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IMPORTANCE: Tafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized. OBJECTIVE: To examine the effect of tafamidis on cardiac function in patients with ATTR-CM. DESIGN, SETTING, AND PARTICIPANTS: This was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023. INTERVENTION: Patients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months. MAIN OUTCOMES AND MEASURES: Patients were categorized based on left ventricular (LV) ejection fraction at enrollment as having heart failure with preserved ejection fraction (≥50%), mildly reduced ejection fraction (41% to 49%), or reduced ejection fraction (≤40%). Changes from baseline to month 30 in LV ejection fraction, LV stroke volume, LV global longitudinal strain, and the ratio of early mitral inflow velocity to septal and lateral early diastolic mitral annular velocity (E/e′) were compared in patients receiving tafamidis, 80 mg, vs placebo. RESULTS: A total of 441 patients were randomized in ATTR-ACT, and 436 patients had available echocardiographic data. Of 436 included patients, 393 (90.1%) were male, and the mean (SD) age was 74 (7) years. A total of 220 (50.5%), 119 (27.3%), and 97 (22.2%) had heart failure with preserved, mildly reduced, and reduced LV ejection fraction, respectively. Over 30 months, there was less pronounced worsening in 4 of the echocardiographic measures in patients receiving tafamidis, 80 mg (n = 176), vs placebo (n = 177) (least squares mean difference: LV stroke volume, 7.02 mL; 95% CI, 2.55-11.49; P = .002; LV global longitudinal strain, −1.02%; 95% CI, −1.73 to −0.31; P = .005; septal E/e′, −3.11; 95% CI, −5.50 to −0.72; P = .01; lateral E/e′, −2.35; 95% CI, −4.01 to −0.69; P = .006). CONCLUSIONS AND RELEVANCE: Compared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function over 30 months in patients with ATTR-CM. Approximately half of patients had mildly reduced or reduced LV ejection fraction at enrollment, suggesting that ATTR-CM should be considered as a possible diagnosis in patients with heart failure regardless of underlying LV ejection fraction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01994889

During acute pulmonary embolism (PE) a compensatory increase in right ventricular (RV) contractility is required to match increased afterload to maintain right ventricular-pulmonary arterial (RV-PA) coupling. The aim of this study was to assess the prognostic utility of RV-PA decoupling in acute PE. We assessed the association between measures of transthoracic echocardiography (TTE)-derived RV-PA coupling including tricuspid annular plane systolic excursion (TAPSE)/right ventricular systolic pressure (RVSP) and right ventricular fractional area change (FAC)/RVSP as well as stroke volume index (SVI)/RVSP (a measure of pulmonary artery capacitance) with adverse PE-related events (in-hospital PE-related mortality or cardiopulmonary decompensation) using logistic regression analysis. In 820 normotensive patients TTE-derived markers of RV-PA coupling were associated with PE-related adverse events. For each 0.1 mm/mmHg decrease in TAPSE/RVSP the odds of an adverse event increased by 2.5-fold [adjusted OR (aOR) 2.49, 95% confidence interval (CI) 1.46–4.24, p = 0.001], for every 0.1%/mmHg decrease in FAC/RVSP the odds of an adverse event increased by 1.4-fold (aOR 1.42, CI 1.09–1.86, p = 0.010), and for every 0.1 mL/mmHg m2decrease in SVI/RVSP the odds of an event increased by 2.75-fold (aOR 2.78, CI 1.72–4.50, p < 0.001). In multivariable analysis, TAPSE/RVSP and SVI/RVSP were independent of other risk stratification methods including computed tomography-derived right ventricular dysfunction (RVD), the Bova score, and subjective assessment of TTE-derived RVD. In patients with normotensive acute PE, TTE-derived measures of RV-PA coupling are associated with adverse in-hospital PE-related events and provide incremental value in the risk assessment beyond computed tomography-derived RVD, the Bova score, or subjective TTE-derived RVD.

3-Dimensional (3D) myocardial deformation analysis (3D-MDA) enables novel descriptions of geometry-independent principal strain (PS). Applied to routine 2D cine cardiovascular magnetic resonance (CMR), this provides unique measures of myocardial biomechanics for disease diagnosis and prognostication. However, healthy reference values remain undefined. This study describes age- and sex-stratified reference values from CMR-based 3D-MDA, including 3D PS. One hundred healthy volunteers were prospectively recruited following institutional ethics approval and underwent CMR imaging. 3D-MDA was performed using validated software. Age- and sex-stratified global and segmental strain measures were derived for conventional geometry-dependent [circumferential (CS), longitudinal (LS), and radial (RS)] and geometry-independent [minimum (minPS) and maximum principal (maxPS)] directions of deformation. Layer-specific contraction angle interactions were determined using local minPS vectors. The average age was 43 ± 15 years and 55% were women. Strain measures were higher in women versus men. 3D PS-based assessment of maximum tissue shortening (minPS) and maximum tissue thickening (maxPS) were greater than corresponding geometry-dependent markers of LS and RS, consistent with improved representation of local tissue deformations. Global maxPS amplitude best discriminated both age and sex. Segmental analyses showed greater strain amplitudes in apical segments. Transmural PS contraction angles were higher in females and showed a heterogeneous distribution across segments. In this study we provided age and sex-based reference values for 3D strain from CMR imaging, demonstrating improved capacity for 3D PS to document maximal local tissue deformations and to discriminate age and sex phenotypes. Novel markers of layer-specific strain angles from 3D PS were also described.

The clinical utility of transthoracic echocardiography with contrast (TTE-C) for detection of right-to-left shunt (RLS) remains unknown. In this meta-analysis we evaluated the accuracy of TTE-C for RLS diagnosis compared with transesophageal echocardiography (TEE) as the reference standard.

ABSTRACT:Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

ABSTRACT:Background:Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain.Methods:This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls.Results:Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III–IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III–IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I–II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9–29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient.Conclusions:Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.

Cardiac allograft vasculopathy (CAV) is an important adverse prognostic factor for pediatric heart transplant (HT) recipients. Invasive coronary angiography (ICA) is the gold standard for CAV detection but lacks sensitivity for early microvascular changes and cumulative radiation exposure is of concern. Real-time myocardial contrast echocardiography (RTMCE) using ultrasound enhancing (contrast) agents performed during dobutamine stress echocardiography (DSE) can assess myocardial function, perfusion, and microvascular integrity. The objective of this study was to determine the safety and feasibility of RTMCE during DSE to detect CAV in a pediatric HT population.

Cardiac amyloidosis is an emerging and important cause of heart failure, arrhythmia, and other cardiovascular disease in Canada. In this context, many centres have expressed interest in the development of effective care pathways for screening, evaluating, and treating this rapidly growing patient population. In October 2019, a group of Canadian stakeholders met, including specialists in cardiac amyloidosis, experts in heart failure and chronic disease management, and academic and community-based cardiologists at various stages of cardiac amyloidosis clinic development. Objectives of the meetings included discussion of existing care pathways, consideration of barriers to program development, and achieving a consensus on essential and desirable components of a best-practice cardiac amyloidosis program. Topics discussed included optimal settings for cardiac amyloidosis clinics and integration with other specialty clinics, funding limitations that act as barriers to program development and potential solutions to these barriers, the roles of the multidisciplinary team and specialist physicians in amyloidosis care, and diagnostic pathways and strategies for the identification of patients with cardiac amyloidosis. In this report, we summarize the discussion points and key recommendations for the development of a cardiac amyloidosis clinic that emerged from this meeting, focused on program integration and care coordination, human resource elements, access to care, and quality improvement and outcome measures in cardiac amyloidosis.

There remains uncertainty in the optimal prognostication and management of patients with intermediate-risk pulmonary embolism (PE). Transthoracic echocardiography can identify right ventricular dysfunction to recognize intermediate–high-risk patients.

Right heart function is an important prognostic determinant in cardiac amyloidosis. In this study we characterized serial changes in right and left heart function and evaluated their prognostic significance.

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

Multi-phase Computed Tomography Angiography (mpCTA) is routinely performed prior to transcatheter aortic valve replacement (TAVR) to determine eligibility and enable pre-procedural planning. Incremental prognostic value may be realized from full-cycle, multi-phase reconstructions to assess the contractile health of cardiac chambers. This study aimed to assess the feasibility of 4D chamber modelling of the left ventricle (LV) to support 3D minimum principal strain (3DminPS) based predictions of clinical outcomes following TAVR.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic “red flags” that can assist in its diagnosis among the wider population of patients with heart failure.

Pulmonary arterial hypertension (PAH) can cause maladaptive right ventricular (RV) functional changes associated with adverse prognosis that are challenging to accurately quantify noninvasively. The aim of this study was to explore principal strain (PS) with contraction angle analysis using three-dimensional echocardiography to characterize RV deformation changes in patients with PAH.

The diagnosis of cardiac amyloidosis can be challenging because it is regarded as a rare disease, frequently presents with nonspecific signs and symptoms, and there are a variety of diagnostic tests available. Approaches for the evaluation of patients with suspected cardiac amyloidosis have improved dramatically in recent years. The initial workup is similar to all patients with heart failure, and certain findings on routine investigations may heighten the index of suspicion. Laboratory testing to screen for light chain (AL) amyloidosis must be performed in all patients, prompting further hematologic assessment if abnormalities are identified. Nuclear scintigraphy with bone-seeking radiotracer has emerged as an effective technique for diagnosing cardiac transthyretin amyloidosis (ATTR) noninvasively. Patients with ATTR cardiac amyloidosis should be referred for genetic testing to confirm or exclude a transthyretin gene mutation. Endomyocardial biopsy remains the diagnostic gold standard and should be performed if the evaluation yields equivocal or discordant findings; however, this is becoming necessary less often, owing to the improved diagnostic yield of noninvasive cardiac imaging modalities. As a result, patients may be diagnosed at earlier stages of disease, potentially improving their likelihood of response to therapy and overall prognosis.

Recent developments in cardiac amyloidosis have raised awareness of the disease and have advanced diagnostic and treatment strategies. Novel therapies may vastly improve the prognosis of the disease but will be associated with significant costs. Data are needed to inform clinical decisions and to drive resource allocation within the health care system. Many aspects of disease management are unlikely to be addressed by clinical trials and are better suited to nonrandomized cohort studies, but the limited numbers of patients in any single centre present barriers to high-quality observational research. Disease registries offer opportunities to assemble large numbers of patients from multiple institutions for adequately powered observational studies, to recruit patients for randomized clinical trials; to provide real-world effectiveness and safety data, to study cost-effectiveness of novel therapies, and to engage patients in the collection of patient-reported outcome data. Existing amyloidosis registries have limitations. Canada is an ideal setting for a national amyloidosis registry, with ethnic diversity, relatively few academic centres, access to advanced diagnostic and therapeutic options, and a track record of collaboration among institutions. The Canadian Registry for Amyloidosis Research aims to capitalize on this opportunity and provide high-quality data to inform clinical practice and health care policy in Canada and beyond.

Right ventricular (RV) strain imaging using speckle-tracking echocardiography (STE) is a quantitative method of assessing RV systolic function that has shown prognostic utility in patients with pulmonary hypertension (PH). However, its prognostic value for a large and mixed PH population remains poorly defined.

A 54-year-old man with the lysosomal storage disorder Anderson-Fabry disease (AFD) and cardiac involvement was placed on amiodarone for treatment of symptomatic paroxysmal atrial fibrillation. Shortly thereafter, he developed symptoms of acute decompensated heart failure, requiring hospital admission. Endomyocardial biopsy demonstrated findings consistent with AFD and possible amiodarone toxicity. Amiodarone was discontinued, and the patient’s heart failure resolved with return to baseline status. Amiodarone is known to alter lysosomal pH and enzyme activity, and this case illustrates how it should be used with considerable caution in patients with AFD.

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review.The overview summarizes the growing body of data regarding the use of mammalian target of rapamycin inhibitors in cardiothoracic transplantation. The beneficial effects on acute rejection, renal function and cardiac vasculopathy should be balanced against the adverse events and the increasing complexity of the recipients.

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

Introduction:The respective value of different late gadolinium enhancement (LGE) phenotypes in patients with suspected infiltrative cardiomyopathy remains uncertain.Methods:In a large cohort of patients referred for suspected infiltrative cardiomyopathy, we evaluated respective associations between the dominant LGE phenotype and the composite endpoint of heart failure hospitalization, survived cardiac arrest or death. Kaplan-Meier survival curves were executed for six pre-defined LGE phenotypes. Multivariable analysis was performed to assess their independent association with the composite outcome, adjusted for relevant confounders. Final diagnosis was adjudicated using standardized disease-specific criteria.Results:588 patients (68% male, median age 70 years, mean LVEF 54.7±12.7%) were studied. Of these patients, 139 (24%) were confirmed to have cardiac amyloidosis (CA) (81 [58%] transthyretin, 54 [39%] light chain and 4 [3%] undifferentiated) by objective non-CMR diagnostic criteria. Any LGE was present in 394 patients (67%) with the dominant phenotype being diffuse in 137 (23%), mid-wall patchy in 118 (20%), ischemic in 55 (9.4%), subepicardial in 18 (3.1%), mid-wall striae in 8 (1.4%), and RV insertion site in 58 (9.9%). The sensitivity and specificity of diffuse LGE for CA was 86% and 96%, respectively. Over a median 855 (IQR 372, 1542) days, 239 (41%) experienced the primary outcome. Unadjusted survival curves for each LGE phenotype are shown in the Figure. Following adjustment, diffuse (HR 2.30, p<0.001), mid-wall patchy (HR 1.52, p=0.040) and ischemic LGE (HR 1.78, p=0.023) remained independently associated (Figure).Conclusions:In patients referred for suspected infiltrative cardiomyopathy, diffuse, mid-wall patchy and ischemic patterns all showed independent prognostic value. We confirm that diffuse LGE pattern reliably identifies CA patients with high sensitivity and specificity while delivering strong prognostic value.

Introduction: Multi-phase computed tomography angiography (CTA) for the pre-procedural planning of TAVR presents a unique opportunity to assess 3D myocardial biomechanics. Using a novel approach, we assessed the feasibility and predictive utility of 3D myocardial deformation analysis (3D-MDA) to deliver principal strain (PS) based markers of left ventricular (LV) health for the prediction of time to heart failure hospitalization or death following TAVR.Methods:205 patients undergoing a pre-TAVR CTA and followed clinically for >6 months were identified. Whole-heart segmentation with 3D-mesh modelling was followed by 3D-MDA of the LV. 3D global LV minimum PS (minPS) was calculated for endocardial, epicardial and transmural layers. Cox regression models were performed to evaluate associations between 3D minPS and the composite outcome of all-cause mortality or heart failure hospitalization.Results:Of 205 patients, 196 (96%) had analyzable CTA data for 3D-MDA. Median (IQR) age was 85 (79.5-88) years (55% male) with median STS-PROM score 3.10 (2.10-4.55)% and median echocardiography LVEF 60 (55.9-65.0)%. Over 25 (11-36) months 55 patients (28%) experienced all-cause death or HF hospitalization. Patients with lower 3D minPS, below -23.7%, experienced a 3-fold increased risk of the primary outcome (p<0.001). Following adjustment for baseline characteristics, inclusive of STS and LVEF, 3D minPS remained independently associated with the primary outcome: endocardial 3D minPS providing highest prognostic value [HR (95% CI) of 1.09 per 1% change (1.04-1.15), p<0.001].Conclusions:3D-MDA of pre-TAVR multi-phase CTA is feasible and delivers principal-strain based markers strongly predictive of future clinical outcomes. The potential of this approach to optimize patient selection and post-procedural management requires future evaluation in a multi-centre setting.