Venkatachalam Senthilnathan

Calcium-Activated Potassium Channels Contribute to Human Coronary Microvascular Dysfunction After Cardioplegic Arrest

Background— Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (KCa) channels in this dysfunction in the human coronary microvasculature. Methods and Results— Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 μm in diameter) in a pressurized no-flow state were examined in the presence of KCa channel activators/blockers and several other vasodilators. We also examined expression and localization of KCa channel gene products in the coronary microvasculature using reverse transcriptase–polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance KCa channels (IKCa/SKCa), NS309 (10−5 M), and to the endothelium-dependent vasodilators, substance P (10−8 M) and adenosine 5′diphosphate (10−5 M), were significantly reduced compared with pre-CP responses (P<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance KCa channels (BKCa), NS1619 (10−5 M), and to the endothelium-independent vasodilator, sodium nitroprusside (10−4 M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5′ diphosphate-induced relaxation (P<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BKCa, IKCa, and SKCa and the expression of IKCa mRNA were not altered post-CP reperfusion. Conclusion— Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SKCa and IKCa channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.

Coarctation Repair: Modification of End-to-End Anastomosis With Subclavian Flap Angioplasty

BACKGROUND Subclavian angioplasty and resection and end-to-end anastomosis for coarctation repair carry a substantial risk of recurrence of coarctation. The combined technique using both these methods has shown good results but requires a longer period of continuous cross-clamping of the aorta. METHODS A modified technique using intermittent cross-clamping with a period of reperfusion between cross-clamping periods was used. After the end-to-end anastomosis the clamps are released for 10 minutes and reapplied to do the subclavian angioplasty. Between 1991 and 1996 this was done in 26 infants (mean age, 5 weeks; range, 1 day to 6 months; median, 3 weeks). Mean weight was 3.85 kg (range, 1.5 to 8.4 kg). Mean length of follow-up was 23 months. Twenty-two patients (85%) had associated anomalies, excluding patent ductus arteriosus, and 5 patients (19%) had another procedure performed at the same time. RESULTS There was no mortality. The mean echocardiographic gradient was 4 mm Hg in the immediate postoperative period and 2.9 mm Hg during follow-up. Residual or recurrent coarctation as detected by significant echocardiography or blood pressure gradient did not develop in any infant. CONCLUSIONS This modified technique of anastomosis is an effective way of relieving coarctation with excellent intermediate-term results.

Pilot Proteomic Profile of Differentially Regulated Proteins in Right Atrial Appendage Before and After Cardiac Surgery Using Cardioplegia and Cardiopulmonary Bypass

Background— Although highly protective, cardiac surgery using cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function which results in a greatly enhanced risk of mortality. Acute changes in myocardial contractile activity are likely regulated via protein modifications. We performed the following study to determine changes in the protein profile of human myocardium following CP/CPB. Methods and Results— Right atrial appendage was collected from 8 male patients pre and post-CP/CPB. Atrial tissue lysates were subjected to 2-dimensional electrophoresis, total protein staining, gel averaging, and quantitative densitometry. Ten prominent spots regulated in response to CP/CPB were identified using mass spectrometry. Two hundred twenty-five and 256 protein spots were reliably detected in 2D-gels from pre- and post-CP/CPB patients, respectively. Five unique (ie, not detected post-CP/CPB) and 17 significantly increased spots were detected pre-CP/CPB. Thirty-four unique and 25 significantly increased spots were detected in the post-CP/CPB group. Identified proteins that changed after CP/CPB included: MLC-2a, ATP-synthase delta chain and Enoyl-CoenzymeA hydratase, glutathione-s-transferase omega, α-1-acid-glycoprotein, and phosphatidylethanolamine-binding protein. Conclusions— Cardiac surgery results in multiple consistent changes in the human myocardial protein profile. CP/CPB modifies specific cytoskeletal, metabolic, and inflammatory proteins potentially involved in deleterious effects of CP/CPB.

Management of a patient with lupus anticoagulant and antiphospholipid syndrome for off-pump coronary artery bypass grafting using the Hepcon system.

Patients with serum lupus anticoagulant antibodies (LAC) with or without antiphospholipid syndrome who present for cardiac surgery provide a unique set of challenges. Chief among these are the interference with anticoagulation monitoring by LAC. We present a case of such a patient who presented to us for coronary artery bypass grafting. We follow with a review of LAC and antiphospholipid syndrome and present a strategy for ensuring adequate anticoagulation during cardiac surgery in the background of previously published reports.

Mitochondrial DAMPs Are Released During Cardiopulmonary Bypass Surgery and Are Associated With Postoperative Atrial Fibrillation

BACKGROUND Atrial fibrillation (AF) is the most frequent complication of surgery performed on cardiopulmonary bypass (CPB) and recent work associates CPB with postoperative inflammation. We have shown that all tissue injury releases mitochondrial damage associated molecular patterns (mtDAMPs) including mitochondrial DNA (mtDNA). This can act as a direct, early activator of neutrophils (PMN), eliciting a systemic inflammatory response syndrome (SIRS) while suppressing PMN function. Neutrophil Extracellular Traps (NETs) are crucial to host defence. They carry out NETosis wherein webs of granule proteins and chromatin trap and kill bacteria. We hypothesised that surgery performed on CPB releases mtDAMPs into the circulation. Molecular patterns thus mobilised during CPB might then participate in the pathogenesis of SIRS and predict postoperative complications like AF [1]. METHODS We prospectively studied 16 patients undergoing elective operations on CPB. Blood was sampled preoperatively, at the end of CPB and on days 1-2 postoperatively. Plasma samples were analysed for mtDNA. Neutrophil IL-6 gene expression was studied to assess induction of SIRS. Neutrophils were also assayed for the presence of neutrophil extracellular traps (NETs/NETosis). These biologic findings were then correlated to clinical data and compared in patients with and without postoperative AF (POAF). RESULTS Mitochondrial DNA was significantly elevated following CPB (six-fold increase post-CPB, p=0.008 and five-fold increase days 1-2, p=0.02). Patients with POAF showed greater increases in mtDNA post-CPB than those without. Postoperative AF was seen in all patients with a ≥2-fold increase of mtDNA (p=0.037 vs. <2-fold). Neutrophil IL-6 gene transcription increased postoperatively demonstrating SIRS that was greatest days 1-2 (p=0.039). Neutrophil extracellular trap (NET) formation was markedly suppressed in the post-CPB state. CONCLUSION Mitochondrial DNA is released by CPB surgery and is associated with POAF. IL-6 gene expression increases after CPB, demonstrating the evolution of postoperative SIRS. Lastly, cardiac surgery on CPB also suppressed PMN NETosis. Taken together, our data suggest that mtDNA released during surgery on CPB, may be involved in the pathogenesis of SIRS and related postoperative inflammatory events like POAF and infections. Mitochondrial DNA may therefore prove to be an early biomarker for postoperative complications with the degree of association to be determined in appropriately sized studies. If mtDNA is directly involved in cardiac inflammation, mtDNA-induced toll-like receptor-9 (TLR9) signalling could also be targeted therapeutically.

Anomalous Right Coronary Artery Arising From the Pulmonary Artery

A42-year-old man with a history of cocaine abuse presented to the emergency department with severe acute exertional chest pain. Electrocardiographic findings were consistent with ischemia. However troponin levels were normal. A 64-slice coronary computed tomography angiogram was performed, which revealed an anomalous dominant right coronary artery originating from the pulmonary artery (ARCAPA) (Fig 1 [LAD left anterior descending; PA pulmonary artery and Fig 2 [Ao aortic artery; PA pulmonary artery; RCA right coronary artery]). There were extensive collaterals from the left anterior descending artery to the ARCAPA in the absence of coronary artery disease. After confirmation of these findings by cardiac catheterization, the patient was scheduled for immediate surgical repair to prevent further ischemic episodes. Intraoperative transesophageal echocardiography revealed the ARCAPA, which was implanted into the ascending aorta (Fig 2, Videos 1 and 2; accompanying videos for this article can be viewed at http://ats.ctsnetjournals.org/content/vol93/issue3/ images/data/e75/DC1/warraich1.avi and http://ats. ctsnetjournals.org/content/vol93/issue3/images/data/e75/ DC1/warraich2.avi.). ARCAPA is a rare but potentially fatal congenital abnormality, with surgical repair recommended even in asymptomatic patients [1]. The extent of collateralization

Tricuspid annulus: A spatial and temporal analysis

Background: Traditional two-dimensional (2D) echocardiographic evaluation of tricuspid annulus (TA) dilation is based on single-frame measurements of the septolateral (S-L) dimension. This may not represent either the axis or the extent of dynamism through the entire cardiac cycle. In this study, we used real-time 3D transesophageal echocardiography (TEE) to analyze geometric changes in multiple axes of the TA throughout the cardiac cycle in patients without right ventricular abnormalities. Materials and Methods: R-wave-gated 3D TEE images of the TA were acquired in 39 patients undergoing cardiovascular surgery. The patients with abnormal right ventricular/tricuspid structure or function were excluded from the study. For each patient, eight points along the TA were traced in the 3D dataset and used to reconstruct the TA at four stages of the cardiac cycle (end- and mid-systole, end- and mid-diastole). Statistical analyses were applied to determine whether TA area, perimeter, axes, and planarity changed significantly over each stage of the cardiac cycle. Results: TA area (P = 0.012) and perimeter (P = 0.024) both changed significantly over the cardiac cycle. Of all the axes, only the posterolateral-anteroseptal demonstrated significant dynamism (P < 0.001). There was also a significant displacement in the vertical axis between the points and the regression plane in end-systole (P < 0.001), mid-diastole (P = 0.014), and mid-systole (P < 0.001). Conclusions: The TA demonstrates selective dynamism over the cardiac cycle, and its axis of maximal dynamism is different from the axis (S-L) that is routinely measured with 2D TEE.

Early Cellular Changes in the Ascending Aorta and Myocardium in a Swine Model of Metabolic Syndrome

Background Metabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome. Methods Yorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD). Results There was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-β (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and–dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group. Conclusion Preclinical metabolic syndrome initiates pro-apoptosis and pro-fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification.

Changes in Tricuspid Annular Geometry in Patients with Functional Tricuspid Regurgitation

OBJECTIVE To determine whether the indices of tricuspid annular dynamics that signify irreversible tricuspid valvular remodeling can improve surgical decision making by helping to better identify patients with functional tricuspid regurgitation who could benefit from annuloplasty. DESIGN Retrospective analysis study. SETTING Tertiary hospital. PARTICIPANTS A total number of 55 patients were selected, 18 with functional tricuspid valve (TV) regurgitation and 37 normal nonregurgitant TVs. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS When comparing the basal, mid, and longitudinal diameters of the right ventricle between the nonregurgitant valve (NTR) group and the functional tricuspid regurgitation (FTR) group, tricuspid annulus was more dilated (p < 0.001, p = 0.001, and p = 0.006, respectively) and less nonplanar (p < 0.001) in the FTR group. At end-systole (ES), the posterolateral-anteroseptal axis was significantly greater in the FTR group than in the NTR group (mean difference = 7.15 mm; p < 0.001). The right ventricle in the FTR group was also significantly dilated with greater leaflet restriction (p = 0.015). CONCLUSIONS As compared to NTR TVs, FTR is associated with identifiable indices of tricuspid annular structural changes that are indicative of irreversible remodeling.