Guideline-Directed Medical Therapy in Patients With Heart Failure With Reduced Ejection Fraction and Incident Cancer.

BACKGROUND: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard. METHODS: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis. RESULTS: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy. CONCLUSIONS: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up.

Implementation of the Care Bundle for the Management of Chronic Obstructive Pulmonary Disease with/without Heart Failure.

Chronic obstructive pulmonary disease (COPD) is often part of a more complex cardiopulmonary disease, especially in older patients. The differential diagnosis of the acute exacerbation of COPD and/or heart failure (HF) in emergency settings is challenging due to their frequent coexistence and symptom overlap. Both conditions have a detrimental impact on each other's prognosis, leading to increased mortality rates. The timely diagnosis and treatment of COPD and coexisting factors like left ventricular overload or HF in inpatient and outpatient care can improve prognosis, quality of life, and long-term outcomes, helping to avoid exacerbations and hospitalization, which increase future exacerbation risk. This work aims to address existing gaps, providing management recommendations for COPD with/without HF, particularly when both conditions coexist. During virtual meetings, a panel of experts (the authors) discussed and reached a consensus on the differential and paired diagnosis of COPD and HF, providing suggestions for risk stratification, accurate diagnosis, and appropriate therapy for inpatients and outpatients. They emphasize that when COPD and HF are concomitant, both conditions should receive adequate treatment and that recommended HF treatments are not contraindicated in COPD and have favorable effects. Accurate diagnosis and therapy is crucial for effective treatment, reducing hospital readmissions and associated costs. The management considerations discussed in this study can potentially be extended to address other cardiopulmonary challenges frequently encountered by COPD patients.

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome. METHODS: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality. RESULTS: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P<0.001), whereas Perugini grade was not associated with survival (P=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P<0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P=0.004), National Amyloidosis Centre stage (each category, P<0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P=0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P=0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P=0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P<0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P<0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (P<0.001 and P=0.02, respectively). CONCLUSIONS: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.

Ischaemic heart disease in patients with cancer.

Cardiologists are encountering a growing number of cancer patients with ischaemic heart disease (IHD). Several factors account for the interrelationship between these two conditions, in addition to improving survival rates in the cancer population. Established cardiovascular (CV) risk factors, such as hypercholesterolaemia and obesity, predispose to both IHD and cancer, through specific mechanisms and via low-grade, systemic inflammation. This latter is also fuelled by clonal haematopoiesis of indeterminate potential. Furthermore, experimental work indicates that IHD and cancer can promote one another, and the CV or metabolic toxicity of anticancer therapies can lead to IHD. The connections between IHD and cancer are reinforced by social determinants of health, non-medical factors that modify health outcomes and comprise individual and societal domains, including economic stability, educational and healthcare access and quality, neighbourhood and built environment, and social and community context. Management of IHD in cancer patients is often challenging, due to atypical presentation, increased bleeding and ischaemic risk, and worse outcomes as compared to patients without cancer. The decision to proceed with coronary revascularization and the choice of antithrombotic therapy can be difficult, particularly in patients with chronic coronary syndromes, necessitating multidisciplinary discussion that considers both general guidelines and specific features on a case by case basis. Randomized controlled trial evidence in cancer patients is very limited and there is urgent need for more data to inform clinical practice. Therefore, coexistence of IHD and cancer raises important scientific and practical questions that call for collaborative efforts from the cardio-oncology, cardiology, and oncology communities.

Early diagnosis and management of cardiac amyloidosis: A clinical perspective.

Cardiac amyloidosis multidisciplinary team (MDT). We propose the creation of a multidisciplinary team (MDT) for cardiac amyloidosis in which internal medicine physicians could take a lead role in coordinating other specialists involved in patient care. Created with BioRender.com.

Diagnosing Fabry nephropathy: the challenge of multiple kidney disease.

Fabry disease (FD) is an X-linked inherited lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A (α-gla) due to mutations in the GLA gene. These mutations result in plasma and lysosome accumulation of glycosphingolipids, leading to progressive organ damage and reduced life expectancy. Due to the availability of specific disease-modifying treatments, proper and timely diagnosis and therapy are essential to prevent irreversible complications. However, diagnosis of FD is often delayed because of the wide clinical heterogeneity of the disease and multiple organ involvement developing in variable temporal sequences. This observation is also valid for renal involvement, which may manifest with non-specific signs, such as proteinuria and chronic kidney disease, which are also common in many other nephropathies. Moreover, an additional confounding factor is the possibility of the coexistence of FD with other kidney disorders. Thus, suspecting and diagnosing FD nephropathy in patients with signs of kidney disease may be challenging for the clinical nephrologist. Herein, also through the presentation of a unique case of co-occurrence of autosomal dominant polycystic kidney disease and FD, we review the available literature on cases of coexistence of FD and other renal diseases and discuss the implications of these conditions. Moreover, we highlight the clinical, laboratory, and histological elements that may suggest clinical suspicion and address a proper diagnosis of Fabry nephropathy.

ECG/echo indexes in the diagnostic approach to amyloid cardiomyopathy: A head-to-head comparison from the AC-TIVE study.

BACKGROUND AND AIMS: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients. METHODS: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed. RESULTS: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007). CONCLUSIONS: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted.

Incidence and determinants of atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening. METHODS: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. RESULTS: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008). CONCLUSIONS: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Electrocardiographic heterogeneity of patients with variant transthyretin amyloid cardiomyopathy: Genotype-phenotype correlations.

BACKGORUND: Hereditary transthyretin(vATTR) cardiac amyloidosis has extremely different features according to the type of transthyretin(TTR) mutation. Data about electrocardiographic findings(ECG) in vATTR are limited and not informative of genotype correlation. Aim of this study is to analyze ECG characteristics and their correlation to clinical and echocardiographic aspects in patients with vATTR, focusing on different TTR mutations. METHODS AND RESULTS: This is a multicentric, retrospective, observational study performed in six Italian referral centres. We divided patients in two groups, according to the previously described phenotypic manifestations of the TTR mutation. Of 64 patients with vATTR, 23(36%) had prevalent cardiac(PC) TTR mutations and 41(64%) patients had a prevalent neurological(PN) TTR mutations. Patients with PC mutations were more frequently males and older, with advanced NAC staging. At baseline ECG, atrial fibrillation was more common in patients with PC, while pacemaker induced rhythm in PN mutations. PQ and QRS durations were longer and voltage to mass ratio was lower in PC mutations. Different TTR mutations tend to have distinctive ECG features. CONCLUSIONS: ECG in vATTR is extremely heterogeneous and the specific mutations are associated with distinct instrumental and clinical features. The differences between PN and PC vATTR are only partially explained by the different degree of cardiac infiltration.

Temporal trends in evidence supporting therapeutic interventions in heart failure and other European Society of Cardiology guidelines.

AIMS: This study aimed to determine whether any change occurred over time in level of evidence (LoE) of therapeutic interventions supporting heart failure (HF) and other European Society of Cardiology guideline recommendations. METHODS AND RESULTS: We selected topics with at least three documents released between 2008 and April 2022. Classes of recommendations (CoR) and supporting LoE related to therapeutic interventions within each document were collected and compared over time. A total of 1822 recommendations from 18 documents on 6 topics [median number per document = 112, 867 (48%) CoR I] were included in the analysis. There was a trend towards a reduction over time in the percentage of CoR I in HF (46-36-34%), non-ST elevation myocardial infarction (NSTEMI; 78-58-54%), and pulmonary embolism (PE; 65-50-39%) guidelines, with a decrease in the total number of recommendations for HF only. Percentage of CoR I was stable over time around 40% for valvular heart disease (VHD) and atrial fibrillation (AF), and around 60% for cardiovascular prevention (CVP), with an increase in the total number of recommendations for VHD and CVP and a decrease for AF. Among CoR I, 319 (37%) were supported by LoE A, with a decrease over time for HF (56-46-42%), an increase for NSTEMI (29-38-48%) and AF (28-31-36%), a bimodal distribution for PE and CVP, and a lack for VHD. CONCLUSIONS: LoE supporting therapeutic recommendations in contemporary European guidelines is generally low. Physicians should be aware of these limitations, and scientific societies promote a greater understanding of their significance and drive future research directions.

Diagnostic yield and predictive value on left ventricular remodelling of genetic testing in dilated cardiomyopathy.

AIMS: We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ≤40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m2 , P = 0.03) compared with patients with P/LP variants. CONCLUSIONS: Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.

Treating amyloid transthyretin cardiomyopathy: lessons learned from clinical trials.

An increasing awareness of the disease, new diagnostic tools and novel therapeutic opportunities have dramatically changed the management of patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Supportive therapies have shown limited benefits, mostly related to diuretics for the relief from signs and symptoms of congestion in patients presenting heart failure (HF). On the other hand, huge advances in specific (disease-modifying) treatments occurred in the last years. Therapies targeting the amyloidogenic cascade include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Tafamidis, a TTR stabilizer that demonstrated to prolong survival and improve quality of life in the ATTR-ACT trial, is currently the only approved drug for patients with ATTR-CM. The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen have been approved for the treatment of patients with hereditary ATTR polyneuropathy regardless of the presence of cardiac involvement, with patisiran also showing preliminary benefits on the cardiac phenotype. Ongoing phase III clinical trials are investigating another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR-CM. CRISPR-Cas9 represents a promising strategy of genome editing to obtain a highly effective blockade of TTR gene expression.

From the phenotype to precision medicine: an update on the cardiomyopathies diagnostic workflow.

Cardiomyopathies are disease of the cardiac muscle largely due to genetic alterations of proteins with 'structural' or 'functional' roles within the cardiomyocyte, going from the regulation of contraction-relaxation, metabolic and energetic processes to ionic fluxes. Modifications occurring to these proteins are responsible, in the vast majority of cases, for the phenotypic manifestations of the disease, including hypertrophic, dilated, arrhythmogenic and restrictive cardiomyopathies. Secondary nonhereditary causes to be excluded include infections, toxicity from drugs or alcohol or medications, hormonal imbalance and so on. Obtaining a phenotypic definition and an etiological diagnosis is becoming increasingly relevant and feasible, thanks to the availability of new tailored treatments and the diagnostic advancements made particularly in the field of genetics. This is, for example, the case for transthyretin cardiac amyloidosis, Fabry disease or dilated cardiomyopathies due to laminopathies. For these diseases, specific medications have been developed, and a more tailored arrhythmic risk stratification guides the implantation of a defibrillator. In addition, new medications directly targeting the altered protein responsible for the phenotype are becoming available (including the myosin inhibitors mavacantem and aficamten, monoclonal antibodies against Ras-MAPK, genetic therapies for sarcoglycanopathies), thus making a precision medicine approach less unrealistic even in the field of cardiomyopathies. For these reasons, a contemporary approach to cardiomyopathies must consider diagnostic algorithms founded on the clinical suspicion of the disease and developed towards a more precise phenotypic definition and etiological diagnosis, based on a multidisciplinary methodology putting together specialists from different disciplines, facilities for advanced imaging testing and genetic and anatomopathological competencies.

Prevalence and prognostic implications of hypertensive response to exercise in patients with hypertrophic cardiomyopathy.

Objective: Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear. Methods: In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened. Results: 347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death. Conclusion: HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise.

[Rationale and significance of the Italian Network for Cardiac Amyloidosis]. / Razionale e valore fondamentale della Rete Italiana integrata dell'Amiloidosi Cardiaca.

The perspective on amyloidosis has changed deeply over the last 10 years following major advances in diagnosis and treatment options, especially in cardiac amyloidosis. This intrinsically heterogeneous disease exposes to the risk of fragmentation of knowledge and requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, clinical management and therapeutic strategies represent essential steps to be taken. Missing or delaying the diagnosis may have dramatic impact on patient outcome, as in the case of chemotherapy in unrecognized light-chain amyloidosis. Therefore, there is an urgent need for the foundation of an Italian Amyloidosis Network to deal with the challenges of this condition and orient clinical management at national and local levels. The present consensus document aims to provide the rationale and scopes of the Italian Amyloidosis Network, which has been conceived as an organizational framework for professionals managing patients with amyloidosis.

Clinical application of CMR in cardiomyopathies: evolving concepts and techniques : A position paper of myocardial and pericardial diseases and cardiac magnetic resonance working groups of Italian society of cardiology.

Cardiac magnetic resonance (CMR) has become an essential tool for the evaluation of patients affected or at risk of developing cardiomyopathies (CMPs). In fact, CMR not only provides precise data on cardiac volumes, wall thickness, mass and systolic function but it also a non-invasive characterization of myocardial tissue, thus helping the early diagnosis and the precise phenotyping of the different CMPs, which is essential for early and individualized treatment of patients. Furthermore, several CMR characteristics, such as the presence of extensive LGE or abnormal mapping values, are emerging as prognostic markers, therefore helping to define patients' risk. Lastly new experimental CMR techniques are under investigation and might contribute to widen our knowledge in the field of CMPs. In this perspective, CMR appears an essential tool to be systematically applied in the diagnostic and prognostic work-up of CMPs in clinical practice. This review provides a deep overview of clinical applicability of standard and emerging CMR techniques in the management of CMPs.

Deformation Imaging by Strain in Chronic Heart Failure Over Sacubitril-Valsartan: A Multicenter Echocardiographic Registry.

AIMS: Sacubitril/valsartan has changed the treatment of heart failure with reduced ejection fraction (HFrEF), due to the positive effects on morbidity and mortality, partly mediated by left ventricular (LV) reverse remodelling (LVRR). The aim of this multicenter study was to identify echocardiographic predictors of LVRR after sacubitril/valsartan administration. METHODS AND RESULTS: Patients with HFrEF requiring therapy with sacubitril/valsartan from 13 Italian centres were included. Echocardiographic parameters including LV global longitudinal strain (GLS) and global peak atrial longitudinal strain by speckle tracking echocardiography were measured to find the predictors of LVRR [= LV end-systolic volume reduction ≥10% and ejection fraction (LVEF) improvement ≥10% at follow-up] at 6 month follow-up as the primary endpoint. Changes in symptoms [New York Heart Association (NYHA) class] and neurohormonal activations [N-terminal pro-brain natriuretic peptide (NT-proBNP)] were also evaluated as secondary endpoints; 341 patients (excluding patients with poor acoustic windows and missing data) were analysed (mean age: 65 ± 10 years; 18% female, median LVEF 30% [inter-quartile range: 25-34]). At 6 month follow-up, 82 (24%) patients showed early complete response (LVRR and LVEF ≥ 35%), 55 (16%) early incomplete response (LVRR and LVEF < 35%), and 204 (60%) no response (no LVRR and LVEF < 35%). Non-ischaemic aetiology, a lower left atrial volume index, and a higher GLS were all independent predictors of LVRR at multivariable logistic analysis (all P < 0.01). A baseline GLS < -9.3% was significantly associated with early response (area under the curve 0.75, P < 0.0001). Left atrial strain was the best predictor of positive changes in NYHA class and NT-proBNP (all P < 0.05). CONCLUSIONS: Speckle tracking echocardiography parameters at baseline could be useful to predict LVRR and clinical response to sacubitril-valsartan and could be used as a guide for treatment in patients with HFrEF.

Low QRS Voltages in Cardiac Amyloidosis: Clinical Correlates and Prognostic Value.

Background: Low QRS voltages (LQRSVs) are a common electrocardiographic feature in patients with light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) cardiac amyloidosis (CA). Objectives: The aim of this study was to identify clinical and echocardiographic correlates of LQRSV and to investigate their prognostic significance in patients with CA. Methods: This was a multicenter, retrospective study performed in 6 CA referral centers including consecutive patients with AL and ATTR CA. LQRSVs were defined as a QRS amplitude ≤5 mm (0.5 mV) in all peripheral leads. The study outcome was cardiovascular (CV) mortality. Results: Overall, 411 (AL CA: n = 120, ATTR CA: n = 291) patients were included. LQRSVs were present in 66 (55%) patients with AL CA and 103 (35%) with ATTR CA (P < 0.001). In AL CA, LQRSVs were independently associated with younger age (P = 0.015), higher New York Heart Association functional class (P = 0.016), and natriuretic peptides (P = 0.041); in ATTR CA, LQRSVs were independently associated with pericardial effusion (P = 0.008) and lower tricuspid annulus peak systolic excursion (P = 0.038). During a median follow-up of 33 months (Q1-Q3: 21-46), LQRSVs independently predicted CV death in both AL CA (HR: 1.76; 95% CI: 2.41-10.18; P = 0.031) and ATTR CA (HR: 2.64; 95% CI: 1.82-20.17; P = 0.005). Together with the National Amyloidosis Centre (NAC) staging, LQRSVs provided incremental prognostic value in ATTR CA (AUC for NAC model: 0.83 [95% CI: 0.77-0.89]; AUC for NAC + LQRSV model: 0.87 [95% CI: 0.81-0.93]; P = 0.040). Conclusions: LQRSVs are common but not ubiquitous in CA; they are more frequent in AL CA than in ATTR CA. LQRSVs reflect an advanced disease stage and independently predict CV death. In ATTR CA, LQRSVs can provide incremental prognostic accuracy over the NAC staging system in patients with intermediate risk.