Schaff, Hartzell V.

Background Coarctation of the aorta is commonly associated with recoarctation or additional cardiovascular disorders that require intervention. The best surgical approach in such patients is uncertain. Ascending-to-descending aortic bypass graft via the posterior pericardium (CoA bypass) allows simultaneous intracardiac repair or an alternative approach for the patient with complex coarctation. Methods and Results Between 1985 and 2000, 18 patients (13 males and 5 females, mean age 43±13 years) with coarctation of the aorta underwent CoA bypass through median sternotomy. Before operation, average New York Heart Association class was II (range I to IV), and 15 patients (83%) had systemic hypertension. One or more previous cardiovascular operations had been performed in 12 patients (67%); 10 patients had ≥1 prior coarctation repair. Two patients had prior noncoarctation cardiovascular surgery. Concomitant procedures performed in 14 patients (78%) included the following: aortic valve replacement in 9; coronary artery bypass surgery in 3; mitral valve repair in 2; and septal myectomy, mitral valve replacement, aortoplasty, subaortic stenosis resection, ventricular septal defect closure, and ascending aorta replacement in 1 patient each. All patients survived the operation and were alive with patent CoA bypass at a mean follow-up of 45 months. No graft-related complications occurred, and there were no instances of stroke or paraplegia. Systolic blood pressure fell from 159 mm Hg before surgery to 125 mm Hg after surgery. Conclusions CoA bypass via median sternotomy can be performed with low morbidity and mortality. Although management must be individualized, extra-anatomic CoA bypass via the posterior pericardium is an excellent single-stage approach for patients with complex coarctation or recoarctation and concomitant cardiovascular disorders.

Background —The role of surgical closure of patent foramen ovale (PFO) for cerebral infarction (CI) or transient ischemic attack (TIA) resulting from paradoxical embolism is unclear, and its effect on recurrence is unknown. Our objective was to determine the outcome of surgical closure of PFO in patients with a prior ischemic neurological event, define the rate of CI or TIA recurrence after PFO closure, and identify risk factors for these recurrences. Methods and Results —We retrospectively analyzed 91 patients (58 men, 33 women) with ≥1 previous cerebrovascular ischemic events who underwent surgical PFO closure between April 1982 and March 1998. The presence of a PFO with a right-to-left shunt was confirmed with transesophageal echocardiography. Mean age was 44.2±12.2 years. The index event was a CI in 59 and a TIA in 32; a Valsalva-like episode preceded the event in 15 patients. Deep venous thrombosis was documented in 9 patients, and a hypercoagulable state was identified in 10. Surgical closure was performed with extracorporeal circulation by either direct suture (n=82) or patch closure (n=9). Limited incisions were used in 18.7% of patients. There was no operative mortality. Morbidity included transient atrial fibrillation (n=11), pericardial drainage for effusion (n=4), exploration for bleeding (n=3), and superficial wound infection (n=1). Follow-up totaled 176.3 patient-years, and mean follow-up was 2.0 years. No one had a CI, and 8 had a TIA during follow-up, with 1 caused by temporal arteritis. Transesophageal echocardiography demonstrated all closures to be intact in these patients. The overall freedom from TIA recurrence during follow-up was 92.5±3.2% at 1 year and 83.4±6.0% at 4 years. Having multiple neurological events before PFO closure was the only significant risk factor for TIA or CI recurrence after closure by univariate analysis ( P =0.05); the small number of post-PFO closure cerebral ischemic events precluded multivariate analysis. Conclusions —Surgical closure of PFO can be performed with minimal morbidity and mortality. PFO closure may decrease the risk of recurrent stroke or TIA and may avoid lifelong anticoagulation in the young adult if there is no other indication. Recurrent cerebrovascular ischemic events after surgery should prompt further evaluation to identify causes other than paradoxical embolism.

Background Carcinoid heart disease characteristically affects tricuspid (TV) and pulmonary valves (PV), and TV replacement is helpful in selected patients. There is uncertainty, however, regarding optimal surgical management of PV regurgitation. Methods and Results We reviewed 22 patients having operation for carcinoid heart disease and compared those having TV and PV replacement (n=12), to those who underwent TV replacement and excision of the PV (n=10). Pre- and postoperative right ventricular (RV) size and dysfunction were assessed by consensus of 2 echocardiographers blinded to type of surgical treatment. RV dysfunction was graded as none (0), mild (1), moderate (2), or severe (3). RV size was graded as normal (0), or mild (1), moderate (2), or severe (3) enlargement. Preoperatively, RV size (2.2±0.8 [no PVR]versus 2.7±0.6 [with PVR], P =0.15), RV dysfunction (0.9±0.9 [no PVR]versus 1.4±0.7 [with PVR], P =0.14), and NYHA class were similar in the 2 groups. Postop RV size decreased inpatients with PVR, 2.7±0.6 to 1.7±1.0 ( P =0.008), but did not change appreciably in those without PVR, 2.2±0.8 to 2.3±0.8 ( P =0.67). There was no significant change in RV dysfunction after surgery, 1.4±0.7 to 1.8±0.9 with PVR ( P =0.26) and 0.9±0.9 to 1.6±0.9 without PVR ( P =0.07). Conclusions PV replacement appears to have a beneficial effect on RV size in patients after surgery for carcinoid heart disease. This may have important implications for RV remodeling after PV replacement.

Background Pericardiectomy for post-radiation constrictive pericarditis has been reported to generally have unfavorable outcomes. This study sought to evaluate surgical outcomes in a large cohort of patients undergoing pericardiectomy for radiation-associated pericardial constriction. Methods A retrospective analysis of all patients (≥18years) who underwent pericardiectomy for a diagnosis of constrictive pericarditis with a prior history of mediastinal irradiation from June 2002 to June 2019 was conducted. There were 100 patients (mean age 57.2±10.1 years, 49% females) who met the inclusion criteria. Records were reviewed to look at surgical approach, extent of resection, early mortality and late survival. Results The overall operative mortality was 10.1% (n=10). The rate of operative mortality decreased over the study period; however, the test of trend was not statistically significant (P=0.062). Hodgkin’s disease was the most common malignancy (64%) for which mediastinal radiation had been received. Only 27% patients had an isolated pericardiectomy, and concomitant pericardiectomy and valve surgery was performed in 46% patients. Radical resection was performed in 50% patients, whereas 47% patients underwent a subtotal resection. Prolonged ventilation (26%), atrial fibrillation (21%) and pleural effusion (16%) were the most common post-operative complications. The overall 1,5- and 10-years survival was 73.6%, 53.4% and 32.1% respectively. Increasing age (HR 1.044, 95%CI 1.017-1.073) appeared to have a significant negative effect on overall survival in the univariate model. Conclusion Pericardiectomy performed for radiation associated constrictive pericarditis has poor long-term outcomes. The early mortality, though high (~10%), has been showing a decreasing trend in the test of time.

Background Contemporary nationwide data on the use, predictors, and outcomes of mechanical valve replacement in patients less than 70 years of age are limited. Methods and Results We identified hospitalizations for aortic valve replacement (AVR) or mitral valve replacement (MVR) in the Nationwide Inpatient Sample between January 1, 2008, and December 31, 2017. The study's end points included predictors of mechanical valve replacement and risk‐adjusted in‐hospital mortality. Among 253 100 hospitalizations for AVR, the use rate of mechanical prosthesis decreased from 45.3% in 2008 to 17.0% in 2017. Among 284 962 hospitalizations for MVR, mechanical prosthesis use decreased from 59.5% in 2008 to 29.2% in 2017 ( P for trend<0.001). In multilogistic regression analyses, female sex, prior sternotomy, prior defibrillator, and South/West geographic location were predictive of mechanical valve use. The presence of bicuspid valve was a negative predictor of mechanical AVR (odds ratio [OR], 0.68; 95% CI, 0.66–0.69; P <0.001), whereas mitral stenosis was associated with higher mechanical MVR (OR, 1.28; 95% CI, 1.22–1.33; P <0.001). Unadjusted in‐hospital mortality decreased over time with AVR but not with MVR, regardless of prosthesis choice. Using years 2008 and 2009 as a reference, risk‐adjusted mortality also decreased over time with AVR but did not decrease after MVR. Conclusions There is a substantial decline in the use of mechanical valve replacement among patients aged ≤70 years in the United States. Long‐term durability data on bioprosthetic valve replacement are needed to better define the future role of mechanical valves in this age group.

Background Structural and functional mitral valve abnormalities are commonly encountered in the general population. In order to determine which functional protein classes may be important to normal valve function we performed the first reported comprehensive proteomic profiling of structurally normal human mitral valves. Methods We harvested mitral valve leaflets from 5 patients who underwent orthotopic cardiac transplantation for cardiomyopathy. The morphologic appearance of mitral valves was normal with only mild functional mitral regurgitation on echocardiogram. High resolution 2D gel electrophoresis was performed to separate proteins. Gel spots were excised from 2 representative samples and protein identification was carried out using liquid chromatography tandem mass spectrometry. Results We identified 190 unique proteins with >99% probability and at least 2 unique peptides. The proteins were from various cellular locations, including cell surface, cytoskeleton, endoplasmic reticulum, extracellular matrix, mitochondrion, nucleus, cytoplasm, and plasma membrane. Functional clustering revealed that the identified proteins were involved in major molecular pathways including, energy along with fatty acid metabolism, calcium signaling acute phase response & oxidative stress, and anti‐apoptosis pathways. Conclusion Proteomic profiling of the normal human mitral valve demonstrates a pattern of expression suggesting multiple biological functions. Further quantification of protein levels and comparison with diseased mitral valves will provide new insights into the etiology and therapy of mitral valve disease in humans.

Myxomatous mitral valve disease (MMVD) is associated with increases in valvular fibrosis, matrix remodeling, and transforming growth factor beta (TGF β) signaling. While interleukin 10 (IL‐10) can suppress tissue fibrosis and matrix metalloproteinase (MMP) expression, its role in MMVD is unknown. We tested the hypotheses that reduced IL‐10 expression contributes to increased tissue fibrosis in MMVD, and that IL‐10 tonically suppresses TGF‐β signaling in normal mitral valves. We used qRT‐PCR to measure expression of IL10, TGF‐β1, MMP 2 and 9, and connective tissue growth factor (CTGF) in normal and myxomatous human mitral valves and in mitral and tricuspid valves from wild‐type and IL‐10 knockout mice. IL‐10 expression was significantly reduced in human myxomatous valves compared to normal valves (53± 12%), and was associated with increases in TGFβ, CTGF, and MMP2. Mitral valve gene expression patterns in IL‐10 −/− mice favored fibrosis and matrix remodeling compared to wild‐type littermates, with increases in TGF β (132±7%), CTGF (154±3%), and MMP9 (259±7%) (p< 0.05 for all), but not MMP2. Interestingly, expression of these genes was not altered in tricuspid valves from IL‐10 −/− mice. Collectively, these data are the first to show that IL‐10 tonically suppresses TGF β signaling in normal mitral valves and that deficiency of IL‐10 is likely to contribute to fibrosis and matrix remodeling in MMVD. NHLBI

Myxomatous mitral valve disease is characterized by fibrosis and matrix degradation and increases in transforming growth factor beta‐1 (TGFbeta‐1). Little is known, however, about changes in molecules that regulate TGFbeta‐1 signaling in myxomatous valves. Thus, we tested the hypothesis that TGFbeta‐1 promotes valvular fibrosis and matrix remodeling in myxomatous valves through canonical Smad2 signaling and permissive reductions in Smad inhibitors. Expression of TGFbeta‐1, TGFbeta‐1 target genes (connective tissue growth factor, matrix metalloproteinases 2/9), E3 ubiquitin‐protein ligases (Smurf 1/2, which degrade Smad2), and NAD(P)H oxidase catalytic subunits (Nox 2, 4, and 5) was measured using quantitative real‐time RT‐PCR. Phospho‐Smad2 levels were measured using western blotting. TGFbeta‐1 expression was higher in myxomatous valves (138.3 ± 12.5% of control, n = 24 per group; p < 0.05), while CTGF and MMP2 were increased by 5‐ and 2‐fold, respectively. Surprisingly, phospho‐Smad2 levels were unchanged between myxomatous and control tissue due to selective increases in Smurf2 expression in myxomatous valve tissue (165.2 ± 17.7% of control, p < 0.05), as Smurf1 expression was unchanged. Expression of Nox2 and Nox4—which can drive pro‐fibrotic and matrix remodeling gene expression in other tissues—were significantly elevated in myxomatous valves (211 ± 44% and 224 ± 35 % of control, respectively; p < 0.05). In conclusion, our data suggest that canonical TGFbeta‐1/Smad2 signaling is not required for progression of myxomatous valve disease, and that reducing Nox2‐and Nox4‐derived reactive oxygen species may be a novel intervention to slow progression of fibrosis and matrix remodeling in myxomatous valves.

Objective Bioprosthetic valve thrombosis (BPVT) is increasingly recognised as a major cause of prosthetic dysfunction in the first years postimplantation. How early abnormal gradients can be detected prior to diagnosis and how fast they normalise with anticoagulant therapy is unknown. We set forth to (1) evaluate patterns of increase in gradients prior to BPVT diagnosis and (2) characterise time-course of response to anticoagulation. Methods Patients treated with warfarin for BPVT (1999–2019) with clinically significant reduction of mean gradients (≥25%) were identified retrospectively. Recovery was defined as gradient decrease ≥50%, to postimplantation or to normal-range gradients per position, model and size. Time-to-BPVT (implantation—BPVT diagnosis), potential diagnostic delay (first abnormal gradient by position, model and size—BPVT diagnosis) and time-to-recovery (BPVT diagnosis—complete resolution) were recorded. Results 77 patients were identified; 32 (42%) aortic (23 surgical—12 porcine, 11 pericardial; 9 transcatheter); 24 (31%) mitral; 21 (27%) tricuspid. Median time-to-BPVT was 24, 21 and 10 months, respectively. Potential diagnostic delay was median 21 months for aortic, 4 months for mitral, but 0 for tricuspid. Recovery was significantly faster in mitral than aortic (median 2.5 vs 4.8 months, p=0.038) and tricuspid (median 5.9 months, p=0.025) positions. Porcine aortic valves responded faster than pericardial aortic valves (median 2.9 vs 20.3 months, p=0.004). Conclusion Gradients start to increase months before the clinical BPVT diagnosis. Recovery is faster in mitral and surgical aortic porcine valves; a longer warfarin trial seems indicated in tricuspid and surgical aortic pericardial valves.