The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology.

BACKGROUND: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997 and 2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials. METHODS AND RESULTS: This article describes the design and methodology of CARS, including procedures for data collection and preliminary results. As of February 2023, 20 centers in the United States enrolled 1415 patients, including 1155 (82%) with ATTR and 260 (18%) with AL CA. Among those with ATTR, wild-type is the most common ATTR (71%), and most of the 305 patients with variant ATTR have the p.V142I mutation (68%). A quarter of the total population identifies as Black. More individuals with AL are female (39%) compared to those with ATTR (13%). CONCLUSIONS: CARS will answer crucial clinical questions about CA natural history and permit comparison of different therapeutics not possible through current clinical trials. Future international collaboration will further strengthen the validity of observations of this increasingly recognized condition.

The Emerging Significance of Amyloid Deposits in the Ligamentum Flavum of Spinal Stenosis Patients: A Review.

Spinal stenosis is one of the most common neurosurgical diseases and a leading cause of pain and disability. Wild-type transthyretin amyloid (ATTRwt) has been found in the ligamentum flavum (LF) of a significant subset of patients with spinal stenosis who undergo decompression surgery. Histologic and biochemical analyses of LF specimens from spinal stenosis patients, normally discarded as waste, have the potential to help elucidate the underlying pathophysiology of spinal stenosis and possibly allow for medical treatment of stenosis and screening for other systemic diseases. In the present review, we discuss the utility of analyzing LF specimens after spinal stenosis surgery for ATTRwt deposits. Screening for ATTRwt amyloidosis cardiomyopathy through LF specimens has led to the early diagnosis and treatment of cardiac amyloidosis in several patients, with more expected to benefit from this process. Emerging evidence in the literature also point to ATTRwt as a contributor to a previously unrecognized subtype of spinal stenosis in patients who might, in the future, benefit from medical therapy. In the present report, we review the current literature regarding the early detection of ATTRwt cardiomyopathy via LF screening and the possible contribution of ATTRwt deposits in the LF to spinal stenosis development.

Emerging Therapies for Transthyretin Amyloidosis.

PURPOSE OF REVIEW: This review provides an overview of the available therapies for treating neuropathic and/or cardiac manifestations of transthyretin amyloidosis (ATTR), as well as investigational therapeutic agents in ongoing clinical trials. We discuss additional emergent approaches towards thwarting this life-threatening disease that until recently was considered virtually untreatable. RECENT FINDINGS: Advances in noninvasive diagnostic methods for detecting ATTR have facilitated easier diagnosis and detection at an earlier stage of disease when therapeutic interventions are likely to be more effective. There are now several ATTR-directed treatments that are clinically available, as well as investigational agents that are being studied in clinical trials. Therapeutic strategies include tetramer stabilization, gene silencing, and fibril disruption. ATTR has been historically underdiagnosed. With advances in diagnostic methods and the advent of disease-modifying treatments, early diagnosis and initiation of treatment is revolutionizing management of this disease.

The effect of tablet computer-based telemonitoring added to an established telephone disease management program on heart failure hospitalizations: The Specialized Primary and Networked Care in Heart Failure (SPAN-CHF) III Randomized Controlled Trial.

BACKGROUND: Mobile health applications are becoming increasingly common. Prior work has demonstrated reduced heart failure (HF) hospitalizations with HF disease management programs; however, few of these programs have used tablet computer-based technology. METHODS: Participants with a diagnosis of HF and at least 1 high risk feature for hospitalization were randomized to either an established telephone-based disease management program or the same disease management program with the addition of remote monitoring of weight, blood pressure, heart rate and symptoms via a tablet computer for 90 days. The primary endpoint was the number of days hospitalized for HF assessed at 90 days. RESULTS: From August 2014 to April 2019, 212 participants from 3 hospitals in Massachusetts were randomized 3:1 to telemonitoring-based HF disease management (n = 159) or telephone-based HF disease management (n = 53) with 98% of individuals in both study groups completing the 90 days of follow-up. There was no significant difference in the number of days hospitalized for HF between the telemonitoring disease management group (0.88 ± 3.28 days per patient-90 days) and the telephone-based disease management group (1.00 ± 2.97 days per patient-90 days); incidence rate ratio 0.82 (95% confidence interval, 0.43-1.58; P = .442). CONCLUSIONS: The addition of tablet-based telemonitoring to an established HF telephone-based disease management program did not reduce HF hospitalizations; however, study power was limited.

Automated Detection of Aortic Stenosis Using Machine Learning.

BACKGROUND: Aortic stenosis (AS) is a degenerative valve condition that is underdiagnosed and undertreated. Detection of AS using limited two-dimensional echocardiography could enable screening and improve appropriate referral and treatment of this condition. The aim of this study was to develop methods for automated detection of AS from limited imaging data sets. METHODS: Convolutional neural networks were trained, validated, and tested using limited two-dimensional transthoracic echocardiographic data sets. Networks were developed to accomplish two sequential tasks: (1) view identification and (2) study-level grade of AS. Balanced accuracy and area under the receiver operator curve (AUROC) were the performance metrics used. RESULTS: Annotated images from 577 patients were included. Neural networks were trained on data from 338 patients (average n = 10,253 labeled images), validated on 119 patients (average n = 3,505 labeled images), and performance was assessed on a test set of 120 patients (average n = 3,511 labeled images). Fully automated screening for AS was achieved with an AUROC of 0.96. Networks can distinguish no significant (no, mild, mild to moderate) AS from significant (moderate or severe) AS with an AUROC of 0.86 and between early (mild or mild to moderate AS) and significant (moderate or severe) AS with an AUROC of 0.75. External validation of these networks in a cohort of 8,502 outpatient transthoracic echocardiograms showed that screening for AS can be achieved using parasternal long-axis imaging only with an AUROC of 0.91. CONCLUSION: Fully automated detection of AS using limited two-dimensional data sets is achievable using modern neural networks. These methods lay the groundwork for a novel method for screening for AS.

Left ventricular stroke volume index following transcatheter aortic valve replacement is an early predictor of 1-year survival.

BACKGROUND: Adverse cardiac events are common following transcatheter aortic valve replacement (TAVR). Our aim was to investigate the low left ventricular stroke volume index (LVSVI) 30 days after TAVR as an early echocardiographic marker of survival. HYPOTHESIS: Steady-state (30-day) LVSVI after TAVR is associated with 1-year mortality. METHODS: A single-center retrospective analysis of all patients undergoing TAVR from 2017 to 2019. Baseline and 30-day post-TAVR echocardiographic LVSVI were calculated. Patients were stratified by pre-TAVR transaortic gradient, surgical risk, and change in transvalvular flow following TAVR. RESULTS: This analysis focuses on 238 patients treated with TAVR. The 1-year mortality rate was 9% and 124 (52%) patients had normal flow post-TAVR. Of those with pre-TAVR low flow, 67% of patients did not normalize LVSVI at 30 days. The 30-day normal flow was associated with lower 1-year mortality when compared to low flow (4% vs. 14%, p = .007). This association remained significant after adjusting for known predictors of risk (adjusted odds ratio [OR] of 3.45, 95% confidence interval: 1.02-11.63 [per 1 ml/m2 decrease], p = .046). Normalized transvalvular flow following TAVR was associated with reduced mortality (8%) when compared to those with persistent (15%) or new-onset low flow (12%) (p = .01). CONCLUSIONS: LVSVI at 30 days following TAVR is an early echocardiographic predictor of 1-year mortality and identifies patients with worse intermediate outcomes. More work is needed to understand if this short-term imaging marker might represent a novel therapeutic target.

The use of PYP scan for evaluation of ATTR cardiac amyloidosis at a tertiary medical centre.

Cardiac transthyretin amyloidosis (ATTR) is an often underdiagnosed disease that can lead to significant morbidity and mortality for patients. In recent years, technetium-99m pyrophosphate scintigraphy (PYP) imaging has become a standard of care diagnostic tool to help clinicians identify this disease. With newly emerging therapies for ATTR cardiomyopathy, it is critical to identify patients who are eligible for therapy as early as possible. At our institution, we sought to describe the frequency of PYP scanning and how it has impacted the management of a patient suspected to have amyloid cardiomyopathy. Between 1 January 2017 and 31 December 2020, we identified 273 patients who completed PYP scanning for evaluation of cardiac amyloidosis at Tufts Medical Center, a tertiary care centre. We reviewed pertinent clinical data for all study subjects. A PYP scan was considered positive when the heart to contralateral lung ratio was greater than or equal to 1.5, with a visual grade of 2 or 3, and confirmation with single-photon emission computerised tomography (SPECT) imaging. In total there were 55 positive, 202 negative, and 16 equivocal PYP scans. Endomyocardial biopsies were rarely performed following PYP results. Of the seven patients with a positive PYP scan who underwent biopsy, five were positive for ATTR amyloid; of the patients with a negative scan who were biopsied, none were positive for ATTR amyloidosis and two were positive for amyloid light-chain (AL) amyloidosis. The biomarkers troponin I, B-type naturietic peptide (BNP), and N-terminal pro-BNP (NT-proBNP), as well as the interventricular septal end-diastolic thickness (IVSd) seen on echocardiogram, were all found to be statistically higher in the PYP positive cohort than in the PYP negative cohort using Mann-Whitney U statistical analysis. In total, 27 out of the 55 patients with a positive PYP scan underwent therapy specific for cardiac amyloid. In conclusion, this study reinforces the clinical significance of the PYP scan in the diagnosis and management of cardiac amyloidosis. A positive scan allowed physicians to implement early amyloid-directed treatment while a negative scan encouraged physicians to pursue an alternative diagnosis.

Analysis of lumbar spine stenosis specimens for identification of amyloid.

BACKGROUND: Lumbar spinal stenosis (LSS) is a common reason for spine surgery in which ligamentum flavum is resected. Transthyretin (TTR) amyloid is an often unrecognized and potentially modifiable mechanism for LSS that can also cause TTR cardiac amyloidosis. Accordingly, older adult patients undergoing lumbar spine (LS) surgery were evaluated for amyloid and if present, the precursor protein, as well as comprehensive characterization of the clinical phenotype. METHODS: A prospective, cohort study in 2 academic medical centers enrolled 47 subjects (age 69 ± 7 years, 53% male) undergoing clinically indicated LS decompression. The presence of amyloid was evaluated by Congo Red staining and in those with amyloid, precursor protein was determined by laser capture microdissection coupled to mass spectrometry (LCM-MS). The phenotype was assessed by disease-specific questionnaires (Swiss Spinal Stenosis Questionnaire and Kansas City Cardiomyopathy Questionnaire) and the 36-question short-form health survey, as well as biochemical measures (TTR, retinol-binding protein, and TTR stability). Cardiac testing included technetium-99m-pyrophosphate scintigraphy, electrocardiograms, echocardiograms, and cardiac biomarkers as well as measures of functional capacity. RESULTS: Amyloid was detected in 16 samples (34% of participants) and was more common in those aged ≥ 75 years of age (66.7%) compared with those <75 years (22.3%, p < 0.05). LCM-MS demonstrated TTR as the precursor protein in 62.5% of participants with amyloid while 37.5% had an indeterminant type of amyloid. Demographic, clinical, quality-of-life measures, electrocardiographic, echocardiographic, and biochemical measures did not differ between those with and without amyloid. Among those with TTR amyloid (n = 10), one subject had cardiac involvement by scintigraphy. CONCLUSIONS: Amyloid is detected in more than a third of older adults undergoing LSS. Amyloid is more common with advancing age and is particularly common in those >75 years old. No demographic, clinical, biochemical, or cardiac parameter distinguished those with and without amyloid. In more than half of subjects with LS amyloid, the precursor protein was TTR indicating the importance of pathological assessment.

Accuracy of echocardiographic estimations of right heart pressures in adult heart transplant recipients.

BACKGROUND: Accurate assessment of right atrial pressure (RAP) and pulmonary artery systolic pressure (PASP) is critical in the management of heart transplant recipients. The accuracy of echocardiography in estimating these pressures has been debated. OBJECTIVE: To assess the correlation and agreement between echocardiographic estimations of right heart pressures with those of respective invasive hemodynamic measurements by right heart catheterization (RHC) in adult heart transplant recipients. METHODS: This is a prospective evaluation of 84 unique measurements from heart transplant recipients who underwent RHC followed by standard echocardiographic evaluation within 159 ± 64 min with no intervening medication changes. The relationship between noninvasive pressure estimations and invasive hemodynamic measurements was examined. RESULTS: Mean RAP was 7 ± 5 mmHg and mean PASP was 33 ± 8 mmHg by RHC. There was no significant correlation between echocardiographic estimation of RAP and invasive RAP (Spearman's rho = -0.05, p = .7), and no significant agreement between these two variables (weighted kappa = -0.1). There was a modest correlation between echocardiographic estimation of PASP and invasive PASP (r = .39, p = .002). Bland-Altman analysis showed a mean bias of 2.1 ± 9 mmHg (limits of agreement = -15 to 20 mmHg). CONCLUSION: In heart transplant recipients, there is no significant correlation or agreement between echocardiographic RAP estimation and invasively determined RAP. Noninvasive PASP estimation correlates significantly but modestly with invasively measured PASP. Further refinement of echocardiographic methods for assessment of RAP is warranted in this unique patient population.

Association between spinal stenosis and wild-type ATTR amyloidosis.

Age-related cardiac amyloidosis results from deposits of wild-type tranthyretin amyloid (ATTRwt) in cardiac tissue. ATTR may play a role in carpal tunnel syndrome (CTS) and in spinal stenosis (SS), indicating or presaging systemic amyloidosis. We investigated consecutive patients undergoing surgery for SS for ATTR deposition in the resected ligamentum flavum (LF) and concomitant risk of cardiac amyloidosis. Each surgical specimen (LF) was stained with Congo red, and if positive, the amyloid deposits were typed by mass spectrometry. Patients with positive specimens underwent standard of care evaluation with fat pad aspirates, serum and urine protein electrophoresis with immunofixation, free light-chain assay, TTR gene sequencing and technetium 99 m-pyrophosphate-scintigraphy. In 2018-2019, 324 patients underwent surgery for SS and 43 patients (13%) had ATTR in the LF with wild-type TTR gene sequences. Two cases of ATTRwt cardiac amyloidosis were diagnosed and received treatment. In this large series, ATTRwt was identified in 13% of the patients undergoing laminectomy for SS. Patients with amyloid in the ligamentum flavum were older and had a higher prevalence of CTS, suggesting a systemic form of ATTR amyloidosis involving connective tissue. Further prospective study of patients with SS at risk for systemic amyloidosis is warranted.

Usefulness of Global Longitudinal Strain to Predict Heart Failure Progression in Patients With Nonobstructive Hypertrophic Cardiomyopathy.

While predicting prognosis to anticipate adverse disease course has long been an aspiration in hypertrophic cardiomyopathy (HC), reliable markers of progressive and unrelenting heart failure symptoms in the absence of obstruction are not well characterized. We sought to evaluate markers of systolic function, including the role of global longitudinal strain (GLS), to identify nonobstructive HC patients at risk for future heart failure. A cohort of 296 consecutive nonobstructive HC patients (42 ± 18years; 75% male) with NYHA class I/II symptoms and preserved systolic function at study entry (EF: 65 ± 6%), were followed for progressive heart failure symptoms (increase in ≥ 1 NYHA functional class) and/or development of systolic dysfunction (EF < 50%). Over median follow-up of 4 ± 3 years, 35 study patients (10%) experienced new heart failure events, including 31 with progressive symptoms and 4 who developed systolic dysfunction. Abnormal GLS < 16% was associated with a 5-fold increase in risk for heart failure compared to GLS > 18% (p < 0.001). GLS remained an independent predictor of heart failure even after adjustment for other relevant disease variables including EF (OR 1.23, p = 0.005). However, notably, when GLS and EF were combined, the prediction of heart failure for individual patients was enhanced (net reclassification improvement 0.55; p = 0.002). Together, GLS < 16% and EF 50% to 59% were associated with a 12.5-fold greater risk for heart failure versus patients with GLS > 18% and EF ≥ 60%, who were at the lowest risk. In conclusion, in nonobstructive HC with no or mild symptoms and preserved EF, abnormal GLS is a strong independent predictor for subsequent development of progressive heart failure symptoms and/or systolic dysfunction. Furthermore, the greatest power in predicting outcome in nonobstructive HC is achieved by combining GLS with EF to identify HC patients at the highest risk for heart failure progression and systolic dysfunction.

Lumbar ligamentum flavum burden: Evaluating the role of ATTRwt amyloid deposition in ligamentum flavum thickness at all lumbar levels.

BACKGROUND: Wild-type transthyretin (ATTRwt) amyloid deposition has been found in the ligamentum flavum (LF) of patients undergoing spinal stenosis surgery. Our group previously reported that ATTRwt amyloid is associated with an increased lumbar ligamentum flavum thickness at symptomatic levels that required surgery. A comprehensive evaluation of LF thickness at asymptomatic levels in addition to symptomatic, treated levels has never been performed in ATTRwt patients. In this study, we compare the total LF thickness of all lumbar levels (lumbar LF burden) in ATTRwt and non-ATTRwt patients. METHODS: We retrospectively identified 177 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 885 lumbar levels was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and subtype of ATTRwt was confirmed using mass-spectrometry and gene sequencing. RESULTS: Of the 177 patients, 30 (16.9%) were found to have ATTRwt in the ligamentum flavum. One hundred and fifty ATTRwt levels and 735 non-ATTRwt levels were measured by four different reviewers, with an intraclass coefficient (ICC) of 0.79. Mean ligamentum flavum thickness was 4.64 (±1.31) mm in the ATTRwt group and 3.99 (±1.45) mm in the non-ATTRwt group (p < 0.001). The lumbar LF burden (sum of ligamentum flavum thickness at all lumbar levels) for ATTRwt patients was 23.22 (±4.48) mm, and for non-ATTRwt patients was 19.96 (±5.49) mm (p = 0.003) CONCLUSION: The lumbar LF burden is greater in patients with ATTRwt amyloid compared to non-ATTRwt patients. This supports prior evidence that ATTRwt amyloid deposition might be associated with increased LF thickness and lumbar stenosis. This potential association requires more research and could be an important finding, as medications have recently become available that can treat patients with ATTRwt amyloid deposition.

Increased thickness of lumbar spine ligamentum flavum in wild-type transthyretin amyloidosis.

BACKGROUND: Wild-type transthyretin (ATTRwt) amyloid deposits have been found in the ligamentum flavum of patients undergoing surgery for spinal stenosis. The relationship between ATTRwt and ligamentum flavum thickness is unclear. We used pre-operative magnetic resonance imaging (MRI) to analyze ligamentum flavum thickness in lumbar spinal stenosis patients with and without ATTRwt amyloid. METHODS: We retrospectively identified 178 patients who underwent lumbar spine surgery. Ligamentum flavum thickness of 253 specimens was measured on T2-weighted axial MRI. Amyloid presence was confirmed through Congo red staining of specimens, and ATTRwt was confirmed using mass-spectrometry and gene sequencing. RESULTS: Twenty four of the 178 patients (13.5%) were found to have ATTRwt in the ligamentum flavum. Forty ATTRwt specimens and 213 non-ATTRwt specimens were measured. Mean ligamentum flavum thickness was 4.92 (±1.27) mm in the ATTRwt group and 4.00 (±1.21) mm in the non-ATTRwt group (p < 0.01). The ligamentum flavum was thickest at L4-L5, with a thickness of 5.15 (±1.27) mm and 4.23 (±1.29) mm in the ATTRwt and non-ATTRwt group, respectively (p = 0.007). There was a significant difference in ligamentum flavum thickness between ATTRwt and non-ATTRwt case for both patients younger than 70 years (p = 0.016) and those older than 70 years (p = 0.004). ATTRwt patients had greater ligamentum flavum thickness by 0.83 mm (95% confidence interval (CI): 0.41-1.25 mm, p < 0.001) when controlled for age and lumbar level. CONCLUSION: Patients with ATTRwt had thicker ligamentum flavum compared to patients without ATTRwt. Further studies are needed to investigate the pathophysiology of ATTRwt in ligamentum flavum thickening.

Systemic Amyloidosis due to Monoclonal Immunoglobulins: Cardiac Involvement.

Amyloid light chain amyloidosis (AL) is the most commonly diagnosed systemic form of amyloidosis, resulting from deposition of amyloid fibrils into various organs, such as the heart. Over the past several decades, significant advances in diagnosis and treatment have reduced overall mortality. Short-term survival, however, has not improved, in large part due to cardiovascular mortality from advanced AL cardiac amyloidosis. Early clinical suspicion of cardiac involvement is critical in order to initiate appropriate treatment and referrals for successful management. This review discusses the current challenges in diagnosis as well as available treatment options for different stages of cardiac involvement.

Sex differences in mechanisms of arterial stiffness.

Arterial stiffness progressively increases with aging and is an independent predictor of cardiovascular disease (CVD) risk. Evidence supports that there are sex differences in the time course of aging-related arterial stiffness and the associated CVD risk, which increases disproportionately in postmenopausal women. The association between arterial stiffness and mortality is almost twofold higher in women versus men. The differential clinical characteristics of the development of arterial stiffness between men and women indicate the involvement of sex-specific mechanisms. This review summarizes the current literature on sex differences in vascular stiffness induced by aging, obesity, hypertension, and sex-specific risk factors as well as the impact of hormonal status, diet, and exercise on vascular stiffness in males and females. An understanding of the mechanisms driving sex differences in vascular stiffness has the potential to identify novel sex-specific therapies to lessen CVD risk, the leading cause of death in males and females. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.