Non-invasive diagnostic imaging tests largely underdiagnose cardiac cirrhosis in patients undergoing advanced therapy evaluation: How can we identify the high-risk patient?

BACKGROUND: Patients with liver cirrhosis are generally considered ineligible for isolated cardiac transplantation or left ventricular assist device (LVAD) implantation. The aim of this retrospective study is to explore the diagnostic value of abdominal ultrasound, computed tomography scan (CT scan) and liver-spleen scintigraphy to detect the presence of cirrhosis in patients with advanced heart failure. METHODS: Among 567 consecutive patients who underwent pre-transplantation or LVAD evaluation, 54 had a liver biopsy to rule out cardiac cirrhosis; we compared the biopsy results with the imaging investigations. RESULTS: In about 26% (n = 14) of patients undergoing liver biopsy, histopathological evaluation identified cirrhosis. The respective sensitivity of abdominal ultrasound, CT scan and liver-spleen scintigraphy to detect cirrhosis was 57% [29-82], 50% [16-84], and 25% [3-65]. The specificity was 80% [64-91], 89% [72-98], and 44% [20-70], respectively. CONCLUSION: Ultrasonography has the best-combined sensitivity and specificity for the diagnosis of cirrhosis. However, more than a third of patients with cirrhosis will go undiagnosed by conventional imaging. As liver biopsy is associated with a low rate of complication, it should be considered in patients with a high-risk of cirrhosis or with evidence of portal hypertension to assess their eligibility for heart transplantation or LVAD implantation.

An autopsy view of the Hemi-commando procedure.

Invasive endocarditis involving the fibrous skeleton of the heart requires complex high-risk surgical management. For combined aortic and mitral infection in whom the posterior mitral leaflet and at least the free edge of anterior mitral valve could be spared, a modification of the Commando procedure was suggested: the "Hemi-commando procedure." We report the autopsy images of a Hemi-commando procedure after in unfortunate death in a 24 years old man 17 days after surgery.

Missense variants in the spectrin repeat domain of DSP are associated with arrhythmogenic cardiomyopathy: A family report and systematic review.

Rare loss of function variants in DSP, which codes for the desmosomal protein desmoplakin, have been implicated in dilated and arrhythmogenic right ventricular cardiomyopathies. We present a family with arrhythmogenic cardiomyopathy associated with a novel missense variant in DSP (NM_004415.4): c.877G>A, p.(Glu293Lys). The phenotype is characterized by predominant involvement of the left ventricle with systolic dysfunction, fibrosis, and life-threatening arrhythmias. We performed a systematic review of literature collecting all cardiomyopathy cases with rare missense variants in DSP. We demonstrate that the distribution of missense variants across the protein domains in cardiomyopathy cases differs from that in gnomAD (p = .04), with a case enrichment of rare missense variants in the spectrin repeat domain (36/78 [46%] in cases vs. 449/1495 [30%] in gnomAD; p = .004). Our findings highlight the predominance of cardiac arrhythmia and left ventricular involvement in desmoplakin cardiomyopathy and pinpoint to a potential mutation hotspot in DSP thereby facilitating missense variant interpretation in the diagnostic setting.

Sex-Related Discordance Between Aortic Valve Calcification and Hemodynamic Severity of Aortic Stenosis: Is Valvular Fibrosis the Explanation?

RATIONALE: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification loads than men for the same AS hemodynamic severity. OBJECTIVE: We, thus, aimed to assess sex differences in aortic valve fibrocalcific remodeling. METHODS AND RESULTS: One hundred and twenty-five patients underwent Doppler echocardiography and multidetector computed tomography within 3 months before aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed, and fibrosis degree was determined. Sixty-four men and 39 women were frequency matched for age, body mass index, hypertension, renal disease, diabetes mellitus, and AS severity. Mean age (75±9 years), mean gradient (41±18 mm Hg), and indexed aortic valve area (0.41±0.12 cm2/m2) were similar between men and women (all P≥0.18). Median aortic valve calcification (1973 [1124-3490] Agatston units) and mean valve weight (2.36±0.99 g) were lower in women compared with men (both P<0.0001). Aortic valve calcification density correlated better with valve weight in men (r2=0.57; P<0.0001) than in women (r2=0.26; P=0.0008). After adjustment for age, body mass index, aortic valve calcification density, and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (P=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (P=0.01), and Masson trichrome staining revealed a greater proportion of dense connective tissue (P=0.02) in women compared with men. CONCLUSIONS: In this series of patients with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared with men. These findings suggest that the pathophysiology of AS and thus potential targets for drug development may be different according to sex.

Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve.

BACKGROUND: Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve. METHODS AND RESULTS: We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches, we have also investigated the role of ATX-lysophosphatidic acid in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR(-/-)/ApoB(100/100)/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. CONCLUSIONS: ATX is transported in the aortic valve by Lp(a) and is also secreted by valve interstitial cells. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent a novel therapeutic target in CAVD.

Paradoxical low-flow, low-gradient aortic stenosis despite preserved left ventricular ejection fraction: new insights from weights of operatively excised aortic valves.

AIMS: We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. 'paradoxical' low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG<40 mmHg with the AVW of patients with NF and MG≥40 mmHg. METHODS AND RESULTS: We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) ≤ 35 mL/m(2)] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m(2)) with MG ≥ 40 mmHg (NF-HG group). Despite a much lower MG (29 ± 7 vs. 53 ± 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 ± 0.12 vs. 0.69 ± 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63-2.50) vs. 2.60 (1.66-3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63-2.50) vs. 2.30 (1.58-3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73-3.61) vs. 2.60 (2.10-3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non-consecutive patients (n = 150, Cohort B) with NF and concordant Doppler-echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. CONCLUSION: The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low-gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients.

Angiotensin receptor blockers are associated with reduced fibrosis and interleukin-6 expression in calcific aortic valve disease.

BACKGROUND: Calcific aortic valve disease (CAVD) is a chronic disorder characterized by the mineralization of the aortic valve and involving fibrosis. OBJECTIVES: In this work we sought to determine if the fibrotic component of the remodeling process of CAVD was related to the use of angiotensin-converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). METHODS: In 477 patients with CAVD, the aortic valve was examined by histology. A semiquantitative score of fibrosis was generated and associations with clinical/cardiometabolic variables examined. In a subset of 103 patients the aortic valve was available to study the infiltration by inflammatory cells and expression of interleukin-6 (IL-6) by quantitative real-time PCR. RESULTS: The fibrosis score of the aortic valve was independently related to the hemodynamic severity of CAVD measured by echocardiography. The fibrotic score of the aortic valve was also related to the expression of IL-6. The use of ARBs but not of ACEi was associated with a lower fibrosis score of the aortic valve even after correction for covariates. In addition, patients under ARBs had lower aortic valve inflammation and expression of IL-6. CONCLUSIONS: These findings suggest that ARBs may alter the fibrotic process of the aortic valve in CAVD, possibly by lowering tissue inflammation.

Angiotensin II Receptor Blockers Are Associated With Reduced Valvular Fibrosis in Women With Aortic Stenosis.

BACKGROUND: Angiotensin receptor blockers (ARBs) may slow down the progression of aortic stenosis (AS) through their antifibrotic effect. Women present more valvular fibrosis than men, so ARBs may have more effect in females. Our aim was to assess the impact of ARBs on the remodelling of the aortic valve in men and women. METHODS: We included patients who had an aortic valve replacement with or without coronary bypass grafting from 2006 to 2013. Patients with missing echocardiographic or histologic data were excluded. Warren-Yong and fibrosis scores of the explanted valves were performed. Patients were divided into 4 phenotypes according to their Warren-Yong and fibrosis scores: mild calcification/fibrosis, severe calcification/fibrosis group, predominant fibrosis group, predominant calcification group. RESULTS: Among the 1321 included patients, the vast majority (89%) has severe AS. Patients in the predominant fibrosis group, compared with the predominant calcium group, were more often female (39% vs 31%; P = 0.008) with bicuspid valves (44% vs 34%; P = 0.002), and less often used ARBs (25% vs 30%; P = 0.046). Female sex was independently associated with being in the predominant fibrosis group (odds ratio 1.45, 95% confidence interval 1.08-1.95; P = 0.01), with a significant interaction between female sex and ARBs. Women taking ARBs compared with women not taking ARBs had significantly lower fibrosis scores (P < 0.001). This difference was not seen in men. CONCLUSIONS: In this large series of patients with moderate-severe AS, among the women there was a negative association between intake of ARBs and valvular fibrosis. Thus, the possible effects of ARBs may be sex specific, with a larger therapeutic role in women.

Lipoprotein lipase in aortic valve stenosis is associated with lipid retention and remodelling.

BACKGROUND: Calcific aortic valve disease (CAVD) is a chronic disorder characterized by a fibrocalcific remodelling. It is suspected that lipid retention within the aortic valve may be one important mechanism participating to aortic valve remodelling. Lipoprotein lipase (LPL) is implicated in lipid metabolism and may play a role in lipid retention within the aortic valve. METHODS: In 57 patients, CAVD were analysed for the expression of LPL by q-PCR and immunohistochemistry. Expression of oxidized-LDL (ox-LDL) and decorin was also documented. In addition, a complete blood profile, including the size of LDL and high-density lipoprotein (HDL) particles, were performed to find associations between the blood lipid profile and expression of ox-LDL and LPL within CAVD. RESULTS: Immunohistochemistry studies revealed that LPL was expressed in stenotic aortic valves as a diffuse staining and also in dense cellular areas where macrophages were abundant. Expression of LPL co-localized with decorin and ox-LDL. In turn, valves with higher amount of ox-LDL had elevated number of LPL transcripts. In addition, we documented that the small, dense HDL phenotype was associated with an elevated amount of ox-LDL and LPL transcripts within CAVD. Furthermore, expression of LPL was associated with several indices of fibrocalcific remodelling of the aortic valve. CONCLUSION: Expression of LPL within CAVD is related to the amount of ox-LDL, which is, in turn, associated with the small, dense HDL phenotype. Lipid retention associated with smaller HDL particles may participate in the expression of LPL, whereby a fibrocalcific remodelling of the aortic valve is promoted.

A Simplified Version of the IASLC Grading System for Invasive Pulmonary Adenocarcinomas With Improved Prognosis Discrimination.

Tumor grading enables better management of patients and treatment options. The International Association for the Study of Lung Cancer (IASLC) Pathology Committee has recently released a 3-tier grading system for invasive pulmonary adenocarcinoma consisting of predominant histologic patterns plus a cutoff of 20% of high-grade components including solid, micropapillary, and complex glandular patterns. The goal of this study was to validate the prognostic value of the new IASLC grading system and to compare its discriminatory performance to the predominant pattern-based grading system and a simplified version of the IASLC grading system without complex glandular patterns. This was a single-site retrospective study based on a 20-year data collection of patients that underwent lung cancer surgery. All invasive pulmonary adenocarcinomas confirmed by the histologic review were evaluated in a discovery cohort (n=676) and a validation cohort (n=717). The median duration of follow-up in the combined dataset (n=1393) was 7.5 years. The primary outcome was overall survival after surgery. The 3 grading systems had strong and relatively similar predictive performance, but the best parsimonious model was the simplified IASLC grading system (log-rank P =1.39E-13). The latter was strongly associated with survival in the validation set ( P =1.1E-18) and the combined set ( P =5.01E-35). We observed a large proportion of patients upgraded to the poor prognosis group using the IASLC grading system, which was attenuated when using the simplified IASLC grading system. In conclusion, we identified a histologic simpler classification for invasive pulmonary adenocarcinomas that outperformed the recently proposed IASLC grading system. A simplified grading system is clinically convenient and will facilitate widespread implementation.

Impact of Specimen Characteristics on PD-L1 Testing in Non-Small Cell Lung Cancer: Validation of the IASLC PD-L1 Testing Recommendations.

INTRODUCTION: Molecules targeting programmed cell death 1 or its ligand programmed death ligand 1 (PD-L1) revolutionized the treatment of patients with NSCLC. The only approved biomarker for predicting treatment response is the PD-L1 tumor proportion score (TPS) determined by immunohistochemistry. According to International Association for the Study of Lung Cancer recommendations, specimens that include fewer than 100 tumor cells or are older than 3 years should not be used for PD-L1 testing and the reliability of cell blocks has yet to be validated. METHODS: This retrospective study included 1249 consecutive patients with NSCLC who were tested for PD-L1 (using the clone 22C3) between September 2016 and April 2017. The associations between the presence of suboptimal characteristics (specimens with <100 tumor cells, specimens older than 3 years, or cell blocks) and PD-L1 TPS were examined by using a multinomial logistic regression. RESULTS: Specimens from 35.5% of the patients had at least one suboptimal characteristic. For patients with a PD-L1 TPS of higher than 50%, there was a significantly higher probability that they had a specimen with more than 100 tumor cells (OR = 1.97, p = 0.008) and a more recent block (within 30 days versus after >3 years) (OR = 2.46, p = 0.023). There was no statistical difference in PD-L1 TPS between cell blocks and tissue specimens (biopsy OR = 0.99 [p = 0.996] and surgery OR = 0.73 [p = 0.302]). CONCLUSIONS: Our results suggest that specimens containing fewer than 100 tumor cells or older than 3 years may lead to an underestimation of PD-L1 status. Our findings also provide support for the use of cell blocks for PD-L1 testing, although further research is needed.

Coronary artery fixation at iso-arterial pressure: impacts on histologic evaluation and clinical management.

Coronary angiography is the standard imaging method for determining the site, extent, and severity of coronary artery disease. Several publications have reported discordance between the degree of coronary artery stenosis determined from post-mortem histologic evaluation and coronary angiography. While the 2-dimensional limitations of coronary angiography are well established, the determination of coronary stenosis based on histologic evaluation of passively fixed samples is also associated with significant biases. In this study, we used patients with chronic coronary artery disease to compare the stenosis severity estimates that were determined using the passive fixation method with those determined using the active fixation method. Our results showed a significant discrepancy between the stenosis in passively fixed coronary arteries when compared with coronary angiography in all major coronary vessels combined (P=.002), and in Cx (P=.045) and CD (P=.026). However, there was no mean difference when compared with perfused (actively fixed) samples when all vessels were combined or examined individually. Iso-physiologic mechanical perfusion (active) fixation yielded significantly reduced coronary artery stenosis means when compared to the passive fixation method in post-mortem evaluations during autopsies. This was evident when all vessels were combined (P=.0001) and assessed individually (Cx (P=.003), LAD (P=.025), LM (P=.056) and RC (P=.007)). Autopsies including cardiac explant patients also showed differences in estimates for all vessels combined (P=.0001) and in Cx (P=.016) and RC (P=.006). In summary, our quantitative histopathology analyses using perfused coronary artery stenosis at physiologic pressure showed significant discrepancies when compared with passive histopathology.

Identification of Grossing Criteria for Intraoperative Evaluation by Frozen Section of Lung Cancer Resection Margins.

Because of a lack of official guidelines, systematic use of intraoperative frozen section for the evaluation of surgical margins in lung oncology constitutes standard practice in many pathology departments. This costly and time-consuming procedure seems unjustified as reported rates of positive margins remain low. We aimed to evaluate clinicopathologic criteria associated with positive margins and establish evidence-based recommendations regarding the use of frozen sections. This retrospective cohort included 1903 consecutive patients with a lung resection for malignant neoplasm between 2006 and 2015. Clinicopathologic data were retrieved from medical files. Univariate and multivariate analyses were used to identify variables associated with a positive margin. Receiver operating characteristic curves and a probability table of positive margins based on tumor-margin distance were created. Our results were confirmed in a validation cohort of 27 patients with positive margins. The rate of positive margins was 3.8%. A positive margin status changed the surgical management in 48.6% of patients. A short macroscopic tumor-margin distance was associated with a higher risk of positive bronchovascular and parenchymal margins in univariate and multivariate analyses. Selecting a 2.0 cm tumor-margin distance cut-off for performing a frozen section would result in a 55.3% reduction of intraoperative evaluations, with a risk of missing a positive margin of 0.61%. Overall, we showed that systematic use of frozen section for intraoperative evaluation of surgical margins is unnecessary. A better selection of patients with a higher risk of a positive margin can be achieved with tumor-margin distance as a simple gross evaluation parameter.

Transcriptomic Microenvironment of Lung Adenocarcinoma.

Background: Tissues surrounding tumors are increasingly studied to understand the biology of cancer development and identify biomarkers.Methods: A unique geographic tissue sampling collection was obtained from patients that underwent curative lobectomy for stage I pulmonary adenocarcinoma. Tumor and nontumor lung samples located at 0, 2, 4, and 6 cm away from the tumor were collected. Whole-genome gene expression profiling was performed on all samples (n = 5 specimens × 12 patients = 60). Analyses were carried out to identify genes differentially expressed in the tumor compared with adjacent nontumor lung tissues at different distances from the tumor as well as to identify stable and transient genes in nontumor tissues with respect to tumor proximity.Results: The magnitude of gene expression changes between tumor and nontumor sites was similar with increasing distance from the tumor. A total of 482 up- and 843 downregulated genes were found in tumors, including 312 and 566 that were consistently differentially expressed across nontumor sites. Twenty-nine genes induced and 34 knocked-down in tumors were also identified. Tumor proximity analyses revealed 15,700 stable genes in nontumor lung tissues. Gene expression changes across nontumor sites were subtle and not statistically significant.Conclusions: This study describes the transcriptomic microenvironment of lung adenocarcinoma and adjacent nontumor lung tissues collected at standardized distances relative to the tumor.Impact: This study provides further insights about the molecular transitions that occur from normal tissue to lung adenocarcinoma and is an important step to develop biomarkers in nonmalignant lung tissues. Cancer Epidemiol Biomarkers Prev; 26(3); 389-96. ©2016 AACR.

What the Cardiologist Should Know About Cardiac Involvement in Behçet Disease.

Behçet disease (BD) is a chronic multisystem inflammatory vasculitis affecting mainly young adults and is characterized by a remitting-relapsing course. In North America, the prevalence is 5.2 per 100,000 population. It is believed that cardiac involvement is one of the most severe complications in patients with BD despite its sporadic occurrence, being greatly correlated with mortality.

Inflammation is associated with the remodeling of calcific aortic valve disease.

Calcific aortic valve disease (CAVD) is the most frequent heart valve disorder. Studies indicate that mineralization of the aortic valve may be related to the inflammatory process. However, no clear evidence has been given regarding clinical evolution of aortic stenosis and the inflammatory process within the aortic valve. Aortic valves excised from 285 patients with CAVD undergoing aortic valve replacement were analyzed for the presence of chronic inflammatory infiltrates, and those findings were related to the hemodynamic severity of aortic stenosis. In a subset of 57 patients, in whom additional valvular tissue and the clinical progression rate of aortic stenosis were available, the density of leukocytes was determined as well as the number of TNF-α transcripts. Histological analyses revealed that in 81 (28.4 %) patients, the presence of chronic inflammatory infiltrates was documented within CAVD tissue, which was characterized by the existence of a cluster of cells as well as the presence of neovascularisation and osseous metaplasia. The presence of an inflammatory process within the CAVD tissue was independently related to the remodeling process and the peak transaortic gradient. In addition, the density of leukocytes within CAVD tended to correlate (r = 0.25, p = 0.05) with the progression rate of aortic stenosis. Dense inflammatory infiltrate within CAVD is associated with an active remodeling process, the severity of aortic stenosis, and the hemodynamic progression rate.