of chronic sub-clinical inflammation remains a plausible but unproven cause. Non-invasive means to identify sub-clinical inflammation may facilitate research efforts towards understanding its contribution to disease progression. METHODS: Patients with chronic RHD, without clinical evidence of ARF, undergoing elective valve surgery were enrolled. Sub-clinical inflammation was ascertained by histological evaluation of left atrial appendage and valve tissue excised during surgery. We assessed the diagnostic utility of Gallium-67 scintigraphy imaging, and inflammatory biomarkers, hsCRP, IL-2, IL-6, Tumor Necrosis Factor-Alpha(TNF-α), Interferon-gamma(IFN-γ), and Serum Amyloid A(SAA), in identifying patients with sub-clinical inflammation. RESULTS: Of the 93 RHD patients enrolled(mean age 34 ± 11 years, 45% females), 86 were included in final analysis. Sub-clinical inflammation was present in 27 patients(31.4%). Patients with dominant regurgitant lesions were more likely to have sub-clinical inflammation compared to those with stenotic lesions, though this association was not statistically significant(dominant regurgitant lesions vs isolated mitral stenosis: OR 3.5, 95%CI 0.68-17.96, p = 0.133). Inflammatory biomarkers were elevated in the majority of patients: hsCRP, IL-2, IL-6, TNF-α, and IFN-γ in 44%, 89%, 90%, 79%, and 81% patients, respectively. However, there was no significant association between biomarker elevation and histologically ascertained sub-clinical inflammation. Ga-67 imaging was unable to identify inflammation in the 15 patients in whom it was performed. CONCLUSION: Sub-clinical inflammation is common in RHD patients. Conventional inflammatory markers are elevated in the majority, but aren't discriminatory enough to identify the presence of histologic inflammation.

Ventilatory management of patients on ECMO.

Extracorporeal membrane oxygenation (ECMO) is the final treatment offered to patients of acute respiratory distress syndrome (ARDS). The survival (to discharge) of patients on veno-venous ECMO is approximately 59% with an average duration of 8 days. The ventilatory management of lungs during the ECMO may have an impact on mortality. An ideal ventilation modality should promote recovery, prevent further damage to the alveoli, and enable weaning from mechanical ventilation. This article reviews the concept of "baby lung" in ARDS and the current evidence for the use of lung protective ventilation, prevention of ventilator-induced lung injury, recommended modes of mechanical ventilation, ideal ventilatory parameters (tidal volume, positive end expiratory pressure, plateau pressure, respiratory rate, fractional inspired oxygen concentration), and use of adjuncts (prone positioning, neuromuscular blocking agents) during the ECMO course.

Delayed presentation of superficial femoral artery pseudoaneurysm 45 years following gunshot injury.

This case report is a description of an uncommon delayed presentation of penetrating trauma of lower limb with history of inciting event being 45 years ago, as there are only 4 such reported cases in the literature. A 65-year-old male presented with progressive enlargement of swelling over the anterior aspect of the right thigh with difficulty in walking due to mechanical effects and paraesthesia in the affected limb. Clinical signs of a large lump in the right anteromedial thigh with no pulsations were present. Computerised tomographic angiography revealed the presence of a superficial femoral artery pseudoaneurysm. The open surgical management involved resection of the pseudoaneurysm and autologous vein patch angioplasty. The rarity of incidence and paucity of physical signs suggest that a high index of suspicion, careful clinical review and radiological investigation is indispensable to diagnose and treat this condition.

Opportunities and challenges for thoracic organ transplantation in government institutions.

The first successful heart transplant in India was performed by Panangipalli Venugopal on 3 August 1994 at the All India Institute of Medical Sciences, New Delhi. Twenty-five years later, only seven government institutions are performing heart transplants and only one government hospital has an established heart transplant program in India. Only one lung transplant has been performed in a government institution all over the country. This article reviews the history and current status of thoracic organ transplant in India. The authors discuss the factors responsible for the dismal progress of thoracic organ transplant in government hospitals, opportunities available in government institutions for widening the scope of transplant program, and the steps taken by the Government of India to improve healthcare in the country.

Internal iliac artery pseudoaneurysm: a rare presentation with foot drop and sciatica.

Internal iliac artery pseudoaneurysm is rare in incidence with most of them being asymptomatic. It may present with neurologic symptoms like paraesthesia, sciatica, weakness of lower limb, foot drop, etc., and in such scenario, high index of suspicion is needed to diagnose. Early intervention should be the strategy in all symptomatic and in asymptomatic cases with size > 4 cm diameter. We present a case of a 40-year-old female with left internal iliac artery pseudoaneurysm who presented with foot drop and sciatica, which is a very rare presentation, and was managed successfully by resection and interposition grafting.

Genetic polymorphisms and dosing of vitamin K antagonist in Indian patients after heart valve surgery.

PURPOSE: Vitamin K antagonists (VKAs), such as warfarin and acenocoumarol, exert their anti-coagulant effect by inhibiting the subunit 1 of vitamin K epoxide reductase complex (VKORC1). CYP2C9 is a hepatic drug-metabolizing enzyme in the CYP450 superfamily and is the primary metabolizing enzyme of warfarin. Three single nucleotide polymorphisms, two in the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, and one in the VKORC1 gene (c.- 1639G > A, rs9923231), have been identified to reduce VKA metabolism and enhance their anti-coagulation effect. The purpose of this study is to evaluate the prevalence of CYP2C9 and VKORC1 polymorphism in Indians receiving VKA-based anti-coagulation after valve surgery and to evaluate the usefulness of genetic information in managing VKA-based anti-coagulation. METHODS: In the current prospective observational study, 150 patients who underwent heart valve surgery and had stable INR were genotyped for VKORC1 (- 1639 G > A), CYP2C9*2, and CYP2C9*3. The VKA dosage was estimated from published algorithms and compared to the clinically stabilized dosage. RESULTS: Out of 150 patients, 101 (67.33%) were on warfarin and 49 (32.66%) were on acenocoumarol. Majority of the patients, the 83 in warfarin group and the 40 in acenocoumarol group, had a wild CYP2C9 diplotype. The rest had a mutant (CYP2C9*2 or CYP2C9*3) diplotype. Similarly, 67 patients in the warfarin group and 35 patients in the acenocoumarol group had wild type (G/G) of VKORC1 genotype. The rest had a mutant (G/A or A/A) VKORC1 genotype. In the warfarin group, based on the genotype, 51.5% of the patients were extensive or normal metabolizers, and 47.4% of the patients were intermediate metabolizers of VKAs. In the acenocoumarol group, 61.2% of the patients were extensive or normal metabolizers, and 38.8% of the patients were intermediate metabolizers. Individually, alleles of VKORC1 (- 1639 G > A), CYP2C9*2, and CYP2C9*3 had mean dosage reduction effect on VKA dosage, which co-related to the clinically stabilized dosages (P < 0.0001). Among the VKORC1 (- 1639 G > A) cohort, the reduction in warfarin mean weekly dosage was 13.48 mg as compared to the wild-type category (P < 0.0001) and similarly, the reduction in the mean weekly acenocoumarol dose was 6.07 mg (P < 0.03) as compared to the wild type after adjusting for age, gender, and body mass index. CONCLUSION: Single nucleotide polymorphism in the CYP2C9 gene and in the VKORC1 gene is present in nearly 40% of Indian patients. VKORC1 (- 1639 G > A), CYP2C9*2, and CYP2C9*3 genotypes have significant dosage-lowering effects on VKA-based anti-coagulation therapy. The trend in estimated dosages of VKAs co-related to that of observed the clinically stabilized dosage in the cohort. The pharmacogenomic calculators used in this study tend to overestimate the VKA dosages as compared to clinical dosage due to the limitations in the algorithms and in our study. A new algorithm based on a larger dataset capturing the vast genetic variability across the Indian population and relevant clinical factors could provide better results.

Open vertical vein in non-obstructed supracardiac TAPVC: merits and fate.

Data of 18 patients who underwent surgical repair of non-obstructed supracardiac total anomalous pulmonary venous connection between January 2007 and March 2011 were reviewed. The vertical vein was left patent in all patients as an elective surgical strategy. There was no operative mortality in patients with or without preoperative pulmonary infection, but there were significant differences in postoperative airway pressures, ventilation time, intensive care unit and hospital stay between the 2 groups. None of the patients demonstrated any flow in the vertical vein over a 30-day follow-up period. One patient had a mild anastomotic stricture and pulmonary venous hypoplasia. Operative repair of supracardiac total anomalous pulmonary venous connection can be carried out successfully without ligation of the vertical vein, and this strategy possibly reduces early postoperative morbidity and mortality, with no adverse effects detected in the short to midterm follow-up.

Comparison of 48 h and 72 h of prophylactic antibiotic therapy in adult cardiac surgery: a randomized double blind controlled trial.

OBJECTIVES: To determine whether the duration of antibiotic prophylaxis influences the rate of surgical site infection in patients undergoing coronary bypass grafting or valve replacement. PATIENTS AND METHODS: Adult patients undergoing elective coronary artery bypass grafting (CABG) and valve surgery were included in this randomized double blind study. Between April 2007 and April 2008, 235 patients were randomly assigned to one of two groups using random number table and sealed envelope technique. The groups received prophylactic antibiotic therapy for either 48 h (the 48 h group) or 72 h (the 72 h group). These patients were monitored for surgical site infection. RESULTS: The mean age was 52.94 +/- 16.30 and 55.27 +/- 16.63 years, respectively, in the two groups. The incidence of co-morbid conditions as well as operative conditions was similar between the groups. During the study period 20 patients developed surgical site infections and 7 patients other infections. In modified treatment analysis, the infection rates were 7.6% (9 patients, n = 119) in the group receiving 48 h of prophylactic antibiotic therapy and 10.2% (11 patients, n = 108) in the group receiving 72 h of prophylactic antibiotic therapy, and the difference was statistically non-significant (P > 0.05). In the per protocol analysis the infection rates were 5% (5 patients, n = 100) in the group receiving 48 h of prophylactic antibiotic therapy and 8% (8 patients, n = 100) in the group receiving 72 h of prophylactic antibiotic therapy, and the difference was again statistically non-significant (P > 0.05). The results of Fisher's exact test revealed that the duration of surgery lasting for >5 h is an independent risk factor for surgical site infection. CONCLUSIONS: Forty-eight hours of a prophylactic antibiotic combination using a third-generation cephalosporin and an aminoglycoside is as effective as a 72 h regimen for preventing surgical site infection in patients undergoing CABG and valve surgery.