Aortic valve sclerosis is associatedwith systemic endothelial dysfunction

AbstractObjectivesWe sought to examine the association between aortic valve sclerosis (AVS) and systemic endothelial manifestations of the atherosclerotic process.BackgroundClinical and experimental studies suggest that AVS is a manifestation of the atherosclerotic process. Systemic endothelial dysfunction is an early sign of the atherosclerotic process and can be assessed by ultrasonography of the brachial artery.MethodsA total of 102 in-hospital patients (76 men; mean age 63.5 ± 9.7 years) referred to the stress echocardiography laboratory underwent: 1) transthoracic echocardiography, with specific assessment of AVS (thickened valve leaflets with a transaortic flow velocity <2.5 m/s); 2) stress echocardiography; 3) coronary angiography, with evaluation of the Duke score (from 0 [normal] to 100 [most severe disease]); and 4) an endothelial function study, with assessment of endothelium-dependent, post-ischemic, flow-mediated dilation (FMD).ResultsAortic valve sclerosis was present in 35 patients (group I) and absent in 67 (group II). Groups I and II were similar in terms of the frequency of stress-induced wall motion abnormalities (35.3% vs. 19.4%, p = NS) and the angiographic Duke score (33.8 ± 28.6 vs. 35.2 ± 29.1, p = NS). Patients with AVS showed a markedly lower FMD than those without AVS (2.2 ± 3.5% vs. 5.3 ± 5.3%, p < 0.01). On multivariate analysis, only FMD was highly predictive of AVS, with an odds ratio of 1.18 for each percent decrease in FMD (95% confidence interval 1.05 to 1.32; p = 0.01).ConclusionsAortic valve stenosis is associated with systemic endothelial dysfunction. This observation may provide a mechanistic insight into the emerging association between AVS and cardiovascular events

Cardiac calcification by transthoracic echocardiography in patients with known or suspected coronary artery disease

OBJECTIVES: To estimate the correlation between the total heart calcification score index (CSI), assessed by echocardiography, left ventricle mass index (LVMI), Framingham risk score (FRS), and angiographically assessed coronary artery disease (CAD). BACKGROUND: Aortic valve and root sclerosis (AVS, ARS) and mitral annular calcium (MAC) detected by echocardiography have been associated with atherosclerosis. FRS is recommended for estimation of total coronary heart disease risk over the course of 10 years. The anatomic extent of CAD can be assessed with coronary angiography. Total and cardiovascular mortality risk increases with increasing LVMI. METHODS: 167 consecutive in-hospital patients (mean age 66.6+/-9.7 yrs, 119 men) underwent: 1) complete transthoracic echocardiography (TTE), with CSI assessment (from 0=normal to 10=diffuse calcification of aortic valve, mitral annulus and aortic root), 2) the FRS evaluation (FRS</=10=low, FRS>/=11 and </=20=average risk, and a FRS>/=21=high risk), and 3) coronary angiography (with Duke score evaluation, from 0=normal to 100=severe left main disease). RESULTS: The mean CSI of the entire population was 3.94+/-2.1, with a mean of 2.75+/-2 in patients at low risk, with a progressive increase in patients at average risk (4.11+/-2.2), at high risk (4.7+/-1.7), respectively. CSI was associated with the presence of CAD (p=0.003) and the presence of abnormal LVMI (p=0.002). CONCLUSIONS: Echocardiographically assessed CSI is correlated to FRS, Duke score and LVMI and can provide a simple, radiation-free index of cardiovascular risk

Cancer risk from professional exposure in staff working in cardiac catheterization laboratory: Insights from the National Research Council\u27s Biological Effects of Ionizing Radiation VII Report

Background Occupational doses from fluoroscopy-guided interventional procedures are the highest ones registered among medical staff using x-rays. The aim of the present study was to evaluate the order of magnitude of cancer risk caused by professional radiation exposure in modern invasive cardiology practice. Methods From the dosimetric Tuscany Health Physics data bank of 2006, we selected dosimetric data of the 26 (7 women, 19 men; age 46 ? 9 years) workers of the cardiovascular catheterization laboratory with effective dose N2 mSv. Effective dose (E) was expressed in milliSievert, calculated from personal dose equivalent registered by the thermoluminescent dosimeter, at waist or chest, under the apron, according to the recommendations of National Council of Radiation Protection. Lifetime attributable risk of cancer was estimated using the approach of Biological Effects of Ionizing Radiation 2006 report VII. Results Cardiac catheterization laboratory staff represented 67% of the 6 workers with yearly exposure N6 mSv. Of the 26 workers with 2006 exposure N2 mSv, 15 of them had complete records of at least 10 (up to 25) consecutive years. For these 15 subjects having a more complete lifetime dosimetric history, the median individual effective dose was 46 mSv (interquartile range = 24-64). The median risk of (fatal and nonfatal) cancer (Biological Effects of Ionizing Radiation 2006) was 1 in 192 (interquartile range = 1 in 137-1 in 370). Conclusions Cumulative professional radiological exposure is associated with a non-negligible Lifetime attributable risk of cancer for the most exposed contemporary cardiac catheterization laboratory staff

Role of semisupine exercise stress echocardiography in operated Fallot

Background: Right Ventricle (RV) outflow tract anomalies in operated Tetralogy of Fallot (TOF) leads to RV dysfunction. Due to the difficulties to its assessment, timing of RV outflow reconstruction is still a matter of debate. Semi-supine exercise echo (SEE) has potential for simultaneous evaluation of RV function, pressure, and area changes during stress. Aim to assess the feasibility and value of SEE in operated TOF. Methods: we evaluated 62 consecutive operated Fallot by SEE (mean age 24 ? 11 years, 16 pts were less than 18 y. o.). The following parameters were measured at rest and peak exercise: RV area (from apical 4 chamber view), Tricuspid annular plane systolic excursion (TAPSE), Right ventricular pressure (RVP, from tricuspid regurgitant jet velocity); RV fractional area change (RV-FAC). Within 3 days, all patients also underwent cardiac Magnetic Resonance, Cardio-pulmonary Exercise Test and Amino-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) essay. Results: Exercise was stopped at 105 ? 35 Watt; heart rate increased from 83 ?16 bpm to 149 ?17 bpm. During exercise, interpretable images for RV FAC analysis were obtained in 56/62 patients (RV FAC feasibility = 90 %). Due to continent tricuspid valve in 7 patients RVP we couldn\u27t been measured (RVP feasibility = 89%). There was on average an increase in RVP (rest = 45 ? 18 vs. stress= 78 ? 37 mmHg, p<0.01 vs. rest), TAPSE (rest=15?4 vs. stress= 18? 3 mm , p<0.01 vs. rest), and RV-FAC (rest= 48? 9 vs. stress= 52 ? 8 % , p<0.05 vs. rest), with substantial individual variability. In particular, RV FAC increased in 40 ("responders") and remained stable or decreased in the remaining 9 pts, all of them > 18 y.o. ("non responders") (see figure). Compared to responders, non-responders had higher NT-proBNP (366 ? 264 vs 127 ? 92 ng/l,p<0.001), lower peak VO2/Kg (15 ? 4.4 vs 22 ? 5.4 ml/Kg/min, p<0.001), larger MRI-assessed RV End diastolic volume (166 ?61 vs 130 ? 42 ml/m2, p<0.05) and end systolic volume (86 ml/m2 ? 29 vs 58 ? 25, p<0.001) and lower RV EF (47 ? 8 vs 56 ? 8.5 %, p<0.01). Conclusion: SEE is feasible in patient with repaired TOF and allows the integrated assessment of variation of RV pressures, area, and function during exercise, which usefully complement more conventional indices of hemodynamic burden in these patients. Longitudinal follow-up is needed to better delineate the prognostic value of such SEE results

Valve disease in cardiac amyloidosis: an echocardiographic score

Cardiac amyloidosis (CA) may affect all cardiac structures, including the valves. From 423 patients undergoing a diagnostic workup for CA we selected 2 samples of 20 patients with amyloid transthyretin (ATTR-) or light-chain (AL-) CA, and age- and sex-matched controls. We chose 31 echocardiographic items related to the mitral, aortic and tricuspid valves, giving a value of 1 to each abnormal item. Patients with ATTR-CA displayed more often a shortened/hidden and restricted posterior mitral valve leaflet (PMVL), thickened mitral chordae tendineae and aortic stenosis than those with AL-CA, and less frequent PMVL calcification than matched controls. Score values were 15.8 (13.6-17.4) in ATTR-CA, 11.0 (9.3-14.9) in AL-CA, 12.8 (11.1-14.4) in ATTR-CA controls, and 11.0 (9.1-13.0) in AL-CA controls (p = 0.004 for ATTR- vs. AL-CA, 0.009 for ATTR-CA vs. their controls, and 0.461 for AL-CA vs. controls). Area under the curve values to diagnose ATTR-CA were 0.782 in patients with ATTR-CA or matched controls, and 0.773 in patients with LV hypertrophy. Patients with ATTR-CA have a prominent impairment of mitral valve structure and function, and higher score values. The valve score may help identify patients with ATTR-CA among patients with CA or unexplained hypertrophy

Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS: We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS: Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). CONCLUSIONS: Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis

Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS:We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS:Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6 & PLUSMN;1.9 versus 6.3 & PLUSMN;1.3 mm versus 7.7 & PLUSMN;1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min & BULL;1.73 m(2)] versus 65 mL/[min & BULL;1.73 m(2)] versus 63 mL/[min & BULL;1.73 m(2)], P172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). CONCLUSIONS:Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis

Hedgehog-GLI and notch pathways sustain chemoresistance and invasiveness in colorectal cancer and their Inhibition restores chemotherapy efficacy

Colorectal cancer (CRC) is a leading cause of cancer-related mortality and chemoresistance is a major medical issue. The epithelial-to-mesenchymal transition (EMT) is the primary step in the emergence of the invasive phenotype and the Hedgehog-GLI (HH-GLI) and NOTCH signaling pathways are associated with poor prognosis and EMT in CRC. CRC cell lines harboring KRAS or BRAF mutations, grown as monolayers and organoids, were treated with the chemotherapeutic agent 5-Fluorouracil (5-FU) alone or combined with HH-GLI and NOTCH pathway inhibitors GANT61 and DAPT, or arsenic trioxide (ATO) to inhibit both pathways. Treatment with 5-FU led to the activation of HH-GLI and NOTCH pathways in both models. In KRAS mutant CRC, HH-GLI and NOTCH signaling activation co-operate to enhance chemoresistance and cell motility, while in BRAF mutant CRC, the HH-GLI pathway drives the chemoresistant and motile phenotype. We then showed that 5-FU promotes the mesenchymal and thus invasive phenotype in KRAS and BRAF mutant organoids and that chemosensitivity could be restored by targeting the HH-GLI pathway in BRAF mutant CRC or both HH-GLI and NOTCH pathways in KRAS mutant CRC. We suggest that in KRAS-driven CRC, the FDA-approved ATO acts as a chemotherapeutic sensitizer, whereas GANT61 is a promising chemotherapeutic sensitizer in BRAF-driven CRC

Expansion of the National Amyloidosis Centre staging system to detect early mortality in transthyretin cardiac amyloidosis

Aims: Transthyretin cardiac amyloidosis (ATTR-CA) is stratified into prognostic categories using the National Amyloidosis Centre (NAC) staging system. The aims of this study were to further expand the existing NAC staging system to incorporate an additional disease stage that would identify patients at high risk of early mortality. Methods and results: The traditional NAC staging system (stage 1: N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≤3000 ng/L and estimated glomerular filtration rate [eGFR] ≥45 ml/min; stage 3: NT-proBNP &gt;3000 ng/L and eGFR &lt;45 ml/min; stage 2: remainder) was expanded by the introduction of a new stage 4 (defined as NT-proBNP ≥10 000 ng/L irrespective of eGFR) and studied in 2042 patients. The optimal NT-proBNP cut-point was established using time-dependent receiver operating characteristic curves in the subgroup of patients with NAC stage 3 disease. Mortality at 1 year according to NAC stage was 2.3% (n = 20/886) for stage 1, 8.8% (n = 62/706) for stage 2, 10.4% (n = 28/270) for stage 3, and 30.6% (n = 55/180) for stage 4 (log-rank p &lt; 0.001). After adjustment for age, mortality hazard for stage 4 was &gt;15-fold higher than that of stage 1 (hazard ratio [HR] 15.5; 95% confidence interval [CI] 9.3-26.1) and &gt;3-fold higher than that of stage 3 (HR 3.4; 95% CI 2.2-5.4). The increased risk of early mortality was consistent across the different genotypes and subclasses of patients based on the severity of heart failure symptoms and echocardiographic parameters. Conclusions: The proposed modification of the NAC staging system identifies patients with ATTR-CA at a high risk of early mortality, who may benefit from a more intensive treatment strategy, and who are most likely to experience an event early in the course of a clinical trial