Mark R. Bonnell

Transmural heterogeneity of cellular level power output is reduced in human heart failure.

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function. Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06μWmg(-1)) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33kNm(-2)) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain-1. Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure.

Equipoise between radial artery and right internal thoracic artery as the second arterial conduit in left internal thoracic artery-based coronary artery bypass graft surgery: a multi-institutional study

OBJECTIVES Multiple arterial coronary artery grafting (MABG) improves long-term survival compared with single arterial CABG (SABG), yet the best second arterial conduit to be used with the left internal thoracic artery (LITA) remains undefined. Outcomes in patients grafted with radial artery (RA-MABG) versus right internal thoracic artery (RITA-MABG) as the second arterial graft were compared with SABG. METHODS Multi-institutional, retrospective analysis of non-emergent isolated LITA to left anterior descending coronary artery CABG patients was performed using institutional Society of Thoracic Surgeon National Adult Cardiac Surgery Databases. 4484 (54.5%) SABG [LITA ± saphenous vein grafts (SVG)], 3095 (37.6%) RA-MABG (RA ± SVG) and 641 (7.9%) RITA-MABG (RITA ± SVG) patients were included. The RITA was used as a free (68%) or in situ (32%) graft. RA grafts were principally anastomosed to the ascending aorta. Long-term survival was ascertained from US Social Security Death Index and institutional follow-up. Triplet propensity matching and covariate-adjusted multivariate logistic regression were used to adjust for baseline differences between study cohorts. RESULTS Compared with the SABG cohort, the RITA-MABG cohort was younger (58.6 ± 10.2vs65.9 ± 10.4, P < 0.001), had a higher prevalence of males (87% vs 65%, P < 0.001) and was generally healthier (MI: 36.7% vs 56.7%, P < 0.001, smoking: 56.8% vs 61.1%, IDDM: 3.0% vs 14.4%, CVA: 2.6% vs 10.0%). The RA-MABG cohort was generally characterized by a risk profile intermediate to that of SABG and RlTA-MABG. Unadjusted 5-, 10- and 15-year survival rates were best in RITA-MABG (95.2%, 89% and 82%), intermediate in RA-MABG (89%, 74%, 57%) and worst in SABG (82%, 61% and 44%) cohorts (all P < 0.001). Propensity matching yielded 551 RA-MABG, RITA-MABG and SABG triplets, which showed similar 30-day mortality. Late survival (16 years) was equivalent in the RA-MABG and RITA-MABG cohorts [68.2% vs 66.7%, P = 0.127, hazard ratio (HR) = 1.28 (0.96-1.71)] and both significantly better than SABG (61.1%). The corresponding SABG versus RITA-MABG and SABG versus RA-MABG HRs (95% confidence interval) were 1.52 (1.18-1.96) and 1.31 (1.01-1.69) with P < 0.002 and P = 0.038, respectively. CONCLUSIONS RA-MABG or RITA-MABG equally improve long-term survival compared with SABG and thus should be embraced by the Heart Team as the therapy of choice in LITA-based coronary artery bypass surgery.

Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle

Aims Sphingolipid and oxidant signaling affect glucose uptake, atrophy, and force production of skeletal muscle similarly and both are stimulated by tumor necrosis factor (TNF), suggesting a connection between systems. Sphingolipid signaling is initiated by neutral sphingomyelinase (nSMase), a family of agonist-activated effector enzymes. Northern blot analyses suggest that nSMase3 may be a striated muscle-specific nSMase. The present study tested the hypothesis that nSMase3 protein is expressed in skeletal muscle and functions to regulate TNF-stimulated oxidant production. Results We demonstrate constitutive nSMase activity in skeletal muscles of healthy mice and humans and in differentiated C2C12 myotubes. nSMase3 (Smpd4 gene) mRNA is highly expressed in muscle. An nSMase3 protein doublet (88 and 85 kD) is derived from alternative mRNA splicing of exon 11. The proteins partition differently. The full-length 88 kD isoform (nSMase3a) fractionates with membrane proteins that are resistant to detergent extraction; the 85 kD isoform lacking exon 11 (nSMase3b) is more readily extracted and fractionates with detergent soluble membrane proteins; neither variant is detected in the cytosol. By immunofluorescence microscopy, nSMase3 resides in both internal and sarcolemmal membranes. Finally, myotube nSMase activity and cytosolic oxidant activity are stimulated by TNF. Both if these responses are inhibited by nSMase3 knockdown. Innovation These findings identify nSMase3 as an intermediate that links TNF receptor activation, sphingolipid signaling, and skeletal muscle oxidant production. Conclusion Our data show that nSMase3 acts as a signaling nSMase in skeletal muscle that is essential for TNF-stimulated oxidant activity.

A Protocol for Collecting Human Cardiac Tissue for Research

This manuscript describes a protocol at the University of Kentucky that allows a translational research team to collect human myocardium that can be used for biological research. We have gained a great deal of practical experience since we started this protocol in 2008, and we hope that other groups might be able to learn from our endeavors. To date, we have procured ~4000 samples from ~230 patients. The tissue that we collect comes from organ donors and from patients who are receiving a heart transplant or a ventricular assist device because they have heart failure. We begin our manuscript by describing the importance of human samples in cardiac research. Subsequently, we describe the process for obtaining consent from patients, the cost of running the protocol, and some of the issues and practical difficulties that we have encountered. We conclude with some suggestions for other researchers who may be considering starting a similar protocol.

Diaphragm Abnormalities in Patients with End-Stage Heart Failure: NADPH Oxidase Upregulation and Protein Oxidation

Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5–4.6-fold over controls (p < 0.05). Patients also had increased protein levels of Nox2 subunits (p47phox, p22phox, and p67phox) and total p47phox phosphorylation, while phospho-to-total p47phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% (p < 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals.

Embolic Stroke Due to Sinus of Valsalva Aneurysm Thrombus

Embolic Stroke Due to Sinus of Valsalva Aneurysm Thrombus Sinus of valsalva aneurysms are rare and a prevalence of 0.09% in the general population is reported by an autopsy study. Thrombus formation in the sinus of valsalva aneurysms are a rare complication and could lead to embolic phenomena. Herein, we report a rare case of sinus of valsalva aneurysm with a thrombus inside it that lead to embolic stroke. An 83-year-old man presented with left arm weakness. Cardiovascular examination was unremarkable except for an irregular pulse and electrocardiogram confirmed atrial fibrillation. Brain magnetic resonance imaging showed an acute infarct in the right frontal lobe. Transesophageal echocardiogram demonstrated no intracardiac thrombi. However, sinuses of valsalva aneurysm with a large thrombus was observed (Figure A). Computed tomography scan of the chest showed aneurysmal dilatation of 2 sinuses of the valsalva; the first, involving the left coronary sinus, was 6.2 4.7 cm in size and contained a large thrombus, the second aneurysm was 2.1 1.7 cm in size and involved the right coronary sinus (Figure B). Thrombus within the sinus of valsalva aneurysm was considered the source of embolic stroke. Considering the large size of the aneurysms, the risk of rupture and the potential for future thromboembolic events, cardiothoracic consultation was obtained. The patient underwent resection of the sinus of valsalva aneurysms and aortic root repair with Medtronic

A Seedless Grape in the Heart

A 65-year-old woman was admitted with shortness of breath and chest pain. A computed tomographic angiogram of the chest performed for suspected pulmonary embolism showed a filling defect in the left atrium, concerning for a tumor or thrombus (Figure, A). Transesophageal echocardiography revealed a large mobile mass in the left atrium attached to the interatrial septum with a very short pedicle (Figure, B and Movie I in the online-only Data Supplement). The patient had a history of surgical patent foramen ovale closure with a Prolene suture, mitral valve repair, and saphenous vein bypass graft to the right coronary …