Amyloidosis in surgically resected atrial appendages: a study of 345 consecutive cases with clinical implications.

Histomorphologic parameters of atrial appendages removed during the Cox-Maze procedure have been shown to correlate with recurrence of atrial fibrillation. While amyloid deposition has been noted within atrial appendages, the incidence and significance remains incompletely understood. More accurate amyloid typing methodologies and targeted pharmacotherapeutics have recently been developed, prompting pathologists to provide more detailed information about the type of amyloid identified in such samples. This study sought to fully characterize the morphologic characteristics of atrial amyloid as well as its incidence and clinical significance. Tissue archives were queried for atrial appendages removed during the cardiac surgeries (2010-2014). Patient demographics, imaging features, and salient clinical findings were recorded. Pattern and extent of amyloid deposition were recorded. Typing of the amyloid protein, when present, was performed on a subset of cases by laser capture microdissection with mass spectrometry-based proteomic analysis. A total of 383 atrial appendages from 345 consecutive patients were included in the study (mean age, 69 years; range, 26-92 years). Amyloid was present in 46% of patients. A linear relationship was observed between age and presence of atrial amyloidosis. Women were more likely to have atrial amyloidosis. Two distinct morphologies of amyloid were observed: filamentous and nonfilamentous, and correlated perfectly with amyloid type (filamentous = AANF-type amyloid; nonfilamentous = ATTR-type amyloid). Filamentous deposits were observed in 91% of those with amyloid. Amyloid was more likely to be found in the left atrial appendage than the right. Patients with atrial amyloid, irrespective of type, were more likely to have experienced stroke or TIA and more likely to have atrial arrhythmia preoperatively. Postoperatively, those with atrial amyloid are more likely to experience recurrence of arrhythmia than those who did not have atrial amyloid. Understanding the morphologic characteristics of AANF-type amyloid will allow for identification by the light microscopy and obviates the need for expensive ancillary typing techniques. The finding of nonfilamentous amyloid, should still prompt confirmation of amyloid type so that targeted therapy may be employed.

Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction.

BACKGROUND: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. METHODS: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] ≥40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno-occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. RESULTS: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P≤0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. CONCLUSIONS: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF.

Neoplastic embolization to systemic and pulmonary arteries.

OBJECTIVE: Arterial neoplastic emboli are uncommon, accounting for <1% of thromboemboli in the current literature. Nonetheless, this event may be associated with significant morbidity and mortality. Herein, we report a series of 11 cases of arterial neoplastic emboli from a single tertiary care center along with a comprehensive review of the literature to date. The aim of this study was to document the incidence, clinical presentations, and complications of arterial neoplastic emboli as well as to highlight the importance of routine histologic examination of thrombectomy specimens. METHODS: Pathology archives from a single tertiary care institution were queried to identify cases of surgically resected arterial emboli containing neoplasm (1998-2014). Histopathology was reviewed for confirmation of diagnosis. Patient demographics and oncologic history were abstracted from the medical record. Comprehensive literature review documented 332 patients in 275 reports (1930-2016). RESULTS: Eleven patients (six men) with a median age of 63 years (interquartile range, 42-71 years) were identified through institutional archives. Embolism was the primary form of diagnosis in seven (64%) cases. Cardiac involvement (primary or metastasis) was present in more than half of the cohort. Comprehensive literature review revealed that pulmonary primaries were the most common anatomic origin of arterial neoplastic emboli, followed by gastrointestinal neoplasia. Cardiac involvement was present in 18% of patients, and sentinel identification of neoplasia occurred in 30% of cases. Postmortem evaluation was the primary means of diagnosis in 27%. CONCLUSIONS: This study highlights the importance of routine histopathologic evaluation of embolectomy specimens in patients with and without documented neoplasia.

Quadricuspid Aortic Valve: Characteristics, Associated Structural Cardiovascular Abnormalities, and Clinical Outcomes.

BACKGROUND: Quadricuspid aortic valve (QAV) is a rare congenital cardiac defect. This study sought to determine QAV frequency in a large echocardiography database, to characterize associated cardiovascular abnormalities, and to describe long-term outcomes. METHODS AND RESULTS: Fifty patients (mean ± SD age, 43.5 ± 21.8 years at the time of the index diagnosis; female sex, 52%) received a diagnosis of QAV between January 1, 1975, and March 14, 2014 (frequency, 0.006%). The QAV was type A in 32% and type B in 32% (Hurwitz and Roberts classification). Aortic dilatation was present in 29% of the patients, and 26% had moderate or severe aortic valve regurgitation at the index diagnosis. Stenosis affected only 8% of the valves and was mild. Other findings, including abnormalities of other cardiac valves, septal defects, persistent left superior vena cava, and patent ductus arteriosus, were present in 32% of patients. During a mean ± SD follow-up of 4.8 ± 5.6 years, 8 patients underwent aortic valve surgery, with severe aortic valve regurgitation being the surgical indication in 7 patients. One patient with mild to moderate aortic valve regurgitation underwent aortic valve repair for obstruction of the left coronary ostium by the accessory cusp of QAV. No infective endocarditis or aortic dissection was found. Overall survival was 91.5% and 87.7% at 5 and 10 years. CONCLUSIONS: Aortic dilatation and other structural cardiac abnormalities were relatively common among patients with QAV. Aortic valve regurgitation was the predominant hemodynamic abnormality and the indication for aortic valve surgery in most patients who received surgery. Long-term survival was excellent.

Clinical presentation and echocardiographic diagnosis of postinfarction papillary muscle rupture: A review of 22 cases.

BACKGROUND: Acute myocardial infarctions (AMI) continue to be common in the United States. Mechanical complications of AMI can lead to cardiogenic shock (CS) and death. The aim of this study was to review the cases of papillary muscle ruptures in the setting of myocardial infarctions at a tertiary care center, with a focus on the clinical presentation and echocardiographic diagnosis. METHODS: This was a retrospective study from January 1, 2000 through December 31, 2014. In all, 22 patients with AMI and papillary muscle rupture (AMI-PMR) who had surgical intervention were identified. RESULTS: The average age was 70 (±11) with 16 (73%) males. Six patients presented with ST-elevation myocardial infarctions (STEMI) and all underwent emergent revascularization with primary percutaneous coronary intervention (PCI) prior to the diagnosis of AMI-PMR. The other 16 patients presented with a non-STEMI. In total, 17 (77%) of the 22 patients were diagnosed with an AMI-PMR within 7 days from their onset of symptoms. In all, 12 patients (55%) had anterolateral papillary muscle ruptures (ALPMR), and the other 10 had posteromedial papillary muscle ruptures (PMPMR). Ruptures were complete in 10 patients (45%). Patients presented with pulmonary edema early (<7 days) more commonly than late (>14 days). Transthoracic echocardiography was able to demonstrate severe mitral regurgitation in 86% and a definitive or suggestive diagnosis in 93%. All 22 patients survived to operative management, and the overall in-hospital mortality rate was 9%. CONCLUSION: In conclusion, ischemic papillary muscle ruptures continue to occur, but with prompt diagnosis by echocardiography and rapid surgical management, the mortality rate continues to decline.

Sex-related differences in calcific aortic stenosis: correlating clinical and echocardiographic characteristics and computed tomography aortic valve calcium score to excised aortic valve weight.

AIMS: Calcific aortic valve stenosis (AS) is purportedly associated with less calcium burden in women than in men. We sought to examine sex-related differences and correlates of surgically excised aortic valve weight (AVW) in pure AS. METHODS AND RESULTS: Clinical and echocardiographic characteristics of 888 consecutive patients who underwent aortic valve replacement for severe AS were correlated to AVW, and in 126 patients, AVW was also correlated to computed tomography aortic valve calcium (AVC) score. Women and men had similar indexed valve area (0.42 ± 0.09 vs. 0.42 ± 0.07 cm (2)/m(2), P = 0.95) and mean systolic gradient (53 ± 15 vs. 52 ± 13 mmHg, P = 0.11), but women had higher New York Heart Association class (2.63 ± 0.70 vs. 2.50 ± 0.70, P = 0.01) and less prevalent coronary artery disease (38 vs. 52%, P < 0.0001). Aortic valve weight was lower in women (1.94 ± 0.88 vs. 3.08 ± 1.32 g, P < 0.0001) even when indexed to body surface area (1.09 ± 0.48 vs. 1.48 ± 0.62 g/m(2), P < 0.0001) or left ventricular outflow tract (LVOT) area (0.54 ± 0.23 vs. 0.71 ± 0.29 g/cm(2), P < 0.0001). Using multivariate analysis, male sex (P < 0.0001), bicuspid valve (P < 0.0001), and larger LVOT area (P < 0.0001) were the major determinants of increased AVW, along with current cigarette smoking (P = 0.007). Diabetes (P = 0.004) and hypertension (P = 0.03) were independently associated with lower AVW. Aortic valve calcium correlated well with AVW (r = 0.81, P < 0.0001) and was lower in women than in men (2520 ± 1199 vs. 3606 ± 1632 arbitrary units, P < 0.0001). CONCLUSIONS: Despite the same degree of AS severity, women have less AVC and lower AVW compared with men, irrespective of valve morphology. Aortic valve calcium is correlated to excised AVW. Hypertension, diabetes, and current cigarette smoking were independently associated with AVW.

Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

BACKGROUND: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Correlation of histomorphological pattern of cardiac amyloid deposition with amyloid type: a histological and proteomic analysis of 108 cases.

AIMS: Prognostication and treatment selection for cardiac amyloidosis requires accurate amyloid typing. The aim of this study was to investigate the utility of histomorphology for predicting type. METHODS AND RESULTS: Autopsy cases with cardiac amyloidosis (1998-2010) were typed by the use of mass spectrometry-based proteomics. Deposition patterns were correlated with amyloid type. Among 108 decedents (mean age 75 years; 69% men), 107 had a single type, including transthyretin (ATTR) (60 cases), amyloid light chain (AL) (32 λ; 12 κ), amyloid A (AA) (two), and apolipoprotein AIV (AApoAIV) (one). Interstitial deposition was more extensive in AL amyloidosis cases than in ATTR cases [odds ratio (OR) 6.8, P = 0.0004]. Histomorphological patterns of interstitial deposition were mixed in 61% of AL amyloidosis cases and in 61% of ATTR cases, but diffuse pericellular deposits favoured AL amyloidosis (OR 10.7, P = 0.0001), nodular deposits favoured ATTR (OR 3.1, P = 0.0229), and discrete pericellular deposits tended to partially favour ATTR (OR 1.7, P = 0.1970). Arterial and venous deposits each favoured AL amyloidosis (OR ranging from 9.3 to 192.0, P-value ranging from 0.0022 to <0.0001), and were severe in AL amyloidosis. Endocardial deposits favoured AL amyloidosis (OR 46.3, P < 0.0001) and were also more severe in AL amyloidosis. CONCLUSIONS: The extent and distribution of cardiac amyloidosis strongly correlate with amyloid type, suggesting fundamental differences in the pathobiology of deposition. The tendency for mixed patterns to occur limits the practicality and accuracy of using histopathology for amyloid typing.

Echocardiographic Features of Cardiac Angiosarcomas: The Mayo Clinic Experience (1976-2013).

OBJECTIVE: Cardiac angiosarcoma is the most common primary malignant cardiac tumor. The dismal prognosis and nonspecific symptomatology underscore the need for an accurate and cost-effective approach to the identification and characterization of this rare tumor. METHODS: Mayo Clinic tissue registry archives were queried for all histologically confirmed cases of cardiac angiosarcoma (1976-2013) with available imaging data. Echocardiograms were retrospectively reviewed. RESULTS: Thirty-three cases of cardiac angiosarcoma were identified; of these, 17 had echocardiograms available (mean age, 46 years; six men). Transthoracic echocardiography (TTE) as the initial diagnostic test had 75% sensitivity for visualizing primary cardiac angiosarcoma (9/12 patients). Tumor extension into the pericardium was common and pericardial effusion was present in 15 patients (88%); however, pericardial fluid cytology was negative for malignancy in all tested patients (n = 15). Left ventricular ejection fraction (LVEF) was preserved in 16 patients (94%) (average LVEF, 62%). Right ventricular function was mildly reduced in two patients (12%) at initial presentation. Tricuspid valve obstruction was present in three patients (18%; mean diastolic gradient, 6.3 mmHg [range, 3-11 mmHg]). CONCLUSION: The sensitivity of TTE as the first diagnostic imaging modality compared favorably with computed tomography. Pericardial effusion was common, but pericardial fluid cytology was negative in all patients who underwent pericardiocentesis. The absence of a stalk was a universal finding that may help distinguish angiosarcoma from benign, primarily pedunculated tumors such as myxoma and papillary fibroelastoma.

Atrial giant cell myocarditis: a distinctive clinicopathologic entity.

BACKGROUND: Giant cell myocarditis (GCM) typically causes fulminant heart failure, arrhythmias, or heart block, necessitating aggressive immunosuppression, ventricular assist device insertion, or cardiac transplantation. We describe a novel variant of GCM, primarily involving the atria, that displays distinctive clinical features and follows a more benign course than ventricular GCM. METHODS AND RESULTS: We identified 6 patients (median age 67.5 years, 4 male) with atrial GCM in our pathology consultation practices from 2010 to 2012. Clinical history, imaging, and pathology materials were reviewed. Clinically, 4 patients had atrial fibrillation, 1 had acute heart failure, and 1 had incidental disease at autopsy. Among the 5 living patients, echocardiography revealed severe atrial dilatation (5 cases), mitral/tricuspid regurgitation (5), atrial mural thrombus (3), atrial wall thickening (2), and atrial hypokinesis (2). Ventricular function was preserved in all 5. Histological review of surgically resected atria showed giant cell and lymphocytic infiltrates, lymphocytic myocarditis-like foci, cardiomyocyte necrosis, and cardiomyocyte hypertrophy in all cases. Other features included interstitial fibrosis (5), poorly-formed granulomas (4), eosinophils (4), neutrophils (1), and vasculitis (1). Treatment consisted of steroids and cyclosporine (1), pacemaker placement for sick sinus syndrome (1), and supportive care (3). All 5 living patients returned to baseline exercise tolerance after 6 to 16 weeks of follow-up. CONCLUSIONS: Atrial GCM represents a distinct clinicopathologic entity with a more favorable prognosis than classic ventricular GCM. This disorder should be included in the differential diagnosis of atrial dilatation, particularly when associated with atrial wall thickening. The utility of immunomodulatory therapy for this condition remains unknown.

[Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes]. / Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación.

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Este consenso de nomenclatura y clasificación para la válvula aórtica bicúspide congénita y su aortopatía está basado en la evidencia y destinado a ser utilizado universalmente por médicos (tanto pediatras como de adultos), médicos ecocardiografistas, especialistas en imágenes avanzadas cardiovasculares, cardiólogos intervencionistas, cirujanos cardiovasculares, patólogos, genetistas e investigadores que abarcan estas áreas de investigación clínica y básica. Siempre y cuando se disponga de nueva investigación clave y de referencia, este consenso internacional puede estar sujeto a cambios de acuerdo con datos basados en la evidencia1.

PCR-electrospray ionization mass spectrometry for direct detection of pathogens and antimicrobial resistance from heart valves in patients with infective endocarditis.

Microbiological diagnosis is pivotal to the appropriate management and treatment of infective endocarditis. We evaluated PCR-electrospray ionization mass spectrometry (PCR/ESI-MS) for bacterial and candidal detection using 83 formalin-fixed paraffin-embedded heart valves from subjects with endocarditis who had positive valve and/or blood cultures, 63 of whom had positive valvular Gram stains. PCR/ESI-MS yielded 55% positivity with concordant microbiology at the genus/species or organism group level (e.g., viridans group streptococci), 11% positivity with discordant microbiology, and 34% with no detection. PCR/ESI-MS detected all antimicrobial resistance encoded by mecA or vanA/B and identified a case of Tropheryma whipplei endocarditis not previously recognized.

Anatomy of the coronary sinus and epicardial coronary venous system in 620 hearts: an electrophysiology perspective.

INTRODUCTION: Cannulation of the coronary sinus (CS) is a prerequisite for left ventricular (LV) pacing and certain ablation procedures. The detailed regional anatomy for the coronary veins and potential anatomic causes for difficulty with these procedures has not been established. METHODS AND RESULTS: Therefore, we performed macroscopic measurements in 620 autopsied hearts (mean age 60 ± 23 years, 44% female). The CS was preserved for analysis in 96%. Sixty-three percent had a Thebesian valve that covered the posterior aspect of the CS ostium with extension to the superior (50%) and inferior aspects (18%) and was obstructive with fenestrations in 3 specimens. Partial or near occlusive valves were present occasionally at the ostium of the great cardiac vein (Vieussens; 8%) and middle cardiac vein (5%). Ninety-three percent had left atrial branches, and 41% had at least one branch with lumen > 3 French. For CRT lead placement, the mid-lateral LV was accessible from the middle cardiac vein (20%), the left posterior vein (92%) or the anterior interventricular vein (86%). Among specimens where the left phrenic nerve was preserved it crossed the LV mid-lateral wall in 45%. CONCLUSIONS: Epicardial coronary vein anatomy is variable, and the mid-lateral LV wall can potentially be accessed through various tributaries of the epicardial veins. The orientation of the Thebesian valve favors cannulation of the CS from an anterior (ventricular) and inferior approach. Anterobasal, mid-lateral, and inferior apical LV coronary veins lie in proximity to the course of the phrenic nerve.

Diffuse diseases of the myocardium: MRI-pathologic review of nondilated cardiomyopathies.

OBJECTIVE: This article will present correlation of the key radiologic findings with gross and microscopic pathology for the characterization of diffuse myocardial diseases using advanced imaging techniques. Our goal is to provide a focused and in-depth review of the pathophysiology underlying each entity and to emphasize the structural basis for the corresponding imaging characteristics. This article is limited to those disorders characterized by ventricular wall thickening without chamber dilatation, including hypertrophic cardiomyopathy, hypertensive cardiomyopathy, and cardiac amyloidosis. CONCLUSION: For the characterization of diffuse myocardial diseases using advanced imaging techniques, it is essential to understand the underlying pathologic changes in the heart. With these techniques, such as cardiac MRI, the various cardiomyopathies can be differentiated accurately, which may potentially obviate invasive testing and endomyocardial biopsy.

Diffuse diseases of the myocardium: MRI-pathologic review of cardiomyopathies with dilatation.

OBJECTIVE: In this radiologic-pathologic review of the cardiomyopathies, we present the pertinent imaging findings of diffuse myocardial diseases that are associated with ventricular dilatation, including ischemic cardiomyopathy, nonischemic dilated cardiomyopathy, cardiac sarcoidosis, and iron overload cardiomyopathy. CONCLUSION: Correlation of the key radiologic findings with gross and microscopic pathologic features is presented, to provide the reader with a focused and in-depth review of the pathophysiology underlying each entity and the basis for the corresponding imaging characteristics.

Histologic and proteomic remodeling of the pulmonary veins and arteries in a porcine model of chronic pulmonary venous hypertension.

AIMS: In heart failure (HF), pulmonary venous hypertension (PVH) produces pulmonary hypertension (PH) with remodeling of pulmonary veins (PV) and arteries (PA). In a porcine PVH model, we performed proteomic-based bioinformatics to investigate unique pathophysiologic mechanisms mediating PA and PV remodeling. METHODS AND RESULTS: Large PV were banded (PVH, n = 10) or not (Sham, n = 9) in piglets. At sacrifice, PV and PA were perfusion labelled for vessel-specific histology and proteomics. The PA and PV were separately sampled with laser-capture micro-dissection for mass spectrometry. Pulmonary vascular resistance [Wood Units; 8.6 (95% confidence interval: 6.3, 12.3) vs. 2.0 (1.7, 2.3)] and PA [19.9 (standard error of mean, 1.1) vs. 10.3 (1.1)] and PV [14.2 (1.2) vs. 7.6 (1.1)] wall thickness/external diameter (%) were increased in PVH (P < 0.05 for all). Similar numbers of proteins were identified in PA (2093) and PV (2085) with 94% overlap, but biological processes differed. There were more differentially expressed proteins (287 vs. 161), altered canonical pathways (17 vs. 3), and predicted upstream regulators (PUSR; 22 vs. 6) in PV than PA. In PA and PV, bioinformatics indicated activation of the integrated stress response and mammalian target of rapamycin signalling with dysregulated growth. In PV, there was also activation of Rho/Rho-kinase signalling with decreased actin cytoskeletal signalling and altered tight and adherens junctions, ephrin B, and caveolae-mediated endocytosis signalling; all indicating disrupted endothelial barrier function. Indeed, protein biomarkers and the top PUSR in PV (transforming growth factor-beta) suggested endothelial to mesenchymal transition in PV. Findings were similar in human autopsy specimens. CONCLUSION: These findings provide new therapeutic targets to oppose pulmonary vascular remodeling in HF-related PH.

TGFß-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFß Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2±23 years, MLVWT 20.8±4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.

Myocardium of the superior vena cava, coronary sinus, vein of Marshall, and the pulmonary vein ostia: gross anatomic studies in 620 hearts.

INTRODUCTION: Radiofrequency ablation for atrial fibrillation (AF) frequently involves energy delivery at the ostia of the thoracic veins. Detailed evaluation of the myocardium extending into the caval veins, vein of Marshall, as well as at the pulmonary vein ostia has not been completely evaluated. METHODS AND RESULTS: Post-mortem assessment of 620 formalin-fixed hearts (mean age 60 ± 23 years, 44% female) was performed. The hearts were examined for integrity of venous structures and their atrial connections. Systematic gross anatomic evaluation including measurements on myocardial extensions in these veins was performed. Macroscopic myocardial extensions into pulmonary veins were noted in 99% of specimens evaluated and were circumferentially symmetric (99.6%). Myocardial extensions into the superior vena cava (SVC) occurred in 78% with the majority being circumferentially asymmetric (61%). Occasionally, myocardium extended into the azygos vein (6%). There were no myocardial extensions in the inferior vena cava (IVC). In some cases, the right atrial pectinate muscle extended into the coronary sinus (7%). The vein of Marshall was consistently located anterior to the left-sided pulmonary veins and posterior to the left atrial appendage, overlying the left atrial endocardial ridge. CONCLUSIONS: Myocardial extensions into the pulmonary veins are usually circumferential at the ostia validating the necessity for wide area rather than segmental ablation to isolate these veins during AF ablation. Myocardial extensions into the SVC are common and less likely to be circumferential, whereas extensions into the IVC are not present. The left atrial ridge is a reliable endocardial target for radiofrequency ablation of the vein of Marshall.

Incidence of aortic complications in patients with bicuspid aortic valves.

CONTEXT: Bicuspid aortic valve (BAV), the most common congenital heart defect, has been thought to cause frequent and severe aortic complications; however, long-term, population-based data are lacking. OBJECTIVE: To determine the incidence of aortic complications in patients with BAV in a community cohort and in the general population. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, we conducted comprehensive assessment of aortic complications of patients with BAV living in a population-based setting in Olmsted County, Minnesota. We analyzed long-term follow-up of a cohort of all Olmsted County residents diagnosed with definite BAV by echocardiography from 1980 to 1999 and searched for aortic complications of patients whose bicuspid valves had gone undiagnosed. The last year of follow-up was 2008-2009. MAIN OUTCOME MEASURE: Thoracic aortic dissection, ascending aortic aneurysm, and aortic surgery. RESULTS: The cohort included 416 consecutive patients with definite BAV diagnosed by echocardiography, mean (SD) follow-up of 16 (7) years (6530 patient-years). Aortic dissection occurred in 2 of 416 patients; incidence of 3.1 (95% CI, 0.5-9.5) cases per 10,000 patient-years, age-adjusted relative-risk 8.4 (95% CI, 2.1-33.5; P = .003) compared with the county's general population. Aortic dissection incidences for patients 50 years or older at baseline and bearers of aortic aneurysms at baseline were 17.4 (95% CI, 2.9-53.6) and 44.9 (95% CI, 7.5-138.5) cases per 10,000 patient-years, respectively. Comprehensive search for aortic dissections in undiagnosed bicuspid valves revealed 2 additional patients, allowing estimation of aortic dissection incidence in bicuspid valve patients irrespective of diagnosis status (1.5; 95% CI, 0.4-3.8 cases per 10,000 patient-years), which was similar to the diagnosed cohort. Of 384 patients without baseline aneurysms, 49 developed aneurysms at follow-up, incidence of 84.9 (95% CI, 63.3-110.9) cases per 10,000 patient-years and an age-adjusted relative risk 86.2 (95% CI, 65.1-114; P <.001 compared with the general population). The 25-year rate of aortic surgery was 25% (95% CI, 17.2%-32.8%). CONCLUSIONS: In the population of patients with BAV, the incidence of aortic dissection over a mean of 16 years of follow-up was low but significantly higher than in the general population.

Confirmation of Cause of Death Via Comprehensive Autopsy and Whole Exome Molecular Sequencing in People With Epilepsy and Sudden Unexpected Death.

Background Sudden cardiac arrest is the leading mode of death in the United States. Epilepsy affects 1% of Americans; yet epidemiological data show a prevalence of 4% in cases of sudden cardiac arrest. Sudden unexpected death in epilepsy (SUDEP) may share features with sudden cardiac arrest. The objective of this study was to report autopsy and genomic findings in a large cohort of SUDEP cases. Methods and Results Mayo Clinic Sudden Death Registry containing cases (ages 0-90 years) of sudden unexpected and unexplained deaths 1960 to present was queried. Exome sequencing performed on decedent cases. From 13 687 cases of sudden death, 656 (4.8%) had a history of seizures, including 368 confirmed by electroencephalography, 96 classified as SUDEP, 58 as non-SUDEP, and 214 as unknown (insufficient records). Mean age of death in SUDEP was 37 (±19.7) years; 56 (58.3%) were male; 65% of deaths occurred at night; 54% were found in bed; and 80.6% were prone. Autopsies were obtained in 83 cases; bystander coronary artery disease was frequently reported as cause of death; nonspecific fibrosis was seen in 32.6% of cases, in structurally normal hearts. There were 4 cases of Dravet syndrome with pathogenic variants in SCN1A gene. Using whole exome sequencing in 11 cases, 18 ultrarare nonsynonymous variants were identified in 6 cases including CACNB2, RYR2, CLNB, CACNA1H, and CLCN2. Conclusions This study examined one of the largest single-center US series of SUDEP cases. Several cases were reclassified as SUDEP, 15% had an ECG when alive, and 11 (11.4%) had blood for whole exome sequencing analysis. The most frequent antemortem genetic finding was pathogenic variants in SCN1A; postmortem whole exome sequencing identified 18 ultrarare variants.