Brett W. Sperry

Prognostic implication of relative regional strain ratio in cardiac amyloidosis

Objective Cardiac amyloidosis (CA) is a rapidly progressive disease that portends poor prognosis. Our objective was to evaluate the prognostic impact of relative regional strain ratio (RRSR, a measure of the relative apical sparing of longitudinal strain (LS)) in CA. Methods This is a retrospective study evaluating 97 patients with CA from 2004 to 2013. Patients were included if they met criteria for CA based on endomyocardial biopsy or advanced imaging criteria coupled with either extracardiac biopsy or genetic analysis. Baseline clinical and imaging data were collected and compared between light-chain amyloidosis (AL) (n=59) and transthyretin amyloidosis (ATTR) (n=38) subtypes. RRSR was defined as the average apical LS divided by the sum of the average mid and basal LS values. A Cox proportional hazards model was used to assess the effects of clinical and echocardiographic characteristics, including RRSR, on the outcome of time to death or heart transplantation. Results Despite younger age, the AL subtype had a statistically significant association with the composite outcome as compared with ATTR (p=0.022). Log-transformed RRSR was independently associated with the composite outcome at 5 years (HR 2.45 (1.36 to 4.40), p=0.003). Patients with low ejection fraction and high RRSR had the worst prognosis. In multivariable analysis, RRSR remained predictive of the primary outcome (p=0.018). Addition of covariates related to systolic function (global LS and ejection fraction) to the model attenuated this effect. Conclusions High RRSR is adversely prognostic in patients with cardiac amyloid. This novel tool is both diagnostic and prognostic and may have implications in management and suitability for treatment.

Hospital readmission in heart failure, a novel analysis of a longstanding problem

Acute decompensated heart failure is a significant source of morbidity and mortality in the USA. It is the most common reason for admission in the Medicare population and the greatest cause of hospital readmission in both medical and surgical patients. As many of these readmissions are considered preventable, providers and hospital systems are seeking novel strategies to reduce rehospitalization. Several specific interventions have been shown to decrease readmission for heart failure. However, these are typically narrow in scope, focusing on one aspect of patient care and providing a one-size-fits-all approach. We review the data and propose integrating some of these interventions into a comprehensive patient-centered model that is organized into six categories: quality of medical management, early reassessment, health literacy, neuropsychological status, financial means and functional status. By screening for deficiencies in each of these categories, providers and hospital systems can use resources more efficiently to make targeted interventions to improve health outcomes and mitigate readmissions.

Subtype‐Specific Interactions and Prognosis in Cardiac Amyloidosis

Background Light chain (AL) and transthyretin (ATTR) amyloidosis have a similar effect on myocardial function but very different disease trajectories and survival. However, limited data are available evaluating subtype‐specific predictors of outcomes in a large contemporary cohort. Methods and Results We retrospectively investigated 360 patients at the time of initial diagnosis of cardiac amyloidosis (191 AL and 169 ATTR) from 2002 to 2014. Clinical, laboratory, electrical, and morphologic covariates were evaluated based upon amyloid subtype. ATTR etiology was associated with older age, more chronic medical conditions, and the use of standard heart failure medical therapy. Left ventricular mass index and electrocardiographic voltage were higher in ATTR, while there was no difference in ejection fraction or markers of diastology between subtypes. A multivariable Cox model was generated using previously identified predictors of negative outcomes in cardiac amyloidosis and analyzed after stratification for subsequent amyloid‐specific treatment. An AL etiology was the most predictive variable (hazard ratio 3.143, P<0.001) of 3‐year all‐cause mortality. The only covariate that showed a significantly greater magnitude of effect on mortality in 1 amyloid subtype versus the other was amyloid‐specific treatment in AL (P=0.015). The magnitude of effect of other variables on mortality did not significantly differ between subtypes. Conclusions Clinical, morphological, electrical, and biomarker data do not significantly interact with amyloid subtype in its association with mortality, despite the fact that the prognosis in each subtype differs greatly. This suggests an additional factor or factors (such as light chain toxicity) contributing to poorer outcomes in AL amyloid.

Insights into biopsy-proven cardiac sarcoidosis in patients with heart failure

Sarcoidosis is a multisystem inflammatory disease of unknown etiology that is characterized histologically by the presence of non-caseating granulomas. It most commonly affects the lungs and thoracic lymph nodes; however, autopsy studies have shown that up to 27% of patients with sarcoidosis have cardiac involvement.1 The diagnosis of cardiac sarcoidosis (CS) is challenging, because specimens from an endomyocardial biopsy (the gold standard) are confirmatory in only 32% of patients.2 Patients diagnosed with CS who present with heart failure symptoms have a worse prognosis than those who present with other symptoms3 and have acceptable long-term outcomes without recurrence after heart transplantation.4 The Heart Rhythm Society (HRS) recommends that patients with extracardiac sarcoidosis proven by biopsy specimen undergo advanced cardiac imaging if they have an abnormal electrocardiogram (ECG), abnormal echocardiogram, or symptoms (palpitations, syncope, or presyncope).5 We sought to determine how well this recommendation performed if applied to our population of patients with CS proven by biopsy specimen who initially presented with heart failure. A retrospective analysis was performed of 27 consecutive patients at the Cleveland Clinic with CS proven by myocardial biopsy specimen from 2002 to 2014. Patients were included with New York Heart Association Functional Classification ≥ II symptoms and a left ventricular ejection fraction of ≤50%. Baseline data were obtained on all patients before cardiac tissue diagnosis, including clinical characteristics, echocardiographic, ECG, and laboratory findings. Positron emission tomography with 18F-fluoro-2-deoxy-D-glucose (FDG-PET) and cardiac magnetic resonance imaging (CMR) were evaluated when available (Table). Table Clinical Characteristics and Japanese Ministry of Health and Welfare Criteria in Patients with Biopsy Specimen– Proven Cardiac Sarcoidosis and Cardiomyopathy Patients were on average in their sixth decade of life and more likely to be Caucasian and male. The ECGs in all patients showed abnormalities, as defined by a complete right or left bundle branch block, axis deviation, ventricular tachycardia, frequent premature ventricular contractions, or abnormal Q waves. Eighteen patients (67%) had class III or IV heart failure symptoms, 16 (59%) had ventricular tachycardia, and 15 (56%) had advanced heart block requiring pacing. All patients met at least 1 criterion needed to warrant further investigation with FDG-PET or CMR based on the HRS consensus statement.5 In contrast, only 8 of 27 patients (30%) met Japanese Ministry of Health and Welfare criteria for CS before cardiac biopsy. Of the 16 patients who underwent FDG-PET, 12 had matching segmental defects in perfusion and FDG and 12 had segments with reduced perfusion and enhanced FDG uptake (“mismatched segments”). All patients had matching or mismatched defects. In addition, the 10 patients who underwent contrast-enhanced CMR had late gadolinium enhancement in a pattern consistent with CS. Fourteen patients (52%) had isolated CS, defined as lack of extracardiac symptoms, diagnostic biopsy specimen, or imaging findings, including CMR and FDG-PET. There were 19 heart transplantations and 5 left ventricular assist devices (LVADs) in the cohort. Of the 5 patients with LVADs, all of whom went on to heart transplantation, 2 had apical core biopsy specimens that were nondiagnostic but were later confirmed to be sarcoidosis after analysis of the explanted heart. Eight of the 19 patients receiving heart transplantation or LVAD (42%) were previously unaware of a diagnosis of systemic or CS until the time of pathologic confirmation. Ten of the 19 heart transplant patients had isolated CS. All patients were maintained on low-dose prednisone after transplantation. There was no recurrence of CS on endomyocardial biopsy specimens in any of the patients after 25,993 total patient follow-up days with an average follow-up of 4.2 years per patient. This analysis highlights several important points regarding CS proven on biopsy specimen in patients presenting with cardiomyopathy. The LVAD apical core was positive in only 3 of the 5 patients who later went on to heart transplantation, highlighting the heterogeneous involvement of sarcoid granulomas in the myocardium as well as the difficulty in obtaining a positive biopsy sample, even in patients with severe cardiomyopathy. Isolated CS was present in 52% of the patients, validating the high prevalence seen in other studies of biopsy specimen–proven CS.3,4 However, this prevalence may be influenced by selection bias, because patients with extracardiac biopsy specimen–proven sarcoidosis are more likely to have a non-invasive evaluation of cardiac involvement. All patients had an abnormal ECG, reduced LVEF, and findings consistent with the diagnosis of CS on multimodality imaging, including CMR and FDG-PET. This corroborates the findings of the recently published HRS consensus statement on the diagnosis of CS in patients presenting with arrhythmias or heart block and suggests that patients with a cardiomyopathy severe enough to have a positive endomyocardial biopsy specimen or warrant advanced heart failure therapies will have findings consistent with the diagnosis on FDG-PET or CMR.5 Given the difficulty in sampling an affected area for a histologic diagnosis, we agree with the HRS guidelines that a non-invasive approach with CMR or PET imaging is favored. Currently, no consensus recommendations exist regarding the diagnosis and screening of CS in patients presenting with non-ischemic cardiomyopathy. Our results add to the small but growing body of literature in this field.

Emerging Advances in the Management of Cardiac Amyloidosis

Amyloidosis is a disease in which proteins misfold, aggregate into fibrils, and deposit extracellularly disrupting organ architecture and function. There are two main types which affect the heart: light chain (AL) amyloidosis and transthyretin cardiac amyloidosis (ATTR). There is a misconception that cardiac amyloidosis has no effective treatment options. However, over the past decade, there has been extensive research and drug development. Outcomes are improving in AL amyloidosis with evolving chemotherapeutic regimens and novel monoclonal antibodies. In ATTR, therapies that decrease protein production, prevent dissociation, and promote clearance have the potential to slow or even halt a disease which is uniformly fatal. Selected patients may be candidates for heart and/or stem cell transplant and should be promptly referred to an experienced amyloid program. Herein, we discuss the emerging advances for the treatment of cardiac amyloidosis.

Recognizing Transthyretin Cardiac Amyloidosis in Patients With Aortic Stenosis: Impact on Prognosis

Cardiac amyloidosis is an under recognized and underdiagnosed heart failure etiology characterized by protein misfolding, myocardial deposition, and restrictive cardiomyopathy. Cardiac involvement in elderly patients most commonly results from the transthyretin protein (ATTR) and carries a poor

Are classic predictors of voltage valid in cardiac amyloidosis? A contemporary analysis of electrocardiographic findings

BACKGROUND Low voltage electrocardiography (ECG) coupled with increased ventricular wall thickness is the hallmark of cardiac amyloidosis. However, patient characteristics influencing voltage in the general population, including bundle branch block, have not been evaluated in amyloid heart disease. METHODS A retrospective analysis was performed of patients with newly diagnosed cardiac amyloidosis from 2002 to 2014. ECG voltage was calculated using limb (sum of QRS complex in leads I, II and III) and precordial (Sokolow: S in V1 plus R in V5-V6) criteria. The associations between voltage and clinical variables were tested using multivariable linear regression. A Cox model assessed the association of voltage with mortality. RESULTS In 389 subjects (transthyretin ATTR 186, light chain AL 203), 30% had conduction delay (QRS >120ms). In those with narrow QRS, 68% met low limb, 72% low Sokolow and 57% both criteria, with lower voltages found in AL vs ATTR. LV mass index as well as other typical factors that impact voltage (age, sex, race, hypertension, BSA, and smoking) in the general population were not associated with voltage in this cardiac amyloidosis cohort. Patients with LBBB and IVCD had similar voltages when compared to those with narrow QRS. Voltage was significantly associated with mortality (p<0.001 for both criteria) after multivariable adjustment. CONCLUSION Classic predictors of ECG voltage in the general population are not valid in cardiac amyloidosis. In this cohort, the prevalence estimates of ventricular conduction delay and low voltage are higher than previously reported. Voltage predicts mortality after multivariable adjustment.

Amyloid heart disease: genetics translated into disease-modifying therapy

Given increased awareness and improved non-invasive diagnostic tools, cardiac amyloidosis has become an increasingly recognised aetiology of increased ventricular wall thickness and heart failure with preserved ejection fraction. Once considered a rare disease with no treatment options, translational research has harnessed novel pathways and led the way to promising treatment options. Gene variants that contribute to amyloid heart disease provide unique opportunities to explore potential disease-modifying therapeutic strategies. Amyloidosis has become the model disease through which gene therapy using small interfering RNAs and antisense oligonucleotides has evolved.

Prognosis Using Planar Imaging in Cardiac Amyloidosis

Prognosis Using Planar Imaging in Cardiac Amyloidosis To the Editor We read with great interest the article by Castano et al1 and commend the authors on their continuous excellent work in this field. Technetium pyrophosphate scintigraphy has become a cornerstone of the noninvasive diagnostic algorithm in cardiac amyloidosis, and the authors used a retrospective cohort from 3 respected centers to conclude that a heart-to-contralateral (H/CL) ratio greater than 1.6 was associated with worse survival among patients with transthyretin amyloidosis (ATTR). However, there are some points to discuss before this particular number becomes widely used as a prognostic marker. First, the overall cohort was composed of patients from 3 centers with amyloid light chain amyloidosis, ATTR, and heart failure with a preserved ejection fraction, but not all centers used the same scan protocol (ie, some used 1-hour scans and some used 3-hour scans). In our experience, and as the article describes, the H/CL ratio decreases as the incubation delay increases. The median H/CL value of 1.6 was derived from the entire cohort and subsequently applied in a survival model as a dichotomous variable in only the patients with ATTR. This median value would have been different depending on the composition of the cohort with respect to disease etiology or incubation time. An alternative statistical method would have been to use H/CL ratio as a continuous variable in the survival model for patients with ATTR and adjust for the protocol as a covariate or stratification factor. Incorporating the proposed number into clinical practice may be statistically attractive but practically problematic, given the heterogeneity of the 6 cohorts included in its derivation. In addition, patients included in this study presented to major amyloidosis referral centers and were presumably symptomatic (85% with Class II heart failure or worse) with a high pretest probability of having the disease. This was mentioned in the Limitations section, but it cannot be overstated how this referral bias may influence the particular cutoff values described when testing is expanded to less specialized centers and patients with early disease. Finally, the H/CL ratio is a facile yet crude metric, as it relies on the usefulness of planar images. Patients with ATTR are generally older and may have significant osteoarthritis, which may influence the ratio if differential bony uptake or skeletal rotation is present. Similar to the transition from planar to single-photon emission computed tomography imaging in coronary artery disease, methods based on single-photon emission computed tomography for quantifying uptake will likely have superior prognostic ability. Using single-photon emission computed tomography also aides in localizing myocardial uptake to avoid measuring counts in the blood pool, which may skew the H/CL ratio in those with very low cardiac output, renal dysfunction, or pathologic bone uptake without amyloid heart disease. We again praise the authors for their extraordinary and challenging work in pooling multicenter data and maximizing the usefulness of noninvasive scintigraphic techniques in this not-so-rare disease.

Update on Treatment in Cardiac Sarcoidosis

Opinion statementThe prevalence of cardiac sarcoidosis has exponentially increased over the past decade, primarily due to increased awareness and diagnostic modalities for the disease entity. Despite an expanding patient cohort, the optimal management of cardiac sarcoidosis remains yet to be established with a significant lack of prospective trials to support current practice. Corticosteroids remain first-line treatment of this disorder, and we recommend that immunosuppressive therapy should be initiated in all patients diagnosed with cardiac sarcoidosis. Additional pharmacotherapy may be necessary based on disease manifestations and response to treatment. The use of nuclear imaging with 18fluorodeoxyglucose (18FDG) positron emission tomography (PET) to guide treatment has become more common, but lacks rigorous data from larger cohorts. Whether an improvement in inflammatory burden as assessed by 18FDG-PET is correlated with clinical outcomes is as yet unproven. Device therapy with implantable-cardioverter defibrillators should be considered in all cardiac sarcoidosis patients for either primary or secondary prevention of ventricular arrhythmias and cardiac death.