Despite great progress in randomized controlled trial (RCT) design, several methodological issues can still be encountered when reading superiority trials published in leading journals. We propose a 10–step approach to the interpretation of neutral or negative trials to exclude important methodological issues before concluding that the treatment does not work (Figure). 1. Premature interruption Except when there is evidence of superiority at interim analysis, all premature discontinuations make the RCT underpowered. 2. Insufficient power Insufficient power may derive from lower event rates than anticipated or a smaller effect size than expected. Two other possible reasons are a high cross–over rate or a number of events “hypertrophied” by minor events or medical decisions. 3. Logistical peculiarities Logistical issues, e.g., heterogeneous patient selection and management in different geographic areas, are sometimes crucial. 4. Errors or ambiguities in endpoint adjudication Cardiovascular death and HF hospitalization are often used as endpoints. In some cases, the discrepancy between investigator–reported and centrally adjudicated events is quite prominent. Furthermore, some endpoint definitions may be open to interpretation. 5. Suboptimal choice of composite endpoints A composite endpoint should have clinical relevance and should include only elements to be impacted by the intervention. This last requirement is often not met. 6. Nosographic trap The nosographic trap occurs when the study population is heterogeneous, and the importance of the treatment target is not the same across the whole population. 7. Lack of pathophysiological prerequisites for efficacy Some RCTs may prove neutral or negative because they enrolled patients where the treatment was unlikely to be effective. 8. Algebraic cancellation Algebraic cancellation occurs when results are positive in some patients and negative in others. 9. p trap A possible instance is that p value approaches the statistical significance value, leading to uncertainties as to whether borderline significance should be interpreted. 10. The treatment does not really work When a trial is adequately powered and without major methodological flaws, but the p value for the primary endpoint is far from significance (and therefore the p trap is not an issue), the reasonable conclusion is that the treatment is not more effective than its comparator in this specific setting.

AimsThe incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light‐chain (AL) and transthyretin (ATTR) CA.Methods and resultsConsecutive patients with AL and ATTR‐CA diagnosed at participating centres (2017–2020) were included. Clinical data recorded within ±1 month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically‐indicated PM implantation. Patients with PM (n = 41) and/or permanent defibrillator in situ (n = 13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild‐type ATTR; 82.5% were male, median age 76 years. During a median follow‐up of 33 months (interquartile range 21–46), 36 (8.9%) patients experienced the primary outcome: 10 AL‐CA, 2 variant ATTR‐CA and 24 wild‐type ATTR‐CA (p = 0.08 at time‐to‐event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p = 0.002), PR interval (HR 1.013, p = 0.002) and QRS >120 ms (HR 4.7, p = 0.001) on baseline electrocardiogram were independently associated with PM implantation. The absence of these three factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6 months.ConclusionIn a large cohort of AL and ATTR‐CA patients, 8.9% received a PM within 3 years after diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation.

Abstract Background Over the last years, an algorithm for non–invasive diagnosis of amyloid transthyretin cardiac amyloidosis (ATTR–CA) and novel disease–modifying therapies have prompted an active search of CA in different clinical settings. Methods We performed a systematic search of screening studies investigating CA. Results The average prevalence of CA in different settings were as follows: total body scintigraphy with “bone tracers” for non–cardiac reasons (n = 5 studies), 1%; heart failure (HF) with preserved ejection fraction (n = 6), 12%; HF with reduced or mildly reduced ejection fraction (n = 2), 10%, conduction disorders warranting pacemaker implantation (n = 1), 2%; surgery for carpal tunnel syndrome (CTS; n = 3), 7%; hypertrophic cardiomyopathy phenotype (n = 2), 9%; aortic stenosis (AS) undergoing surgical or transaortic valve replacement (n = 7), 10%; autopsy series of “unselected” elderly individuals (n = 4), 15%. Many of these patients had ATTR–CA, but the percentage of cases with amyloid light–chain CA was far from negligible. Conclusions Screening for CA in specific settings allows to identify a relatively high number of cases, in agreement with the notion that CA is not a rare disease. Many patients have ATTR–CA. Most studies focused on elderly subjects, given the clear relationship between age and the likelihood of CA. Men accounted for a high proportion of patients with CA, but women were quite represented.

Abstract Background The prognostic role of bone tracer uptake in transthyretin cardiac amyloidosis (ATTR-CA) is controversial. A further characterization of cardiac retention measured by Perugini scale with differentiation between biventricular (BiV) and isolated left ventricle (LV) uptake has never been attempted previously. Purpose The study investigated the potential prognostic significance of BiV uptake in ATTR-CA. Methods In this multicentre, observational study, we analysed data of ATTR-CA patients who underwent bone tracer scintigraphy with acquisition of both planar and single photon emission computed tomography (SPECT) imaging. Cardiac uptake was defined according to the Perugini visual scale. Planar BiV uptake was defined according to right ventricle (RV) uptake: 0= absent, 1= < bone, 2= equal to bone, and 3= > bone and confirmed by SPECT imaging. The primary outcome was a composite of cardiac death or hospitalization for heart failure. The secondary outcome was all-cause mortality. Results All 124 ATTR-CA patients enrolled had LV and RV free wall uptake on SPECT images. Of them, 93 (75%) had BiV uptake visible on planar scintigraphy. BiV uptake was found in 14%, 70%, and 92% of Perugini grade 1, 2 and 3 respectively. Compared to those with isolated LV uptake, patients with BiV uptake were older (81 vs 77 years, p=0.006) and more frequently in NYHA≥3 (32% vs 10%, p=0.018). During a median follow-up of 21 months, BiV uptake was associated with a greater occurrence of the primary outcome compared to isolated LV uptake (40% vs 19%, p=0.021), whereas the Perugini scale was not (p=0.2) (Figure 1). At multivariable analysis, NYHA class ≥3 (hazard ratio [HR] 8.1, p=0.007), eGFR <60 ml/min (HR 2.1, p=0.025) and higher degree of RV uptake (HR 1.69, p=0.007) emerged as independent prognostic parameters. In an external cohort of 463 ATTR-CA patients with a median follow-up of 30 months, planar BiV uptake was independently associated with all-cause mortality, with an incremental risk in higher grades of RV uptake (p<0.001) (Figure 1). Conclusions The presence of BiV uptake at planar scintigraphy identified ATTR-CA patients with worse cardiovascular and global outcomes (Figure 2), potentially serving as a novel prognostic marker. Funding Acknowledgement Type of funding sources: None.

AimsThe HFA‐PEFF and H2FPEF scores have been developed to diagnose heart failure with preserved ejection fraction (HFpEF), and hold prognostic value. Their value in patients with HFpEF caused by cardiac amyloidosis (CA) has never been investigated.Methods and resultsWe evaluated the diagnostic and prognostic value of the HFA‐PEFF and H2FPEF scores in 304 patients from three cohorts with HFpEF caused by transthyretin CA (n = 160, 53%) or immunoglobulin light‐chain CA (n = 144, 47%). A diagnosis of HFpEF was more likely using the HFA‐PEFF score with 2 (1%), 71 (23%), and 231 (76%) patients ranked as having a low (0–1), intermediate (2–4), or high (5, 6) probability of HFpEF, respectively. Conversely, 36 (12%), 179 (59%) and 89 (29%) of patients ranked as having a low (0–1), intermediate (2–5), or high (6–9) probability of HFpEF using the H2FPEF score. During a median follow‐up of 19 months (interquartile range 8–40), 132 (43%) patients died. The HFA‐PEFF score, but not the H2FPEF score, predicted a high risk of all‐cause death which remained significant after adjustment for age, AL‐CA diagnosis, high‐sensitivity troponin T, N‐terminal pro‐B‐type natriuretic peptide, and echocardiographic parameters, including left ventricular global longitudinal strain, left ventricular diastolic function and right ventricular function (hazard ratio 1.51, 95% confidence interval 1.16–1.95, p = 0.002 for every 1‐point increase in HFA‐PEFF).ConclusionsThe HFA‐PEFF score has a higher diagnostic utility in HFpEF caused by CA and holds independent prognostic value for all‐cause mortality, while the H2FPEF score does not.

Patients with cardiac amyloidosis (CA) display an enlarged and dysfunctional left atrium (LA), because of the effects of left ventricular (LV) diastolic and then systolic dysfunction, as well as the amyloid infiltration of LA wall. A single study reported impaired LA strain in CA, but differences among amyloid light-chain (AL) and transthyretin (ATTR) CA and the correlates of reduced LA strain have not been characterized. We evaluated 426 consecutive patients undergoing a screening for suspected CA in 2 tertiary referral centres. Among them, 262 (61%) were diagnosed with CA (n=117 AL-CA, n=145 ATTR-CA). We measured peak atrial longitudinal strain (PALS) and peak atrial contraction strain (PACS) from 4- and 2-chamber (4C, 2C) views, and correlated them with maximum and minimum LA volumes, E/e' ratio, and LV global longitudinal strain (GLS). LA strain was much more severely impaired in patients with ATTR-CA than those without CA, and to a lesser extent than those with AL-CA (Figure). LA volumes were larger in patients with ATTR-CA than those without CA (maximal LA volume, p=0.042; minimal LA volume, p<0.001), and those with AL-CA (both volumes, p<0.001). LA strain values were more closely correlated with minimal than maximal LA volumes, and patients with AL-CA displayed stronger correlations than those with ATTR-CA or without CA; for example, Spearman's rho values for 4C-PALS vs. minimal LA volume were 0.595, 0.481, and 0.462, respectively (all p<0.001). Furthermore, LA strain correlated with E/e' in patients with AL-CA, but not in those with ATTR-CA: 4C-PALS vs. E/e', rho 0.406, p=0.001 (AL-CA), p=0.401 (ATTR-CA), and p=0.097 (no CA). Finally, LA strain correlated most closely with LV GLS in patients with AL-CA: 4C-PALS vs. LV GLS, rho 0.431, p<0.001 (AL-CA), rho 0.401, p<0.001 (ATTR-CA), rho 0.219, p=0.042 (no CA). LA volume increase and reduced LA strain is particularly prominent in patients with ATTR-CA. Patients with AL-CA seem to display closer relationships between LA strain, size and haemodynamic load, possibly reflecting the most acute disease course, and lower time for amyloid deposition in the LA wall. Type of funding sources: None.

Background: Amyloidosis is a multi-systemic disease potentially leading to failure of affected organs. We aimed to investigate prevalence and prognostic implications of cardiac amyloidosis of any etiology on outcomes of hos-pitalized patients with heart failure (HF) in Germany.Methods: We analyzed data of the German nationwide inpatient sample (2005-2018) of patients hospitalized for HF (including myocarditis with HF and heart transplantation with HF). HF patients with amyloidosis (defined as cardiac amyloidosis [CA]) were compared with those HF patients without amyloidosis and impact of CA on outcomes was assessed.Results: During this fourteen-year observational period 5,478,835 hospitalizations for HF were analyzed. Amyloidosis was coded in 5,407 HF patients (0.1%). CA prevalence was 1.87 hospitalizations per 100,000 German population. CA patients were younger (75.0[IQR 67.0-80.0]vs.79.0[72.0-85.0]years, p < 0.001), pre-dominantly male (68.9%) and had a higher prevalence of cancer (14.8% vs. 3.6%, p < 0.001). Adverse in -hospital events including necessity of transfusions of blood constituents (7.1% vs. 5.4%, p < 0.001) and cardio-pulmonary resuscitation (CPR, 2.7% vs. 1.4%; p < 0.001) were more frequent in CA. CA was indepen-dently associated with acute kidney failure (OR 1.40 [95%CI 1.28-1.52], p < 0.001), CPR (OR 1.58 [95%CI 1.34-1.86], p < 0.001), intracerebral bleeding (OR 3.13 [95%CI 1.68-5.83], p < 0.001) and in-hospital mortality between the 5 and 8th decade of life, but in-hospital mortality was strongly influenced by cancer.Conclusions: CA was identified as an independent risk factor for complications and in-hospital mortality in HF patients, whereby it has to be mentioned that amyloidosis subtypes could not differentiated in the present study. Physicians should be aware of this issue concerning treatments and monitoring of CA-patients.

Abstract Background Heart failure (HF) is one of the main features of amyloidotic cardiomyopathy (AC) and it is supposed to carry important prognostic implications. Despite the intrinsic etiologic heterogeneity of AC, HF has been mainly attributed to diastolic dysfunction, but the role played by the different amyloid subtypes of AC and by the clinical and hemodynamic factors in the pathophysiology of HF remains unclear. Objectives We aimed to assess the hemodynamic profile and outcome of patients with or without advanced HF (defined as NYHA class III-IV) at the time of first evaluation in light-chain (AL), hereditary transthyretin-related (h-ATTR) and non-mutant transthyretin-related (wt-ATTR) AC. Methods Among the 411 patients diagnosed with AC (156 AL, 131 h-ATTR, 124 wt-ATTR) at our Centre between 1990–2019, we analyzed central hemodynamic data, echocardiographic, clinical, ECG details and survival of the whole cohort. Cox regression analysis was used to stratify prognosis. Results 112 (27%) patients presented advanced HF at first evaluation and frequently showed severe symmetric left ventricle wall thickening (higher values in h-ATTR), non-dilated left ventricle, preserved ejection fraction and pathological global longitudinal strain and/or myocardial contraction fraction. At ECG, a significantly lower QRS voltage was present in advanced HF patients. Hemodynamically, elevated filing pressures on both cardiac sides were present in patients in NYHA III-IV class of the three etiologies. Overall survival at 2 years was 35% for AL, 83% for h-ATTR, 65% for wt-TTR. H-ATTR and wt-TTR were favorable predictors of survival, while reduced cardiac index and elevated filling pressures were indepedently associated with higher mortality. Conclusions The characterization of hemodynamic profile plays a central role in predicting the natural history of AC, since reduced stroke volume and elevated filling pressures are the best predictors of mortality, reflecting a physiopathological restrictive model of the disease. Conversely, left ventricular ejection fraction is rarely abnormal and it is not a reliable marker of poor prognosis, especially in the early stages of the disease. AL amyloidosis shows the worst outcome probably due to a combination of the underlying illness and light chains cardiotoxicity. LVEF and cardiac index in HF Funding Acknowledgement Type of funding source: None

Differential diagnosis between Anderson-Fabry (AF) and sarcomeric hypertrophic cardiomyopathy (HCM) is often very challenging particularly in AF patients with late onset cardiac involvement. To gain new insights from standard electrocardiogram (ECG) in AF disease for differential diagnosis from sarcomeric HCM. Additionally, to better understand ECG features in AF patients, a correlation substudy ECG-cardiac magnetic resonance (CMR) has been performed. From 162 patients with definite diagnosis of AF disease, 111 [65 males, median age 57 (51–67) years] with pathologic left ventricular hypertrophy (LVH) (Group A) were compared with 111 sarcomeric HCM patients (Group B) sex, age and maximal wall thickness matched by 1:1 propensity score. AF patients showed shorter PR interval [155 (140–180) vs 163 (149–184) msec; p=0.005) and wider QRS interval [110 (100–134) vs 100 (90–106) msec; p<0.0001). Additionally AF patients had a higher prevalence of complete (22% vs 3%; p<0.0001) and incomplete (13% vs 1%; p<0.0001) right bundle branch block (RBBB) and a higher percentage of ST segment depression (12% vs 1%; p=0.001) and inferior negative T waves (34% vs 19%; p=0.01). No differences in terms of Sokolow-Lyon and Cornell scores were found whereas total QRS score was higher in Group A [20 (16–27) vs 18 [14–22] mV; p=0.0004). Low QRS voltages and inferior Q waves were not present in AF patients. Among the 69 AF patients who underwent MRI, the 44 with late gadolinium enhancement (LGE) were older [59 (52–66) vs 53 (40–59) years; p=0.017] and had more frequently negative T waves on ECG, particularly in the inferior leads (64% vs 8%; p<0.0001), compared to the 25 without LGE. At multivariate analysis, age and negative T waves were independently associated to the presence of LGE on CMR. Compared to matched sarcomeric HCM, AF patients had a shorter PR, wider QRS and a higher percentage of RBBB in relation to to the different aetiology (storage vs “pure” hypertrophy). The higher total QRS score and the absence of inferior Q waves could reflect the more frequent concentric distribution of LVH. Additionally negative T waves, especially in inferior leads, are related to the presence of LGE on CMR (often in the postero-lateral wall). Type of funding source: None

Abstract BACKGROUND Cardiac Masses (CM) represent a rare and heterogeneous group with a prevalence of 0.3% at autopsy, divided in benign masses - primary tumors and pseudotumors - and malignant ones - primitive tumors and metastasis, either directly invading the heart and pericardium or as a consequence of hematologic spread. 2-D Echocardiography is nowadays the first line approach to define nature and management of CM, but is it enough to guide a therapeutic strategy? PURPOSE To evaluate echocardiographic CM malignancy features in patients admitted to our Centre between 1997 and 2017. MATERIALS AND METHODS We retrospectively evaluated a population of 180 consecutive patients (45% males; mean age 60 ± 16 years; BMI 25 ± 5 Kg/m2), referred to our echocardiographic lab with suspicion CM. All patients were examined in both left lateral and supine position, and heart was visualized from all available echocardiographic windows. Definite diagnosis was obtained by histologic examination of biopsy, surgical samples or, in cases of cardiac thrombi, by radiological evidence of thrombus resolution after adequate anticoagulant treatment. We excluded normal anatomical variants in the group of pseudotumors due to the impossibility of obtaining histological examination. Comparisons between categorical variables were performed by Chi-square or Fisher exact test. P values ≤ 0.05 were considered significant. Variables with statistical signification lower than p ≤ 0.05 in univariable analysis were included in logistic regression analysis to determinate independent predictors of malignant masses. RESULTS We detected 129 benign CM (76% primitive tumors and 24% pseudotumors) and 51 malignant cardiac tumors (45% primitive tumors and 55% metastasis). In 7 cases a poor acoustic window did not allow an optimal examination; in remaining 173 patients, the classical 2-D echocardiogram identified 157 masses with a diagnostic accuracy of 91%. Benign tumors and pseudotumours were localized predominantly in left heart chambers, while malignant primitive tumors and metastasis were mainly detected in right heart, in pericardium or in pulmonary artery branches (p < 0.001). The largest ecocardiographic diameter appeared greater for the malignant masses (mean of 49 ± 26 mm) than benign ones (30 ± 16 mm, p = 0.003). The occurrance of any pericardial effusion (p < 0.001), extension to pericardium (p = 0.01) or to main vessels (p = 0.006) were also associated with malignant masses. Finally, multivariate analysis showed only largest diameter (p = 0.001) and pericardial effusion (p < 0.001) were independent predictors of malignancy. CONCLUSION 2D Echocardiography is an excellent, non invasive technique for first line evaluation of patients with suspicion CM. It is safe, accurate and have high diagnostic accuracy in identifying CM and their benign or malignant nature. In particular, a large mass associated with any pericardial effusion must pose suspect of malignancy.

Abstract Background Anderson Fabry (AF) disease is a X-linked lysosomal storage disorder with multiorgan involvement. Cardiac disease, mainly represented by left ventricular hypertrophy (LVH) and arrhythmias, is the most frequent cause of premature death. It is well know that specific therapy is less effective after the development of LVH and myocardial fibrosis, therefore early cardiac detection (before LVH) is important. New cardiac magnetic resonance (CMR) parametric imaging techniques (T1 and T2 maps) enable myocardial tissue changes associated with AF disease. Purpose To evaluate the relationship between CMR tissue characterization and clinical and instrumental manifestations of AF disease to find early markers of cardiac involvement. Methods 31 AF patients (9 males, mean age 49±16 years) underwent ECG, echocardiogram and contrast CMR. TnI, BNP, pro-BNP and serum lyso-Gb3 were dosed. T1 mapping was performed in a pre-contrast acquisition with the modified Look-Locker inversion recovery (MOLLI) sequences. CMR results were compared with those of 43 healthy age and gender-matched controls. Results In AF patients native septal T1 values were significantly lower compared to healthy controls (median 949 vs 991 msec, p=0.0137) and were inversely related to Lyso-Gb3 serum levels (p=0.003). Patients with LVH had lower T1 septal values in comparison with patients without LVH (892 vs 981 msec; p=0.0012). Patients with classic form had abnormal low T1 values more frequently than pts with late onset variant (78 vs 23%; p=0.038). In AF patients native septal T2 values were significantly higher compared to the control group (53 vs 49 msec; p=0.0004) and correlated with troponin I (p=0.008) and NT-pro BNP (p=0.006) serum levels. No difference was found between pts with and without LVH (53.5 vs 52.5 ms; p=0.797) and the prevalence of abnormal high T2 values was similar between patients with late onset AF and pts with classical form (53% vs 50%; p=1.000). All patients with late onset AF and high T2 values were females. Conclusions CMR T1 (low values) and T2 (high values) mapping are useful tools to detect early cardiac involvement before LVH and to better understand the pathophysiology of cardiac disease in AF patients. Subclinical tissue inflammation, detectable through T2 maps, seems to be an additional pathogenetic mechanism related to the Gb3 storage that contributes to organ damage and precedes LVH, particularly in females patients with late onset phenotype. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Sant'Orsola-Malpighi Hospital

Abstract BACKGROUND Cardiac Masses (CM) represent an heterogeneous group with a prevalence of 0.3% at autopsy, divided in benign masses (primary tumors and pseudotumors) and malignant ones (primitive tumors and metastasis). 2-D Echocardiography is nowadays the first line approach to define nature and management of CM, but is it enough to guide a therapeutic strategy? PURPOSE To evaluate echocardiographic diagnosis accuracy for CM in patients admitted to our Centre between 1997 and 2017. MATERIALS AND METHODS We retrospectively evaluated a population of 180 consecutive patients (45% males; mean age 60 ± 16 years; BMI 25 ± 5 Kg/m2), referred to our echocardiographic lab with suspicion CM. All patients were examined in both left lateral and supine position, and heart was visualized from all available echocardiographic windows. Definite diagnosis was obtained by histologic examination of biopsy, surgical samples or, in cases of cardiac thrombi, by radiological evidence of thrombus resolution after adequate anticoagulant treatment. We excluded normal anatomical variants in the group of pseudotumors due to the impossibility of obtaining histological examination. Sensitivity, specificity, predictive accuracy for a positive test, and predictive accuracy for a negative test were calculated by standard formulas (corrected for prevalence by Bayes theorem). RESULTS We detected 129 benign CM and 51 malignant cardiac tumors. In 7 cases a poor acoustic window did not allow an optimal examination; in remaining 173 patients, the classical 2-D echocardiogram identified 157 masses with a diagnostic accuracy of 91%. Of 173 CM diagnosed, 146 were classified by echocardiographer as benign masses (125 true benign on histological examination) and 27 as malignant ones (all malignant after histological confirmation); the results showed 56% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value, with 88% overall diagnostic accuracy in identifying the nature of masses. 23 cases were undetermined and needed second level instrumental investigations to be characterized. Diagnostic accuracy for distinguishing primary benign tumors and pseudotumors decreased to 80%, with a significant increase in both "false" benign tumors (9 out of 91) and "false" pseudotumors (15 out of 34) with 85% sensitivity, 68% specificity, 10% positive predictive value, 99% negative predictive value. CONCLUSION 2D Echocardiography is an excellent, non invasive technique for first line evaluation of patients with suspicion CM. It is safe, reliable with a high predictive value and diagnostic accuracy in identifying CM and their benign or malignant nature. In contrast, these results were insufficient to start an anticoagulant in suspicion thrombus or cardiac surgery for primary tumor, since second level instrumental examinations needed. 2D Echocardiography alone seems unuseful for classifying malignant masses in primitive or metastasis.

Abstract Background In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis was shown to be an effective treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Further assessment of the efficacy of tafamidis in patients with more advanced ATTR-CM would aid treatment decisions. Purpose To characterize the benefits of tafamidis in patients with advanced ATTR-CM. Methods In ATTR-ACT, ATTR-CM patients were randomized to tafamidis (n=264) or placebo (n=177) for 30 months. Efficacy outcomes included all-cause mortality and frequency of cardiovascular (CV)-related hospitalisations. Key secondary endpoints were change from baseline to Month 30 in 6MWT distance and KCCQ-OS score. Efficacy assessments in NYHA Class III patients at baseline (n=141) were a pre-specified analysis. In a post-hoc analysis, mortality and CV-related hospitalizations were assessed in all patients grouped into quartiles of increasing disease severity based on 6MWT distance at baseline. Longer-term all-cause mortality (as of 1 Aug 2019) was assessed in NYHA Class III patients utilizing data from ATTR-ACT patients who enrolled in a long-term, extension study (LTE) and continued treatment with higher dose tafamidis (n=55; median treatment duration 51.6 months); or, if previously treated with placebo, started tafamidis treatment (placebo/tafamidis; n=63 [50.1 months]). Results In advanced ATTR-CM patients (NYHA Class III), tafamidis reduced the risk of death (HR [95% CI] 0.837, [0.541, 1.295], P=0.4253), and the decline in 6MWT distance (LS mean [SE], 31.6 (22.1) m; P=0.1526) and KCCQ-OS score (LS mean [SE], 13.1 (5.0); P=0.0090), vs placebo. Paradoxically, there was a higher frequency of CV-related hospitalizations with tafamidis (RR [95% CI] vs placebo, 1.411 [1.048, 1.900]). In all patients by 6MWT quartile, CV-related hospitalizations/year with tafamidis and placebo increased with disease severity, with the exception that placebo-treated patients in the highest severity quartile had fewer CV-related hospitalisations (0.73) than those in the third quartile (0.92). Mortality with tafamidis and placebo increased, and was greater with placebo, in every quartile (Figure). Survival (NYHA Class III patients in ATTR-ACT and LTE) was improved with high dose tafamidis with longer term follow-up (HR vs placebo/tafamidis [95% CI], 0.6569 [0.4175, 1.0336]; P=0.0692). Conclusions These analyses, including longer-term follow-up, demonstrate that patients with advanced ATTR-CM benefit from tafamidis. The decrease in CV-related hospitalisations in more severe patients treated with placebo suggests that the comparatively greater hospitalisation frequency in NYHA Class III patients treated with tafamidis is a consequence of their lower mortality rate. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Pfizer

Compared to other sections of medicine, cardiology only has a marginal role in the fight against Covid-19. Nevertheless, cardiologists are potentially involved in this story in at least three ways:1)A number of cardiovascular diseases may increase mortality among affected patients. Covid-19 appears less pathogenic than previous viruses such as SARS-COV or MERS-COV. But, deaths in the Wuhan Province where the Covid-19 epidemic started were between 0.5% to 2.5% [[1]Munster V.J. Koopmans M. van Doremalen N. van Riel D. de Wit E. A novel coronavirus emerging in China — key questions for impact assessment.N. Engl. J. Med. 2020 Feb 20; 382: 692-694Crossref PubMed Scopus (934) Google Scholar]. In Europe, where the virus has recently migrated, the rate may be higher from 4% to 6%. However, the death rate depends on the number of infected people which is, at present, still unknown. Hypertension or coronary heart disease is present in 38% and diabetes in 19% of COVID-19 patients [[2]Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Guan L. Wei Y. Li H. Wu X. Xu J. Tu S. Zhang Y. Chen H. Cao B. Clinical course andrisk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: aretrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18500) Google Scholar]. A report on 136 Covid-19 patients shows that 26% of them required cardiovascular intensive care. They had a higher rate of death and a higher prevalence of diabetes and cardiovascular disease than those not requiring intensive care [[3]Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. Wang B. Xiang H. Cheng Z. Xiong Y. Zhao Y. Li Y. Wang X. Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16024) Google Scholar]. A recent report on 72.314 cases from the Chinese centre of the disease control shows a mean death rate of 2.3% which increases to 5% in patients with cardiovascular disease and to 7.3% in those with diabetes [[4]Guan W. Ni Z. Hu Y. et al.China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20075) Google Scholar,[5]Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020 Feb 24; (Epub ahead of print)https://doi.org/10.1001/jama.2020.2648Crossref Scopus (12446) Google Scholar]. Although the vulnerability of the patients with heart diseases to Covid-19 is quite evident in these reports, the single study using multivariable regression analysis shows that only older age, higher Sequential Organ Failure Assessment Score and high values of d-dimer on admission are independent predictive values of mortality [[2]Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. Guan L. Wei Y. Li H. Wu X. Xu J. Tu S. Zhang Y. Chen H. Cao B. Clinical course andrisk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: aretrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18500) Google Scholar].2)Viral infection could be the cause or a contributory cause of a new heart disease. The National Health Commission of China reported that often the first contact of patients with doctors is with reported palpitations or chest pain rather than respiratory symptoms. Only later are they diagnosed as positive for Covid-19 [[6]Zheng Y.Y. Ma Y.T. Zhang J.Y. Xie X. COVID-19 and the cardiovascular system.Nat. Rev. Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (2249) Google Scholar]. Some Covid-19 patients have high sensitivity cardiac troponin 1 levels, suggesting myocardial injury [[6]Zheng Y.Y. Ma Y.T. Zhang J.Y. Xie X. COVID-19 and the cardiovascular system.Nat. Rev. Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (2249) Google Scholar]. 26% of patients hospitalised at Zhongnan University Hospital of Wuhan required cardiovascular intensive care. Of these, 16.7% developed arrhythmias and 7.2% and acute coronary syndrome [[3]Wang D. Hu B. Hu C. Zhu F. Liu X. Zhang J. Wang B. Xiang H. Cheng Z. Xiong Y. Zhao Y. Li Y. Wang X. Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16024) Google Scholar]. It is unclear whether these cardiac conditions are provoked by Covid-19 or are just comorbidities or non-specific complications of infection. Studies during the flu epidemic in the USA and clinical practice show that inflammation due to flu may destabilise coronary plaque and cause myocardial infarction (MI) [[6]Zheng Y.Y. Ma Y.T. Zhang J.Y. Xie X. COVID-19 and the cardiovascular system.Nat. Rev. Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (2249) Google Scholar] This, in turn, is due to multiple mechanisms such as tachycardia, hypoxia, increased wall stress and inflammatory cytokines as well as thrombophilia [[7]Corrales-Medina V.F. Madjid M. Musher D.M. Role of acute infection in triggering acute coronary syndromes.Lancet Infect. Dis. 2010; 10: 83-92Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar]. Similar links with MI were shown for more recent epidemics of SARS and Covid-19 [[8]Halhogbani T. Acute myocarditis associated with novel Middle East respiratory syndrome coronavirus.Ann Saudi Med. 2016; 36: 78-80Crossref PubMed Scopus (266) Google Scholar]. Only future studies will establish a possible relationship between Covid-19 and coronary artery disease. Only the awareness of such a link will encourage the cardiovascular community to search for it and to set appropriate studies to clarify this issue.3)Drugs for patients with cardiovascular disease could interfere with the pathophysiology of Covid-19. As was the case for the SARS-COV infection, the receptor for the new 2019 Covid-19 is human angiotensin-converting enzyme 2 (ACE2), a homologue of ACE1 [[6]Zheng Y.Y. Ma Y.T. Zhang J.Y. Xie X. COVID-19 and the cardiovascular system.Nat. Rev. Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (2249) Google Scholar]. The virus spike protein binds to ACE2 which allows the penetration of the virus into the epithelial cells of the lungs. ACE2 is found primarily in the lower respiratory tract, rather than in the upper airway [[9]Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Drug Dev. Res. 2020 Mar 4; (Epub ahead of print)https://doi.org/10.1002/ddr.21656Crossref PubMed Scopus (604) Google Scholar]. This distribution can explain the few upper respiratory tract symptoms typical of flu and why Covid-19 is not just a common cold [[9]Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Drug Dev. Res. 2020 Mar 4; (Epub ahead of print)https://doi.org/10.1002/ddr.21656Crossref PubMed Scopus (604) Google Scholar]. Contrary to ACE1 which converts angiotensin 1 to angiotensin 2 and is a therapeutic target for hypertension and heart failure, the biology of ACE2 and its therapeutic potential is unclear [[6]Zheng Y.Y. Ma Y.T. Zhang J.Y. Xie X. COVID-19 and the cardiovascular system.Nat. Rev. Cardiol. 2020; 17: 259-260Crossref PubMed Scopus (2249) Google Scholar]. It is believed that ACE2 plays an antagonist part to the effects of ACE1, converting angiotensin 2 back to angiotensin 1. In view of the role of ACE2 in the penetration of 2019-nCov, drugs such as angiotensin 2 receptor blockers (ARBs) that increase angiotensin 2 plasma levels could activate ACE2 and an adverse Covid-19 pandemic [[10]Paules C.I. Marston H.D. Fauci A.S. Coronavirus infections-more than just the common cold.JAMA. 2020 Jan 23; (Epub ahead of print)https://doi.org/10.1001/jama.2020.0757Crossref PubMed Scopus (1349) Google Scholar]. ARBs are mainly prescribed for hypertension and it has been suggested that alternative drugs to ARBs should be used to treat hypertension during the Covid-19 pandemic [[10]Paules C.I. Marston H.D. Fauci A.S. Coronavirus infections-more than just the common cold.JAMA. 2020 Jan 23; (Epub ahead of print)https://doi.org/10.1001/jama.2020.0757Crossref PubMed Scopus (1349) Google Scholar]. The caveats here are a) there is no evidence of increased ACE2 expression with ARBs in the lung b) ACE2 expression is reduced in hypertension models c) hypertension and its treatment with ARBs did not affect previous coronavirus infections. The same considerations apply to heart failure. Although this hypothesis should be considered and further investigated, at present the discontinuation of ARBs in hypertensive and heart failure patients is not supported by any evidence. Finally, although the cardiovascular side effects of the current drugs empirically used for the Covid-19 infection and now tested in experimental protocols (such as anti-viral–remdisivir or lopinavir+ritonavir– or anti-leukin 6 –tocilizumab– or other antinflammatory –chloroquine–) are rare and not serious, an active surveillance is mandatory. In conclusion, besides the possible impact of Covid-19 on cardiology, the pandemic has created a perfect storm for the health organisations across the globe. Cardiologists must be aware of the organisational, emotional, and clinical consequences of this drama and should react accordingly. The authors report no relationships that could be construed as a conflict of interest.

BACKGROUND:Planar diphosphonate scintigraphy is an established diagnostic tool for amyloid transthyretin (ATTR) cardiomyopathy. Characterization of the amyloid burden up to the segmental level by single photon emission computed tomography (SPECT) has not been evaluated so far.METHODS:Data from consecutive patients undergoing cardiac 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) SPECT and diagnosed with ATTR cardiomyopathy at a tertiary referral center from June 2016 to April 2019 were collected.RESULTS:Thirty-eight patients were included (median age 81 years, 79% men, 92% with wild-type ATTR). In patients with Perugini score 1, the most intense diphosphonate regional uptake was found in septal segments, particularly in infero-septal segments. Among patients scoring 2, the amyloid burden in the septum became more significant, and extended to inferior and apical segments. Finally, patients scoring 3 displayed an intense and widespread tracer uptake. All patients with Perugini score 1 had LGE in at least one antero-septal, one infero-septal, and one infero-lateral segment. All patients with score 2 displayed LGE in infero-septal, inferior, and infero-lateral segments. LGE became extensive in patients scoring 3, with all patients having at least one LGE-positive segment in each region.CONCLUSIONS:When assimilating different Perugini grades to evolutive stages of the disease, amyloid deposition seem to progress from the septum to the inferior wall and then to the other regions and from the basis to the apex. The potential of segmental analysis might be particularly relevant in patients with very limited cardiac uptake at planar scintigraphy (Perugini score 1).

Abstract Aim To look for differences in cardiac phenotype and natural history of patients affected by laminopathy, according to the presence or less of neuromuscular involvement at clinical presentation. Methods We prospectively analyzed 47 consecutive pts with a genetic diagnosis of laminopathy followed at a single centre between 1994 and 2017. Additionally, reports of clinical and instrumental evaluations before referral at our centre were retrospectively evaluated. Results Neuromuscular presentation, mainly as Emery-Dreifuss muscular dystrophy (EDMD), was present in 21 (46%) cases (14 LMNA and 7 EMD gene mutations). These pts had symptoms earlier (9 vs 39 years, p<0.001) in life compared to pts without neuromuscular onset (26 LMNA gene mutations), and clinical manifestations anticipated the first evidence of cardiac disease by a mean time of 15±8 years (maximum time gap of 38 years). Despite a similar prevalence of atrial fibrillation/flutter (AF) (71% vs 65%, p=0.758) and atrio-ventricular blocks (48% vs 65%, p=0.250), pts with neuromuscular onset experienced AF and pace-maker implantation at a significantly younger age (27 vs 41 yrs, p=0.015 and 23 vs 44 yrs, p=0.027 respectively). Differently a higher prevalence of sinus node dysfunction (33% vs 4%; p=0.015) and atrial paralysis (14% vs 4%; p=0.311) was reported in pts with neuromuscular onset. Prevalence of cardiomyopathy (CMP) (73% vs 33%, p=0.008) and sustained ventricular tachyarrhythmias were higher among pts with cardiac onset (23% vs 4%, p=0.111) whereas the prevalence of heart transplantations and median age of recipients were similar in the two groups (24% vs 20%, p=1.000 and 46 vs 43, p=0.592 years respectively). All pts with neuromuscular onset who received a diagnosis of CMP had a previous history of rhythm disturbance except 2 cases, where a concomitant diagnosis of the 2 disorders was formulated. On the contrary a strict temporal progression from rhythm disturbances to CMP (or viceversa) was not appreciable in the other group: AF and AVBs could precede the diagnosis of CMP be diagnosed at the same time or later. Conclusions In pts affected by laminopathy neuromuscular involvement, when present, was most often the first clinical manifestation and preceded cardiological involvement, with a long time frame in some cases. Except for sinus node dysfunction, much more frequent in patients with EDMD, a similar prevalence of rhythm disturbances was reported, although pts with neuromuscular clinical onset were younger at diagnosis of AF and at PM implantation. Pts without neuromuscular presentation had a higher prevalence of CMP and ventricular arrhythmias, albeit a similar rate of heart transplantation. In pts with neuromuscular onset, cardiac involvement was characterized by a stepwise progression from rhythm disturbances to CMP, where a strict temporal progression from rhythm disturbances to CMP was not observed in the group of pts without neuromuscular clinical onset.