Prognostic value of cardiopulmonary exercise testing in patients with transthyretin cardiac amyloidosis.

The aim of this study is to evaluate the prognostic value of cardiopulmonary testing (CPET) in a cohort of patients with transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA is associated with a progressive reduction in functional capacity. The prognostic role of CPET parameters and in particular of normalized peak VO2 (%ppVO2) remains to be thoroughly evaluated. In this study, 75 patients with ATTR-CA underwent cardiological evaluation and CPET in a National Referral Center for cardiac amyloidosis (Careggi University Hospital, Florence). Fifty-seven patients (76%) had wild-type ATTR. Median age was 80 (75-83) years, 68 patients (91%) were men. Peak oxygen consumption (14.1 ± 4.1 ml/kg/min) and %ppVO2 (68.4 ± 18.8%) were blunted. Twenty-seven (36%) patients had an abnormal pressure response to exercise. After a median follow-up of 25 (12-31) months, the composite outcome of death or heart failure hospitalization was registered in 19 (25.3%) patients. At univariate analysis %ppVO2 was a stronger predictor for the composite outcome than peak VO2. %ppVO2 and NT-proBNP remained associated with the composite outcome at multivariate analysis. The optimal predictive threshold for %ppVO2 was 62% (sensitivity: 71%; specificity: 68%; AUC: 0.77, CI 0.65-0.88). Patients with %ppVO2 ≤ 62%and NT-proBNP > 3000 pg had a worse prognosis with 1- and 2-year survival of 69 ± 9% and 50 ± 10%, respectively. CPET is a safe and useful prognostic tool in patients with ATTR-CA. CPET may help to identify patients with advanced disease that may benefit from targeted therapy.

Semi-quantitative indices of cardiac uptake in patients with suspected cardiac amyloidosis undergoing 99mTc-HMDP scintigraphy.

BACKGROUND: 99mTc-HMDP scintigraphy has proved its efficacy in non-invasive diagnosis of cardiac amyloidosis (CA) and is currently interpreted according to the Perugini qualitative assessment. Several semi-quantitative indices have been proposed to overcome inherent possible limitations of visual grading. Our aim was to comparatively evaluate six different indices and their diagnostic performance. METHODS: We retrospectively reviewed scintigraphy of 76 patients (53 ATTR, 12 AL, 11 LVH) who underwent diagnostic evaluation at our centre. ROC-curve analysis was performed to identify optimal cut-off and relative diagnostic accuracy of six different indices (of which one was proposed for the first time), both in identifying CA patients and in discriminating patients according to their Perugini score. RESULTS: Heart/Whole-body ratios proved to be the most accurate (100%) in identifying CA patients. Heart/Pelvis ratio (with soft tissue background correction) offered acceptable accuracy (98%), with the largest area under the curve (AUC) (0.98) in discriminating patients with Perugini ≥ 2. Heart/Contralateral Lung ratio confirmed to be exposed to confounding background noise in case of simultaneous lung uptake. Heart/Skull ratio had the worst performance, with six false-negative patients in ATTR identification. CONCLUSION: Heart/Whole-body ratios may be robust and effective semi-quantitative indices for the evaluation of CA by means of scintigraphy.

Poor right ventricular function is associated with impaired exercise capacity and ventilatory efficiency in transthyretin cardiac amyloid patients.

CardioPulmonary Exercise Test (CPET) is the gold standard to evaluate functional capacity in patients at high risk of heart failure (HF). Few studies with a limited number of subjects and conflicting results, analyzed the role of CPET in patients with systemic amyloidosis. Aims of our study were the assessment of the response to exercise in patients with Transthyretin amyloid (ATTR) cardiomyopathy (CA), and the correlation of clinical, biohumoral and echocardiographic parameters with CPET parameters, such as VO2 peak and VE/VCO2 slope. From February 2018 to March 2019, 72 cardiac ATTR patients were prospectively enrolled and underwent a complete clinical, biohumoral, echocardiographic and CPET assessment. All patients completed the exercise stress test protocol, without any adverse event. At CPET, they achieved a mean VO2 peak of 14 mL/Kg/min and a mean VE/VCO2 slope of 31. The blood pressure response to exercise was inadequate in 26 (36%) patients (flat in 25 and hypotensive in 1), while 49/72 patients (69%) showed an inadequate heart rate recovery. In multivariate analysis, s' tricuspidalic was the only independent predictor of VO2 peak, while in the two test models performed to avoid collinearity, both TAPSE and s' tricuspidalic were the strongest independent predictors of VE/VCO2 slope. Our data demonstrate the role of right ventricular function as an independent predictor of exercise capacity and ventilatory efficiency in ATTR. In CPET evaluation, a significant proportion of patients presented an abnormal arterial pressure response and heart rate variation to exercise.

Biomarkers and Prediction of Prognosis in Transthyretin-Related Cardiac Amyloidosis: Direct Comparison of Two Staging Systems.

BACKGROUND: The severity of heart disease varies widely among patients with transthyretin-related cardiac amyloidosis (ATTR-CA) at presentation, and availability of tools able to predict prognosis is essential for clinical and research purposes. Currently, two biomarker-based staging systems are available. The aim of this study was to compare their predictive performance. METHODS: A total of 175 patients diagnosed with ATTR-CA (133 wild-type and 42 hereditary) were stratified into different stages based on 2 systems: the first system included N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR), and the second one included NT-proBNP and troponin I (TnI). Survival estimates and age-adjusted survival for all-cause mortality were analysed over a median follow-up of 27 months (interquartile range 16-43 months). RESULTS: Predictive performance was more accurate when NT-proBNP and eGFR were used, resulting in effective survival stratification: 64.4 months for stage 1, 44.6 months for stage 2, and 20.5 months for stage 3 (P < 0.01 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 stages 2 vs 3). The combination of NT-proBNP and TnI was unable to effectively differentiate survival: 64.5 months for stage 1, 50.9 months for stage 2, and 27.3 months for stage 3 (P = 0.223 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 for stages 2 vs 3). The same results were seen after age adjustment. CONCLUSIONS: A staging system using NT-proBNP and eGFR had better prognostic accuracy for ATTR-CA patients compared with one using NTproBNP and TnI.

Accuracy of 99mTc-Hydroxymethylene diphosphonate scintigraphy for diagnosis of transthyretin cardiac amyloidosis.

BACKGROUND AND AIM: Either 99mTechnetium diphosphonate (Tc-DPD) or pyrophosphate (Tc-PYP) scintigraphy plays a relevant role in diagnosing transthyretin cardiac amyloidosis (CA), and labeled radiotracers have been extensively studied in diagnosing CA. Few studies have analyzed and validated 99mTc-Hydroxymethylene diphosphonate (Tc-HMDP). Our aim was to validate the diagnostic accuracy of Tc-HMDP total-body scintigraphy in a cohort of patients with biopsy-proven transthyretin CA. METHODS AND RESULTS: We retrospectively evaluated all patients undergoing 99mTc-HMDP total-body scintigraphy, in adjunct to a comprehensive diagnostic work-up for suspected CA. Sixty-five patients were finally diagnosed with CA, while it was excluded in 20 subjects with left ventricular hypertrophy of various etiologies. Twenty-six patients had AL-CA, 39 had TTR CA (16 TTRm, 23 TTRwt). At Tc-HMDP scintigraphy, 2 AL patients showed a Perugini score grade 1 heart uptake, while 24 showed no uptake. All TTR patients showed Tc-HMDP uptake, with three patients showing a Perugini score grade 1, 16 grade 2, and 20 grade 3, respectively. No uptake was observed in patients with left ventricular hypertrophy. A positive Tc-HMDP scintigraphy showed a 100% sensitivity and a 96% specificity for TTR CA identification. CONCLUSIONS: Tc-HMDP scintigraphy is as accurate as Tc-DPD or Tc-PYP, and may therefore de facto be considered a valuable tool for the diagnosis of TTR CA.

Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure.

AIMS: Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin-related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild-type transthyretin amyloidosis (ATTRwt). METHODS AND RESULTS: Data of 67 Ile68Leu ATTRm patients from two Italian referral centres (Bologna and Florence) were retrospectively analysed and compared to those of 82 ATTRwt patients. Fifty-five unaffected mutation carriers were also analysed. Cumulative disease onset was 50% at age 71. A total of 56/67 (84%) patients had a predominantly cardiac phenotype at presentation with concentric increase in left ventricular wall thickness [median 17 mm], and normal or near normal left ventricular ejection fraction (79% of patients). Low QRS voltages were present only in 29% of patients but voltage/mass ratio was low (0.5). Carpal tunnel syndrome was noted in 43%. The overall phenotypic profile was similar to ATTRwt but Ile68Leu ATTRm patients typically presented younger (median 71 vs. 78 years) and were more likely to have (mild) symptomatic neurological involvement (19% vs. 2%). Male prevalence was 44% in unaffected mutation carriers and 78% in affected patients. Age-adjusted survival was comparable between groups. CONCLUSIONS: Ile68Leu ATTRm is a cause of familial amyloidotic cardiomyopathy endemic in central-northern Italy and presents as hypertrophic/restrictive cardiomyopathy quite similar to ATTRwt. Male preponderance is present in affected patients but not in unaffected mutation carriers. Age-adjusted survival is similar to ATTRwt.

Epigallocatechin-3-gallate tolerability and impact on survival in a cohort of patients with transthyretin-related cardiac amyloidosis. A single-center retrospective study.

Transthyretin-related (ATTR) cardiac amyloidosis is currently lacking a disease-modifying therapy. Despite demonstration of effectiveness in halting amyloid deposition, no study focused on epigallocatechin-3-gallate (EGCG) impact on patient survival. We sought to explore prognostic impact of EGCG in a cohort of lone cardiac ATTR patients. From the Florence Tuscan Regional Amyloid Centre database, we retrospectively selected ATTR patients treated with EGCG (675mg daily dose) for a minimum of 9 months, between March 2013 and December 2016. As a control group, we selected ATTR patients who received guideline-directed medical therapy alone. End point of the study was time to all cause death or cardiac transplantation. Sixty-five patients (30 treatment groups vs. 35 control groups) had a median follow-up of 691 days. There were no differences in baseline characteristics between groups. Five deaths occurred in EGCG group versus eight in control group; one patient underwent effective cardiac transplantation in EGCG group. There was no difference in survival estimates between EGCG and control group (60 ± 15% vs. 61 ± 12%, p = 0.276). EGCG was well tolerated, without major safety concerns. In a real-world cohort of ATTR patients with lone cardiac involvement, EGCG was a safe therapeutic option, but was not associated with survival improvement.

Lung uptake during 99mTc-hydroxymethylene diphosphonate scintigraphy in patient with TTR cardiac amyloidosis: An underestimated phenomenon.

BACKGROUND: Full body scintigraphy using bone tracers plays an important role in defining the type of amyloidosis and in diagnosing the heart involvement (cardiac amyloidosis, CA). No study has been conducted to explore lung retention (LR) in CA and its correlation to heart retention (HR).We evaluated LR in patients undergoing 99mTc-HMDP scintigraphy during evaluation for suspected CA. METHODS AND RESULTS: We enrolled 93 suspected CA patients. Patients underwent a complete diagnostic work up. After diagnostic process 82 patients resulted affected by certain CA (20 AL and 62 TTR), while 11 subjects showed left ventricular hypertrophy (LVH) not caused by CA. 99mTc-HMDP cardiac uptake was evaluated using the Perugini visual score while the modified Janssen score was used for LR estimation (grade 0 no uptake, grade 1 less than ribs, grade 2 more than ribs). RESULTS: 99mTc-HMDP LR was observed in 1/20 AL patient (5%), while 36/62 (58%) TTR patients showed LR with 29 grade 1 (47%) and 7 grade 2 (11%). No LR was observed in patients with LVH and no CA. LR was not evident in patients without HR, present in 1/3 (33%) of the patients with Perugini 1 HR and 11/24 (46%) and 26/36 (72%) of the patients showing respectively a Perugini 2 and a Perugini 3. CONCLUSION: 99mTc-HMDP scintigraphy shows LR in about 60% of TTR subjects, related to the grade of HR. In AL amyloidosis LR is less frequent than in TTR amyloidosis suggesting an aetiological tropism that seems comparable to the already known TTR related cardiac tropism.

[Percutaneous treatment of coronary chronic total occlusions: state of the art]. / Il trattamento delle occlusioni coronariche croniche: stato dell'arte.

Successful percutaneous coronary intervention of chronic total occlusions (CTO) is associated with favorable clinical outcomes in selected subsets of patients. The success rate of CTO interventions greatly increased over the last decades, thanks to the development of dedicated materials and interventional strategies. Nevertheless, CTO interventions are still challenging with higher complication rates and lower success rates compared to standard percutaneous coronary interventions. Dedicated CTO operators are warranted in order to minimize the rate of complications and to achieve a success rate near to 90%. This state of the art paper is aimed to provide updated evidences on the clinical benefit of CTO recanalization and to describe specific interventional techniques for CTO recanalization.

Incremental prognostic value of coronary CT angiography in patients with suspected coronary artery disease.

BACKGROUND: Multidetector CT coronary angiography (MDCTCA) is capable of detecting coronary artery disease (CAD) with a high diagnostic accuracy. In particular, this technique is credited with having a negative predictive value close to 100%. However, data about the prognostic value of MDCTCA are currently lacking. We sought to determine the prognostic value of MDCTCA in patients with suspected but undocumented CAD and, in particular, the incremental prognostic value as compared with clinical risk and calcium scoring. METHODS AND RESULTS: A total of 441 patients (age, 59.7+/-11.6 years) with suspected CAD underwent MDCTCA to evaluate the presence and severity of the disease. Patients were followed up as to the occurrence of hard cardiac events (cardiac death, nonfatal myocardial infarction, and unstable angina requiring hospitalization). Coronary lesions were detected in 297 (67.3%) patients. During a mean follow-up of 31.9+/-14.8 months, 44 hard cardiac events occurred in 40 patients. CT calcium scoring showed a statistically significant incremental prognostic value as compared to a baseline clinical risk model (P=0.018), whereas MDCTCA provided an additional incremental prognostic value as compared with a baseline clinical risk model plus calcium scoring if considering both nonobstructive versus obstructive CAD (P=0.016) or, better, plaque composition (calcified versus noncalcified and/or mixed plaques, P=0.0001). During follow-up, an excellent prognosis was noted in patients with normal coronary arteries, with an annualized incidence rate of 0.88% if compared with those with mild CAD (3.89%) and with patients with significant coronary disease (8.09%). The presence of noncalcified or mixed plaques, regardless of lesion severity, was found to be the strongest predictor of events (P<0.0001) as a potential marker of plaque vulnerability. CONCLUSIONS: MDCTCA provides independent and incremental prognostic information as compared to baseline clinical risk factors and calcium scoring in patients with suspected CAD.