Echocardiographic derived forward left ventricular output improves risk prediction in systolic heart failure.

BACKGROUND AND AIMS: Though widely used to classify heart failure (HF) patients, the prognostic role of left ventricular ejection fraction (LVEF) is debated. We hypothesized that the echocardiographic measures of forward LV output, being more representative of cardiac hemodynamics, may improve risk prediction in a large cohort of HF patients with systolic dysfunction. METHODS: Consecutive stable HF patients with LVEF <50% on guideline-recommended therapies undergoing an echocardiography including the evaluation of forward LV output (i.e., LV outflow tract velocity-time integral [LVOT-VTI], stroke volume index [SVi], and cardiac index [CI]) over a 6-year period, were selected and followed-up for the endpoint of cardiac and all-cause death. RESULTS: Among the 1,509 patients analyzed (71±12 years, 75% males, LVEF 35±9%), 328 (22%) died during a median 28-month (14-40) follow-up, 165 (11%) of which for cardiac causes. At multivariable regression analysis, LVOT-VTI (<0.001), SVi (p<0.001), and CI (p<0.001), but not LVEF (p>0.05), predicted cardiac and all-cause death. The optimal prognostic cut-offs for LVOT-VTI, SVi, and CI were 15 cm, 38 mL/m2, and 2 L/min/m2, respectively. Adding each of these measures to a multivariable risk model (including clinical, biohumoral, and echocardiographic markers) improved risk prediction (p<0.001). Among the different measures of forward LV output, CI was less accurate than LVOT-VTI and SVi. CONCLUSION: The echocardiographic evaluation of forward LV output improves risk prediction in HF patients across a wide LVEF spectrum over other well-established clinical, biohumoral, and echocardiographic prognostic markers.

Aortopathy and aortic valve surgery in patients with bicuspid aortic valve with and without raphe.

AIM: To evaluate the association between raphe in bicuspid aortic valve (BAV) patients and valve dysfunction, aortopathy and aortic valve surgery in the REBECCA registry [REgistro della valvola aortica Bicuspide della Società Italiana di ECocardiografia e CArdiovascular Imaging (SIECVI)]. METHODS: Prevalence of aortic valve dysfunction and aortopathy was investigated in BAV patients with and without raphe. Aortic valve dysfunction (regurgitation or stenosis) was categorized as mild, moderate and severe. Aortopathy was defined as annulus ≥14 mm/m2; root ≥20 mm/m2; sinotubular junction ≥16 mm/m2; ascending aorta ≥17 mm/m2, and classified in Type A, isolated ascending aorta dilatation; Type B, aortic root and ascending aorta dilatation; and Type C, isolated aortic root dilatation. RESULTS: Overall, 695 patients with BAV were enrolled; 520 (74.8%) with raphe and 175 (25.2%) without raphe. BAV patients with raphe presented more frequently with moderate or severe aortic stenosis than BAV patients without raphe (183 [35.2%] vs 34 [19.4%], p < 0.001). A higher prevalence of aortopathy, particularly Type B, was observed in patients with vs without raphe. At multivariable analysis, raphe was a predictor of aortic valve surgery at three-year follow-up (odds ratio 2.19, 95% confidence interval 1.08-4.44, p < 0.001). CONCLUSIONS: Patients with BAV and raphe have a higher prevalence of significant aortic stenosis, aortopathy, especially Type B, and a higher risk of undergoing aortic valve surgery at three-year follow-up.

Use of new and emerging cancer drugs: what the cardiologist needs to know.

The last decade has witnessed a paradigm shift in cancer therapy, from non-specific cytotoxic chemotherapies to agents targeting specific molecular mechanisms. Nonetheless, cardiovascular toxicity of cancer therapies remains an important concern. This is particularly relevant given the significant improvement in survival of solid and haematological cancers achieved in the last decades. Cardio-oncology is a subspecialty of medicine focusing on the identification and prevention of cancer therapy-related cardiovascular toxicity (CTR-CVT). This review will examine the new definition of CTR-CVT and guiding principles for baseline cardiovascular assessment and risk stratification before cancer therapy, providing take-home messages for non-specialized cardiologists.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

AIMS: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. METHODS AND RESULTS: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. CONCLUSION: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Wild-Type Transthyretin Cardiac Amyloidosis is Not Rare in Elderly Subjects: the CATCH Screening Study.

BACKGROUND: Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) affects older adults and is currently considered as a rare disorder. OBJECTIVE: We investigated for the first time the prevalence of ATTRwt-CA in elderly individuals from the general population. METHODS: General practitioners from Pisa, Italy, proposed a screening for ATTRwt-CA to all their patients aged 65-90 years, until 1,000 accepted. The following red flags were searched: interventricular septal thickness ≥12 mm, any echocardiographic, ECG or clinical hallmark of CA, or high sensitivity-troponin T ≥14 ng/L. Individuals with at least one red flag (n=346) were asked to undergo the search for a monoclonal protein and bone scintigraphy, and 216 accepted. RESULTS: Four patients received a non-invasive diagnosis of ATTRwt-CA. All complained of dyspnea on moderate effort. A woman and a man aged 79 and 85 years, respectively, showed an intense cardiac tracer uptake (grade 3), left ventricular (LV) wall thickening, grade 2 to 3 diastolic dysfunction, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1,000 ng/L. Two other patients (a man aged 74 years and a woman aged 83 years) showed a grade 2 uptake, an increased LV septal thickness, but preserved diastolic function, and NT-proBNP <300 ng/L. The prevalence of ATTR-CA in subjects ≥65 years was calculated as 0.46% (i.e., 4 out of the 870 subjects completing the screening, namely 654 not meeting the criteria for Step 2 and 216 progressing to Step 2). CONCLUSIONS: ATTRwt-CA is uncommon in elderly subjects from the general population, but more frequent than expected for a rare disease.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is a heart condition mostly found in older adults. ATTRwt-CA is considered a rare disease, although no systematic screening have been performed yet. The study aimed to understand how common this disease is among the general population aged 65 to 90 years in Pisa, Italy. To do this, general practitioners offered screening for ATTRwt-CA to their patients within this age group. The initial step of the screening involved checking for certain warning signs (red flags), like abnormal thickness in a part of the heart called the interventricular septum, unusual heart function observed through various tests, or elevated levels of a specific heart protein. Out of 1,000 individuals who began the screening process, 346 showed at least one of these red flags and were further examined using bone scintigraphy (a type of imaging test) and tests for a specific protein related to this condition. Of these, 216 agreed to proceed with these additional tests. The results showed that four of these patients actually had ATTRwt-CA. Their conditions varied in severity, with some showing more intense signs of the disease on the heart scans, thicker heart walls, and higher levels of heart stress proteins. All four patients experienced mild difficulty in breathing during physical activity. Based on these findings, the study concluded that about 0.46% of elderly individuals in the general population might have ATTRwt-CA, indicating that the disease is somewhat more common in this age group than previously thought.

Disease features and management of cardiomyopathies in women.

Over the last years, there has been a growing interest in the clinical manifestations and outcomes of cardiomyopathies in women. Peripartum cardiomyopathy is the only women-specific cardiomyopathy. In cardiomyopathies with X-linked transmission, women are not simply healthy carriers of the disorder, but can show a wide spectrum of clinical manifestations ranging from mild to severe manifestations because of heterogeneous patterns of X-chromosome inactivation. In mitochondrial disorders with a matrilinear transmission, cardiomyopathy is part of a systemic disorder affecting both men and women. Even some inherited cardiomyopathies with autosomal transmission display phenotypic and prognostic differences between men and women. Notably, female hormones seem to exert a protective role in hypertrophic cardiomyopathy (HCM) and variant transthyretin amyloidosis until the menopausal period. Women with cardiomyopathies holding high-risk features should be referred to a third-level center and evaluated on an individual basis. Cardiomyopathies can have a detrimental impact on pregnancy and childbirth because of the associated hemodynamic derangements. Genetic counselling and a tailored cardiological evaluation are essential to evaluate the likelihood of transmitting the disease to the children and the possibility of a prenatal or early post-natal diagnosis, as well as to estimate the risk associated with pregnancy and delivery, and the optimal management strategies.

Magnetic resonance imaging for diagnostic workup of embolic stroke of undetermined source: A systematic review.

BACKGROUND: Embolic stroke of undetermined source (ESUS) refers to ischemic stroke where the underlying cause of thromboembolism cannot be found despite the recommended diagnostic workup. Unidentified source of emboli hinders clinical decision-making and patient management with detrimental consequences on long-term prognosis. The rapid development and versatility of magnetic resonance imaging (MRI) make it an appealing addition to the diagnostic routine of patients with ESUS for the assessment of potential vascular and cardiac embolic sources. AIMS: To review the use of MRI in the identification of cardiac and vascular embolic sources in ESUS and to assess the reclassification value of MRI examinations added to the conventional workup of ESUS. SUMMARY OF REVIEW: We reviewed the use of cardiac and vascular MRI for the identification of a variety of embolic sources associated with ESUS, including atrial cardiomyopathy, left ventricular pathologies, and supracervical atherosclerosis in carotid and intracranial arteries and in distal thoracic aorta. The additional reclassification after MRI examinations added to the workup of patients with ESUS ranged from 6.1% to 82.3% and varied depending on the combination of imaging modalities. CONCLUSION: MRI techniques allow us to identify additional cardiac and vascular embolic sources and may further decrease the prevalence of patients with the diagnosis of ESUS.

Valvular heart disease in patients with cardiac amyloidosis.

Cardiac amyloidosis (CA) is an underdiagnosed condition caused by the deposition of misfolded proteins, namely immunoglobulin light chains and transthyretin, in the extracellular spaces of the heart. Any cardiovascular structure can be affected by amyloid infiltration, including the valves. Amyloid accumulation within the cardiac valves may lead to their structural and functional impairment, with a profound impact on patients' prognosis and quality of life. The most common forms of valvular disease in CA are aortic stenosis (AS), mitral regurgitation (MR), and tricuspid regurgitation (TR). CA and AS share similar risk factors, disease mechanisms, and remodeling patterns, which make their diagnosis particularly challenging. Patients with both CA and AS experience worse outcomes than CA or AS alone, and transcatheter aortic valve replacement may represent a useful therapeutic strategy in this population. Data on MR and TR are quite limited and mainly coming from case reports or small series. This review paper will summarize our current understanding on the epidemiology, disease mechanisms, echocardiographic features, clinical implications, and therapeutic options of AS, MR, and TR in patients with CA.

Exercise Stress Echocardiography of the Right Ventricle and Pulmonary Circulation.

BACKGROUND: Exercise echocardiography is used for assessment of pulmonary circulation and right ventricular function, but limits of normal and disease-specific changes remain insufficiently established. OBJECTIVES: The objective of this study was to explore the physiological vs pathologic response of the right ventricle and pulmonary circulation to exercise. METHODS: A total of 2,228 subjects were enrolled: 375 healthy controls, 40 athletes, 516 patients with cardiovascular risk factors, 17 with pulmonary arterial hypertension, 872 with connective tissue diseases without overt pulmonary hypertension, 113 with left-sided heart disease, 30 with lung disease, and 265 with chronic exposure to high altitude. All subjects underwent resting and exercise echocardiography on a semirecumbent cycle ergometer. All-cause mortality was recorded at follow-up. RESULTS: The 5th and 95th percentile of the mean pulmonary artery pressure-cardiac output relationships were 0.2 to 3.5 mm Hg.min/L in healthy subjects without cardiovascular risk factors, and were increased in all patient categories and in high altitude residents. The 5th and 95th percentile of the tricuspid annular plane systolic excursion to systolic pulmonary artery pressure ratio at rest were 0.7 to 2.0 mm/mm Hg at rest and 0.5 to 1.5 mm/mm Hg at peak exercise, and were decreased at rest and exercise in all disease categories and in high-altitude residents. An increased all-cause mortality was predicted by a resting tricuspid annular plane systolic excursion to systolic pulmonary artery pressure <0.7 mm/mm Hg and mean pulmonary artery pressure-cardiac output >5 mm Hg.min/L. CONCLUSIONS: Exercise echocardiography of the pulmonary circulation and the right ventricle discloses prognostically relevant differences between healthy subjects, athletes, high-altitude residents, and patients with various cardio-respiratory conditions. (Right Heart International NETwork During Exercise in Different Clinical Conditions; NCT03041337).

[Critical reading of cardiovascular trials with neutral or negative findings]. / Approccio critico all'interpretazione dei trial cardiovascolari con risultati neutri o negativi.

Randomized controlled trials showing a significant benefit are met with enthusiasm because they may change the standard of care for patients who share the clinical and pathophysiologic characteristics of trial participants. Nonetheless, a well-designed and fully executed trial with neutral or negative findings also represents a critically important investigation deserving careful scientific scrutiny. In this paper we propose a 10-step approach to the interpretation of neutral or negative trials to exclude important methodological issues before concluding that the treatment really does not work. We will discuss this approach using the most classic trials of the past and some notable examples among superiority trials (mostly phase 3 trials) published over the last years.

Non-pegylated liposomal doxorubicin in older adjuvant early breast cancer patients: cardiac safety analysis and final results of the COLTONE study.

AIMS: To explore the cardiac safety of adjuvant Non-Pegylated Liposomal Doxorubicin (NPL-DOX) plus Cyclophosphamide (CTX) followed by weekly Paclitaxel, in elderly women (≥ 65 years) with high-risk breast cancer. Previously, we described no symptomatic cardiac events within the first 12 months from starting treatment. We now reported the updated results after a median follow-up 76 months. METHODS: The cardiac activity was evaluated with left ventricular ejection fraction (LVEF) echocardiograms assessments, before starting chemotherapy and every 6 months, until 30 months from baseline, then yearly for at least 5 years. RESULTS: Forty-seven women were recruited by two Units of Medical Oncology (Ethics Committee authorization CESM-AOUP, 3203/2011; EudraCT identification number: 2010-024067-41, for Pisa and Pontedera Hospitals). An episode of grade 3 CHF (NCI-CTCAE, version 3.0) occurred after 18 months the beginning of chemotherapy. The echocardiograms assessments were performed comparing the LVEF values of each patient evaluated at fixed period of time, compared to baseline. We observed a slight changed in terms of mean values at 48, 60, 72 and 84 months. At these time points, a statistically significant reduction of - 3.2%, - 4.6%, - 6.4% and - 7.1%, respectively, was observed. However, LVEF remained above 50% without translation in any relevant clinical signs. No other cardiac significant episodes were reported. To this analysis, in 13 patients (28%) occurred disease relapse and,  of them, 11 (23%) died due to metastatic disease. Eight patients died of cancer-unrelated causes. CONCLUSIONS: The combination including NPL-DOX in elderly patients revealed low rate of cardiac toxic effects. Comparative trials are encouraged.

Left ventricular outflow tract velocity-time integral improves outcome prediction in patients with secondary mitral regurgitation.

AIMS: Left ventricular outflow velocity-time integral (LVOT-VTI) has been shown to improve outcome prediction in different patients' subsets, with or without heart failure (HF). Nevertheless, the prognostic value of LVOT-VTI in patients with HF and secondary mitral regurgitation (MR) has never been investigated so far. Therefore, in the present study, we aimed to assess the prognostic value different metrics of LV forward output, including LVOT-VTI, in HF patients with secondary MR. METHODS AND RESULTS: Consecutive patients with HF and moderate-to-severe/severe secondary MR and systolic dysfunction (i.e., left ventricular ejection fraction [LVEF] <50%) were retrospectively selected and followed-up for the primary endpoint of cardiac death. Out of the 287 patients analyzed (aged 74 ± 11 years, 70% men, 46% ischemic etiology, mean LVEF 30 ± 9%, mean LVOT-VTI 20 ± 5 cm), 71 met the primary endpoint over a 33-month median follow-up (16-47 months). Patients with an LVOT-VTI ≤17 cm (n = 96, 32%) showed the greatest risk of cardiac death (Log Rank 44.3, p < 0.001) and all-cause mortality (Log rank 8.6, p = 0.003). At multivariable regression analysis, all the measures of LV forward volume (namely LVOT-VTI, stroke volume index, cardiac output, and cardiac index) were predictors of poor outcomes. Among these, LVOT-VTI was the most accurate in risk prediction (univariable C-statistics 0.70 [95%CI 0.64-0.77]). CONCLUSION: Left ventricular forward output, noninvasively estimated through LVOT-VTI, improves outcome prediction in HF patients with low LVEF and secondary MR.

Role of Imaging in Cardiomyopathies.

Imaging has a central role in the diagnosis, classification, and clinical management of cardiomyopathies. While echocardiography is the first-line technique, given its wide availability and safety, advanced imaging, including cardiovascular magnetic resonance (CMR), nuclear medicine and CT, is increasingly needed to refine the diagnosis or guide therapeutic decision-making. In selected cases, such as in transthyretin-related cardiac amyloidosis or in arrhythmogenic cardiomyopathy, the demonstration of histological features of the disease can be avoided when typical findings are observed at bone-tracer scintigraphy or CMR, respectively. Findings from imaging techniques should always be integrated with data from the clinical, electrocardiographic, biomarker, genetic and functional evaluation to pursue an individualised approach to patients with cardiomyopathy.

Cardiovascular toxicity from therapies for light chain amyloidosis.

Amyloid light-chain (AL) amyloidosis is a hematological disorder characterized by abnormal proliferation of a plasma cell clone producing monoclonal free light chains that misfold and aggregate into insoluble fibrils in various tissues. Cardiac involvement is a common feature leading to restrictive cardiomyopathy and poor prognosis. Current first-line treatments aim at achieving hematological response by targeting the plasma cell clones, and these have been adapted from multiple myeloma therapy. Patients with AL amyloidosis often exhibit multiorgan involvement, making them susceptible to cancer therapy-related cardiovascular toxicity. Managing AL amyloidosis is a complex issue that requires enhanced knowledge of the cardio-oncological implications of hematological treatments. Future research should focus on implementing and validating primary and secondary prevention strategies and understanding the biochemical basis of oncological therapy-related damage to mitigate cardiovascular toxicity.

Haemodynamic forces predicting remodelling and outcome in patients with heart failure treated with sacubitril/valsartan.

AIMS: A novel tool for the evaluation of left ventricular (LV) systo-diastolic function through echo-derived haemodynamic forces (HDFs) has been recently proposed. The present study aimed to assess the predictive value of HDFs on (i) 6 month treatment response to sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) patients and (ii) cardiovascular events. METHODS AND RESULTS: Eighty-nine consecutive HFrEF patients [70% males, 65 ± 9 years, LV ejection fraction (LVEF) 27 ± 7%] initiating sacubitril/valsartan underwent clinical, laboratory, ultrasound and cardiopulmonary exercise testing evaluations. Patients experiencing no adverse events and showing ≥50% reduction in plasma N-terminal pro-B-type natriuretic peptide and/or ≥10% LVEF increase over 6 months were considered responders. Patients were followed up for the composite endpoint of HF-related hospitalisation, atrial fibrillation and cardiovascular death. Forty-five (51%) patients were responders. Among baseline variables, only HDF-derived whole cardiac cycle LV strength (wLVS) was higher in responders (4.4 ± 1.3 vs. 3.6 ± 1.2; p = 0.01). wLVS was also the only independent predictor of sacubitril/valsartan response at multivariable logistic regression analysis [odds ratio 1.36; 95% confidence interval (CI) 1.10-1.67], with good accuracy at receiver operating characteristic (ROC) analysis [optimal cutpoint: ≥3.7%; area under the curve (AUC) = 0.736]. During a 33 month (23-41) median follow-up, a wLVS increase after 6 months (ΔwLVS) showed a high discrimination ability at time-dependent ROC analysis (optimal cut-off: ≥0.5%; AUC = 0.811), stratified prognosis (log-rank p < 0.0001) and remained an independent predictor for the composite endpoint (hazard ratio 0.76; 95% CI 0.61-0.95; p < 0.01), after adjusting for clinical and instrumental variables. CONCLUSIONS: HDF analysis predicts sacubitril/valsartan response and might optimise decision-making in HFrEF patients.

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.

Echocardiographic findings in subjects with an amyloidogenic apolipoprotein A1 pathogenic variant.

BACKGROUND: Very small case series of patients with apolipoprotein A1 (ApoA1) amyloidosis are available. METHODS: We described the clinical and echocardiographic characteristics of individuals with the pathogenic APOA1 variant Leu75Pro (p. Leu99Pro), referred for cardiac screening. RESULTS: We enrolled 189 subjects, 54% men, median age 55 years (interquartile range 42-67), 39% with concomitant renal disease and 31% with liver disease. Median left ventricular ejection fraction was 60% (55-66). Overall, these subjects did not show overt diastolic dysfunction nor left ventricular (LV) hypertrophy. Age correlated with interventricular septal (IVS) thickness (r = 0.484), LV mass index (r = 0.459), E/e' (r = 0.501), and right ventricular free wall thickness (r = 0.594) (all p < 0.001). Some individuals displayed red flags for cardiac amyloidosis (CA), and 14% met non-invasive criteria for CA. Twenty-nine subjects died over 5.8 years (4.1-8.0), with 10 deaths for cardiovascular causes. Individuals meeting echocardiographic criteria for CA had a much higher risk of all-cause death (p = 0.009), cardiovascular death (p = 0.001), cardiovascular death or heart failure (HF) hospitalisation (p < 0.001). Subjects with both renal and liver involvement had a more prominent cardiac involvement, and shortest survival. CONCLUSIONS: Subjects with the APOA1 Leu75Pro variant displayed minor echocardiographic signs of cardiac involvement, but 14% met echocardiographic criteria for CA. Subjects with suspected CA had a worse outcome.