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Cardiac amyloidosis (CA) is an infiltrative disease caused by progressive deposition of amyloid fibres in the heart. The most common forms include immunoglobulin light-chain and transthyretin amyloidosis. Current therapies for CA either stabilize or block the production of amyloidogenic precursors, preventing further amyloid deposition. This approach, while reducing cell damage and disease progression, does not target pre-existing amyloid deposits. Conversely, amyloid removal might stimulate functional recovery of the affected organ, thus improving quality of life and survival. A therapeutic strategy based on monoclonal antibodies capable of selectively binding amyloid deposits and inducing their removal has recently been tested in various clinical trial, with promising results, and could represent a key treatment for CA in the near future.

Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. This study aimed to evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT).Patients with suspected CA (n=1,149) underwent a diagnostic work-up in 3 Centers in Italy, France (n=343, derivation cohort), and United Kingdom (n=806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP180 ng/L or hs-TnT14 ng/L were found in 7% of patients, ruled out without false negatives. In the validation cohort, 20% of patients (2% false negatives) had NT-proBNP180 ng/L or hs-TnT14 ng/L, and 10% showed both biomarkers below cut-offs (0.5% false negatives). These cut-offs refined CA prediction when added to echocardiographic scores in patients with a hematologic disease or an increased wall thickness. In the validation cohort, the 86 ng/L hs-TnT cut-off ruled in 20% of patients (2% false positives). NT-proBNP and hs-TnT cut-offs retained their rule-out and rule-in performance also in cohorts with CA prevalence of 20%, 10%, 5% and 1% derived from the original cohort through bootstrap analysis.Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP180 ng/L and hs-TnT14 ng/L reliably exclude the diagnosis, both in the overall population and subgroups referred for either AL-CA or cardiac (pseudo)hypertrophy.

Background and aims Fibroblast growth factor-23 (FGF23) has been associated with left ventricular (LV) hypertrophy, fibrosis, and heart failure (HF). We aimed to investigate the clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients. Methods Patients with systolic HF (left ventricular ejection fraction – LVEF Results We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher N-terminal pro-B-type natriuretic peptide (NT-proBNP, p=0.001), and lower peak VO2 (p Conclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF. Figure. Prognostic impact of FGF23 levels in patients with systolic heart failure (HF). In a cohort of HF patients with systolic dysfunction, higher iFGF23 levels (marker of increased cardiac fibrosis and hypertrophy) were associated with a more severe disease, as expressed by lower left ventricular systolic function, higher circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), lower oxygen consumption at cardiopulmonary exercise test and worse renal function. Moreover, iFGF23 elevation identified patients at higher risk for all-cause and cardiac mortality, and HF hospitalization.

Background Cardiac amyloidosis (CA) is associated with an elevation of natriuretic peptides and troponins, predicting outcome. Nevertheless, the diagnostic yield of these biomarkers has not been extensively investigated. Aim To evaluate the diagnostic performance for CA of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT). Methods Patients with suspected CA (n=1,149) underwent a diagnostic work-up in 3 Centers in Italy, France (n=343, derivation cohort), and United Kingdom (n=806, validation cohort). Biomarker values with either 100% sensitivity or ≥95% specificity were selected as rule-out/rule-in cut-offs, respectively. Results In the derivation cohort, 227 patients (66%) had CA, and presented with higher NT-proBNP and hs-TnT. NT-proBNP 180 ng/L and hs-TnT 14 ng/L were selected as rule-out cut-offs, and hs-TnT 86 ng/L as rule-in cut-off. NT-proBNP Conclusions Cardiac biomarkers can refine the diagnostic algorithm in patients with suspected CA. NT-proBNP

Introduction Transthyretin (TTR) is a homotetrameric 55-KDa plasma protein that transports thyroxin and retinol complexed to retinol-binding protein (RBP). TTR misfolding and aggregation can lead to the extracellular deposition of amyloid (ATTR) representing one of the most frequent forms of amyloidosis in elderly. Aim of this study is to develop a native electrophoretic method to characterize circulating TTR in plasma samples of ATTR patients before and during treatment with tafamidis, a TTR stabilizer. Methods Plasma from ATTR patients (n=6), collected before (T0) and during tafamidis treatment, and plasma of healthy controls (n=6) were obtained from Fondazione Toscana G. Monasterio (Pisa, Italy). Plasma samples were separated on a native 4–20% Tris-Gly polyacrylamide gel. Western blot analysis was performed with anti-TTR (DAKO) or anti-RBP (Siemens Healthineer) antibodies. Proteins were detected by Clarity ECL substrate (BioRad). Results Circulating forms of TTR were qualitatively similar between ATTRwt patients at T0 and controls. In both groups, the most represented forms were: TTR dimers or trimers (∼37-50 kDa), TTR tetramers complexed with RBP protein in 1:1 ratio (∼80 kDa,) or 1:2 ratio (∼100 kDa), and high molecular weight (MW) aggregates (>150 kDa). Neither TTR monomers nor the tetramers were visible. RBP protein was detectable in association with TTR tetramers and some of the higher MW fractions (∼150 kDa, >250 kDa). Following tafamidis treatment, all ATTRwt patients displayed a progressive increase of the intensity of the band corresponding to TTR-RBP complexes, in agreement with the drug stabilizing action on TTR tetramers. Interestingly dimers and trimers, detectable at T0, were progressively lost during tafamidis treatment. Conclusions The native electrophoretic allowed us to detect several circulating TTR fractions. Data suggest a similar pattern of circulating TTR both in patients and healthy control: TTR tetramer exists only complexed with RBP and in equilibrium with low and high MW forms. Furthermore, the method allowed to appreciate the stabilizing effect of tafamidis on circulating TTR tetramers complexed with RBP. The study of circulating TTR fractions can expand our knowledge on mechanisms triggering its destabilization even when not mutated.

Background Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, has proven to promote left ventricular (LV) reverse remodelling in patients with heart failure (HF) with reduced ejection fraction. However, its molecular and tissue effects have not been fully elucidated yet, due to the paucity of preclinical studies, mostly based on ischaemic models. Aim To evaluate the effects of sacubitril/valsartan on LV remodelling and cardiac mitochondrial function in a murine model of non-ischaemic LV dysfunction. Methods Adult male transgenic mice with cardiac-specific hyperaldosteronism (AS mice) received subcutaneous isoproterenol injection (300 mg/kg BID over two days), to induce LV systolic dysfunction. Mice were then randomized to a 2-week treatment with saline (0,2 mL BID) (ISO-AS n=15), valsartan (26 mg/kg in 0,2 mL of saline) (ISO+V n=12) or sacubitril/valsartan (57 mg/kg in 0,2 mL of saline) (ISO+S/V n=12). Echocardiography was performed at baseline, day 7, 15 and 21 of treatment. Mice were sacrificed at day 21, and histological and immunochemical assays were performed. A control group (Ctrl-AS n=8), not receiving isoproterenol nor pharmacological treatment, was obtained. Results Treatment with sacubitril/valsartan, but not with valsartan, induced a significant improvement of LV ejection fraction (p=0.009 vs ISO-AS) and fractional shortening (p= 0.032 vs ISO-AS) after 2-week treatment. In both ISO+V and ISO+S/V groups, a trend toward reduction of the extent of myocardial fibrosis was detected at histological analysis, confirmed by the lower cardiac collagen 1/3 expression ratio (p= 0.074). ISO+V and ISO+S/V groups showed a significant recovery of mitochondrial morphology and inner membrane function meant for oxidative phosphorylation. Additionally, both treatments reverted the alterations of the expression of genes involved in mitochondrial distribution, transport of organic/inorganic compounds, myocardial cell death, and response to the superoxide. Conclusion In a murine model of non-ischaemic HF, sacubitril/valsartan proved to have beneficial effects on LV remodelling and on cardiac energetics by improving mitochondrial activity.

Background and aims Wild type transthyretin (TTR) cardiac amyloidosis (ATTRwt-CA) is caused by the misfolding, aggregation and tissue deposition of native TTR, leading to cardiac structural remodeling. In the last decade, the validation of non-invasive diagnostic approaches and the development of novel therapeutic options targeting the amyloidogenic cascade, such as the TTR stabilizer tafamidis, have dramatically changed the epidemiology and the prognosis of the disease. Nonetheless, the basic pathophysiological mechanisms underlying TTR misfolding and aggregation are still poorly understood. We aimed to characterize circulating TTR forms in plasma samples of ATTRwt-CA patients before and after treatment with tafamidis through a native electrophoretic method. Methods Plasma samples from 6 male patients with ATTRwt amyloidosis (median age 82 years, IQR 80-83), collected before (T0) and during tafamidis treatment, and from 6 healthy controls were collected. Plasma samples were separated on a native 4–20% Tris-Gly polyacrylamide gel. Western blot analysis was performed with anti-TTR or anti-retinol-binding protein (RBP) antibodies. Proteins were detected by Clarity ECL substrate. Results Circulating TTR forms were qualitatively similar between ATTRwt-CA patients at T0 and controls. In both groups, the most represented forms were TTR dimers or trimers (∼37-50 kDa), TTR tetramers complexed with RBP in 1:1 ratio (∼80 kDa) or 1:2 ratio (∼100 kDa), and high molecular weight (MW) aggregates (>150 kDa). Neither TTR monomers nor tetramers could be detected. RBP protein was detectable in association with TTR tetramers and some of the higher MW fractions (∼150 kDa, >250 kDa). Following tafamidis treatment, all ATTRwt-CA patients displayed a progressive increase of the intensity of the band corresponding to TTR-RBP complexes, in agreement with the a stabilizing action on TTR tetramers. Interestingly, dimers and trimers, detectable at T0, were progressively lost during tafamidis treatment. Conclusions TTR tetramer exists only complexed with RBP and in equilibrium with low and high MW forms, without apparent qualitative differences between ATTR-CA and healthy controls. Tafamidis increases circulating TTR tetramers complexed with RBP. Evaluation of TTR isoform may prove useful as a circulating biomarker for the assessment of response to treatment in patients with ATTRwt-CA.

Background Takotsubo syndrome (TTS) is characterized by an acute and transient left ventricular dysfunction, usually involving the apical and midventricular segments, associated with troponin elevation and often triggered by either emotional or physical stressors. Once considered a benign condition, it is now clear that TTS patients have increased long-term mortality compared with the general population. Prevalence and the determinants of long-term cardiac symptoms in TTS patients have been scarcely investigated. Methods We enrolled consecutive patients admitted to our Centre with a diagnosis of TTS . All patients underwent invasive coronary angiography with left ventriculography at admission and only those fulfilling both the Mayo Clinic and Heart Failure Association criteria for a TTS diagnosis were selected for this study. Clinical, biochemical, and instrumental data were collected at admission and before discharge, and patients were followed-up for: symptoms recurrence (i.e., presence of effort angina and/or dyspnoea in the absence of other obvious causes) and all-cause mortality. The prevalence of long-term symptoms was further compared with a control group of unselected patients admitted for acute coronary syndromes (ACS) in the same period, matched for sex, age, and left ventricular ejection fraction (LVEF) at discharge. Results We eventually enrolled 118 patients (aged 73±10 years, 91% of whom were female). Acute chest pain was the most common presenting symptom (73%), followed by dyspnoea (32%), acute heart failure (16%), cardiogenic shock (9%), and syncope (8%). Most of cases (82%) were classified as having a typical (apical) LV dysfunction. Either a physical or an emotional stressor was identified in 37 (31%) and 31 (26%) of the patients, respectively. At admission, patients showed moderate systolic dysfunction (LVEF 40±9%), which was often improved at discharge (LVEF 52±8%). Over a median follow-up of 21 (interquartile interval 11-53) months, 35% of patients complained of some cardiac symptom: 32% of patients complained of effort dyspnoea and 7% (partially overlapping with the former) complained of effort angina. When compared with ACS patients (n=55, aged 71±10 years, 94% women, LVEF 53±9%), TTS patients featured a similar mortality rate, a lower (non-significant) prevalence of angina, and a significantly higher prevalence of dyspnoea (p=0.02). Notably, while a lower age at presentation (p=0.017) and a physical trigger (p=0.015) were significantly associated with the risk of recurrent angina, the absence of chest pain (p=0.044), a lower LVEF at admission (p=0.019), and a higher troponin T concentration at discharge (p=0.018) were associated with the presence of dyspnoea at follow-up. Finally, older age, male sex, renal dysfunction, cardiogenic shock, and concomitant coronary artery disease were all associated with a higher risk of death. Prescription of ACE-inhibitors and/or beta-blockers were associated with reduced risk (p Conclusion TTS is associated with a high risk of recurrent cardiac symptoms, mostly dyspnoea, over time. Selected clinical, biochemical, and instrumental characteristics may help identify patients more at risk, who may deserve a closer follow-up and potentially tailored therapies, to be investigated in future studies.

Background and aims Becker muscular dystrophy (BMD) is a X-linked recessive inherited skeletal myopathy due to dystrophin deficiency ensuing in a variable phenotype characterized by slowly progressing muscle weakness and, often, the development of dilated cardiomyopathy. The relationship between muscle and cardiac involvement in BMD is yet to be clarified. We aimed to assess the association between ergoreflex sensitivity, a marker of skeletal muscle work regulating ventilatory and autonomic responses to exercise, and cardio-muscular involvement in BMD. Methods Fifteen male BMD patients (median age 37 years [25-42]) underwent a comprehensive evaluation including ECG, biohumoral assessment (high sensitivity troponin T/I [hs-TnT/I], natriuretic peptides, soluble suppression of tumorigenesis 2 [sST2], catecholamines, creatine phosphokinase [CPK], myoglobin), cardiac magnetic resonance (CMR), and ergoreflex determination. Muscular phenotype was distinguished into “classic” (proximal weakness affecting the shoulders and pelvis with waddling gait) or “mild”. Cardiac involvement was defined based on the presence of late gadolinium enhancement (LGE) at CMR. Ergoreflex sensitivity was calculated as the percentage of the ventilatory response to a handgrip exercise maintained by circulatory occlusion through the inflation of a forearm tourniquet (clamp) during the third minute of recovery compared with the third minute of recovery without clamp: [(Rec∕Ex) clamp − (Rec∕Ex) no clamp]∗100, where Ex is the mean ventilation during the last 30 s of exercise, Rec the mean ventilation during the last 30 s of the third minute of recovery. Results Ten patients (67%) had a “classic” muscular phenotype. Nine patients (60%) had LGE at CMR (median number of segments 9 [6-12]). The percentage of patients with cardiac involvement was not different between those with “classic” or mild muscular phenotype. Patients with cardiac involvement had higher ergoreflex sensitivity (24% [8-38] vs. 4% [0-24], p=0.036), hs-TnI (9.8 ng/L [5.9-14.5] vs. 2.1 ng/L [1.7-4.5], p=0.018), and hs-TnT (24 ng/L [20-35] vs. 11 ng/L [5-20], p=0.012), but did not show significant differences in terms of cardiac chamber size or systolic function compared to those without LGE. Ergoreflex sensitivity correlated with biomarkers of both cardiac (hs-TnI, rho=0.654, p=0.008; hs-TnT, rho=0.529, p=0.043; sST2, rho=0.654, p=0.009) and muscular damage (CPK, rho=0.645, p=0.009), as well as with the number of LGE segments (rho=0.583, p=0.022). No difference in ergoreflex sensitivity was detected in patients with “classic” versus mild muscular phenotype. Conclusions In BMD, there is no relationship between cardiac involvement and the muscular phenotype. Nonetheless, cardiac involvement in BMD is characterized by enhanced ergoreflex sensitivity, which is associated with biomarkers of both cardiac and muscular damage.

Aims To evaluate the predictive value of echo-derived hemodynamic forces (HDF) compared to other echocardiographic, biohumoral and cardiopulmonary parameters on: a) angiotensin receptor-neprilysin inhibition (ARNI) response to 6-months treatment; b) cardiovascular events at follow-up. Methods Eighty-nine consecutive patients with heart failure with reduced ejection fraction (HFrEF) performed clinical, laboratory, ultrasound, and cardiopulmonary exercise testing. Patients experiencing no adverse events and showing ≥50% reduction in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and/or ≥10% increase in left ventricle ejection fraction over 6 months were considered responders to ARNI. We conducted a clinical follow-up for the composite endpoint of HF-related hospitalization, new-onset atrial fibrillation and cardiovascular death. Results Out of 89 patients, 45 (51%) were ARNI-responders. Among several variables evaluated at baseline, only the whole cardiac cycle left ventricle strength (wLVS) calculated from HDF was found to be higher in responders (4.4±1.3 vs 3.6±1.2; p=0.01) and the only independent predictor of ARNI-response at multivariate logistic regression analysis (odds ratio 1.36; 95% confidence interval 1.10–1.67; p=0.004), with good accuracy at receiver operating characteristic (ROC) analysis (optimal cut-off ≥3.7%; area under the curve [AUC]=0.736, 0.607–0.840; p Conclusions HDF analysis helps in predicting ARNI-response and optimizing follow-up and medical/device decision-making in patients with HFrEF.

Background Individual randomized controlled trials (RCTs) enrolling patients with venous thromboembolism (VTE) have demonstrated that novel oral anticoagulants (NOACs) are comparable to vitamin K antagonists (VKAs) in reducing the risk of recurrent VTE but hold a safer bleeding profile. Nonetheless, pooled data from RCTs on the safety of NOACs versus VKAs in patients with VTE are still scarce. Purpose We aimed to compare the effect of NOACs versus VKA on the risk of fatal bleeding, major bleeding, clinically relevant non-major bleeding (CRNMB) and any bleeding in patients with VTE through a meta-analysis of RCTs. Methods We performed a systematic review of the literature, from January 1970 to December 2021, using PubMed database with four independent reviewers (L.R.; G.M.; V.C.; F.G.). Discrepancies were solved by consensus with a senior researcher (D.M.). Phase 3 randomized controlled trials comparing NOACs versus VKAs, either as an acute treatment or as an extended therapy, in patients with pulmonary embolism or deep vein thrombosis were selected. We performed a meta-analysis using a random-effects model with the Mantel–Haenszel method for each safety endpoint. Study outcomes were expressed as odd ratios (OR) with 95% confidence interval (CI) and illustrated in a Forest plot diagram. A two-sided p-value Results Seven trials were included (n=29,879 patients), either investigating the direct thrombin inhibitor dabigatran (RE-COVER, RE-COVER II and RESONATE trials) or the factor Xa inhibitors rivaroxaban (EINSTEIN-DVT and EINSTEIN-PE studies), apixaban (AMPLIFY study) and edoxaban (Hokusai-VTE study). Compared to VKAs, treatment with NOACs was associated with lower risk of fatal bleeding (OR 0.35; 95% CI 0.16-0.81), major bleeding (OR 0.60; 95% CI 0.45-0.80), and any bleeding (OR 0.62; 95% CI 0.54-0.72) - fig. 1. There was no significant difference between the two groups concerning the risk of CRNMB. Conclusions In patients with VTE, treatment with NOACs was associated with fewer bleeding complications compared with VKAs.

For decades, cardiologists have largely underestimated the role of the right heart in heart failure due to left heart disease. Nowadays, the importance of evaluating right ventricular (RV) structure and function in left heart failure is well documented and this concept has been emphasized in the most recent heart failure guidelines. However, several relevant questions remain unanswered such as the following: (a) which imaging technique (standard or 3D echocardiography or strain imaging or cardiac magnetic resonance) and, more, which parameters should be used to grade the severity of RV dysfunction? (b) do less widespread and less applied diagnostic tools such as cardiopulmonary stress testing and bioelectrical impedance analysis play a role in this field? (c) are there specific biochemical aspects of RV failure? (d) why notion of pathophysiology of heart and lung interaction are so well appreciated at an academic level but are not applied in the clinical setting? The present review has been prepared by the Heart Failure (HF) working group of the Italian Society of Cardiology and its main objective is to improve our understanding on RV dysfunction in heart failure.

Cardiac fibrosis is characterized by the deposition of extracellular matrix proteins in the spaces between cardiomyocytes following both acute and chronic tissue damage events, resulting in the remodeling and stiffening of heart tissue. Fibrosis plays an important role in the pathogenesis of many cardiovascular disorders, including heart failure and myocardial infarction. Several studies have identified fibroblasts, which are induced to differentiate into myofibroblasts in response to various types of damage, as the most important cell types involved in the fibrotic process. Some drugs, such as inhibitors of the renin–angiotensin–aldosterone system, have been shown to be effective in reducing cardiac fibrosis. There are currently no drugs with primarily anti-fibrotic action approved for clinical use, as well as the evidence of a clinical efficacy of these drugs is extremely limited, despite the numerous encouraging results from experimental studies. A new approach is represented by the use of CAR-T cells engineered in vivo using lipid nanoparticles containing mRNA coding for a receptor directed against the FAP protein, expressed by cardiac myofibroblasts. This strategy has proved to be safe and effective in reducing myocardial fibrosis and improving cardiac function in mouse models of cardiac fibrosis. Clinical studies are required to test this novel approach in humans.

Background Cardiac amyloidosis (CA) may affect all cardiac structures, including the valves. Methods 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. Results 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. Conclusions Patients with ATTR-CA have a prominent impairment of mitral valve structure and function, and higher score values. The valve score is quite effective in identifying patients with ATTR-CA among patients with CA or unexplained hypertrophy. Funding Acknowledgement Type of funding sources: None.

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre-determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with -omics-based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved. © 2022 European Society of Cardiology.

Cardiac amyloidosis (CA) is now recognized as an important cause of heart failure. Increased wall thickness and diastolic dysfunction of the left ventricle are the most easily detectable manifestations of CA, but amyloid accumulates in all cardiac structures. Involvement of the left and right atria may be due to the haemodynamic effects of ventricular diastolic dysfunction, the effects of amyloid infiltration into the atrial wall, and the cardiotoxic damage of atrial cardiomyocytes by amyloid precursors. Atrial amyloidosis is an early manifestation of CA, and is associated with an increased risk of atrial fibrillation and thromboembolic events. Furthermore, atrial amyloidosis can be found even in the absence of systemic disease and ventricular involvement. This condition is named isolated atrial amyloidosis and is due to a local overproduction of atrial natriuretic peptide. In this review we summarize the evidence on the mechanisms and clinical relevance of atrial amyloidosis.

Currently adopted diagnostic flow charts consider transthyretin and light-chain cardiac amyloidosis as mutually exclusive. Here, we report for the first time, to our knowledge, the demonstration of a biopsy-proven dual pathology in an 80-year-old man with sequential development of both wild-type transthyretin amyloidosis and light-chain cardiac amyloidosis cardiomyopathy over a 3-year timespan. (Level of Difficulty: Intermediate.), Graphical abstract

Since the introduction of anthracyclines into clinical practice in the 1960s, chemotherapy has always been associated with cardiotoxicity. Patients on cardiotoxic drugs can develop a wide range of cardiovascular diseases, including left ventricular (LV) systolic dysfunction and heart failure (HF), arrhythmias, hypertension, and coronary artery disease (CAD). The rising number of cancer patients, population ageing, and the frequent overlap of cardiovascular and oncological diseases have highlighted the importance of close collaboration between cardiologists and oncologists. As a result, in 1995, cardiologists at the IEO (European Institute of Oncology) coined the term cardioncology, a new discipline focused on the dynamics of cardiovascular disease in cancer patients. Given the complex scenario characterized by a constant dialogue between the oncological condition and cardiovascular comorbidity, it is essential for the clinician to get the knowledge to properly fulfill the needs of the oncological patient under cardiotoxic treatment. Through the answer to 10 questions, we aim to describe the complex issue of cardiotoxicity by addressing the main critical points and current evidence related to the assessment, management, treatment, and surveillance of cancer patients under chemotherapy.

AimsTo investigate the prognostic significance of heterogeneity in the refractoriness of right ventricular (RV) outflow tract (RVOT) and RV apex at the electrophysiological study (EPS) in Brugada syndrome (BrS).Methods and resultsA cohort of BrS patients (primary prevention) from five Italian centres was retrospectively analysed. Patients with spontaneous or drug-induced Type-1 electrocardiogram (ECG) + symptoms were offered an EPS for prognostic stratification. The primary endpoint was a composite of sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate intervention by the implantable cardioverter-defibrillator (ICD). Three hundred and seventy-two patients with BrS were evaluated (44 ± 15 years, 69% males, 23% with ICD): 4 SCDs and 17 ICD interventions occurred at follow-up (median 48, interquartile range: 36–60 months). Family history of SCD, syncope, and a spontaneous Type-1 ECG pattern were univariate predictors of the primary endpoint in the whole population. In patients undergoing EPS (n = 198, 53%, 44 ± 12 years, 71% males, 39% with ICD), 3 SCD and 15 ICD interventions occurred at follow-up. In this subset, the primary endpoint was not only predicted by ventricular tachycardia/fibrillation inducibility but also by a difference in the refractory period between RVOT and RV apex (ΔRPRVOT-apex) >60 ms. ΔRPRVOT-apex > 60 ms remained an independent predictor of SCD/ICD shock at bivariate analysis, even when adjusted for the other univariate predictors, showing the highest predictive power at C-statistic analysis (0.75, 95% confidence interval 0.63–0.86).ConclusionsHeterogeneity of RV refractory periods is a strong, independent predictor of life-threatening arrhythmias in BrS patients, beyond VT/VF inducibility at EPS and common clinical predictors.

Background Fibroblast growth factor-23 (FGF23) has been associated to left ventricular (LV) hypertrophy and heart failure (HF) severity. We aimed to investigate clinical correlates and prognostic value of intact FGF23 (iFGF23) in HF patients.Methods Patients with systolic HF (left ventricular ejection fraction - LVEFResults We enrolled 150 patients (82% males; median age 65 years). First, second, and third iFGF23 tertiles were 50.9 pg/mL. Patients in the upper iFGF23 tertile had lower LVEF (p=0.014), higher NT-proBNP (p=0.001), and lower peak VO2 (pConclusions Circulating iFGF23 is associated with renal dysfunction, disease severity and outcome in systolic HF.

Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional stress–related death where forensic examination attributed myocardial infarction to a coronary spasm, with the ultimate cause of death being arrhythmias in 4 cases and cardiac rupture in the fifth. (Level of Difficulty: Beginner.), Graphical abstract, Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional…

The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)–GMP–phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.

In non-ischaemic dilated cardiomyopathy (NIDCM), it is uncertain which late gadolinium enhancement (LGE) pattern, extent and location predict ventricular arrhythmias.We analysed 183 NIDCM patients (73% men, median age 66 years) receiving an implantable cardioverter defibrillator (ICD) for primary prevention, undergoing cardiac magnetic resonance within 1 month before implantation. The primary endpoint was appropriate ICD shock, the secondary endpoint was a composite of appropriate ICD shock and cardiac death.LGE was found in 116 patients (63%), accounting for 9% of LV mass (5-13%). Over a 30-month follow-up (10-65), 20 patients (11%) experienced the primary and 30 patients (16%) the secondary endpoint. LGE presence, inferior wall LGE, diffuse (≥2 wall) LGE, the number of segments with LGE, the number of segments with 50-75% transmural LGE, and percent LGE mass were univariate predictors of both endpoints. Also septal LGE predicted the primary, and lateral LGE predicted the secondary endpoint. LGE limited to right ventricular insertion points did not predict any endpoint. Percent LGE mass had an area under the curve of 0.734 for the primary endpoint, with 13% as the best cut-off (55% sensitivity, 86% specificity, 32% PPV, 94% NPV), conferring a 7-fold higher risk compared to patients with no LGE or LGE13%. Survival free from both endpoints was significantly worse for patients with LGE ≥13%.In patients with NIDCM receiving a defibrillator for primary prevention, LGE presence and extent predicted appropriate ICD shock and cardiac mortality; also specific LGE patterns and locations predicted a worse prognosis.

Negative T waves in the inferior leads in an asymptomatic 17-year-old female patient prompted a diagnostic evaluation disclosing the presence of multiple cardiac glomangiomas. The combination of different imaging modalities (echocardiography, magnetic resonance, and positron emission tomography/computed tomography) and myocardial biopsy was crucial to establishing the correct diagnosis. (Level of Difficulty: Advanced.), Graphical abstract, Negative T waves in the inferior leads in an asymptomatic 17-year-old female patient prompted a diagnostic evaluation disclosing the presence of…