Sex and Race Differences in Cardiac Sarcoidosis Presentation, Treatment and Outcomes.

BACKGROUND: Although sex- and race-based patterns have been described in the extracardiac organ involvement of sarcoidosis, cardiac sarcoidosis (CS)-specific studies are lacking. METHODS: We studied CS presentation, treatment and outcomes based on sex and race in a tertiary-center cohort. Multivariable adjusted Cox proportional hazards and survival analyses were performed for primary composite outcomes (left ventricular assist device, heart transplantation, all-cause death) and for secondary outcomes (ventricular arrhythmia and all-cause death. RESULTS: We identified 252 patients with CS (108 female, 109 Black). At presentation with CS, females vs males (P = 0.001) and Black vs White individuals (P = 0.001) more commonly had symptomatic heart failure (HF), with HF most common in Black females (ANOVA P < 0.001). Treatment differences included more corticosteroid use (90% vs 79%; P = 0.020), higher 1-year prednisone dosage (13 vs 10 mg; P = 0.003) and less frequent early steroid-sparing agent use in males (29% vs 40%; P = 0.05). Black participants more frequently received a steroid-sparing agent (75% vs 60%; P = 0.023). Composite outcome-free survival did not differ by sex or race. Male sex had an adjusted hazard ratio of 2.34 (95% CI 1.13, 4.80; P = 0.021) for ventricular arrhythmia. CONCLUSION: CS course may differ by sex and race and may contribute to distinct clinical CS phenotypes.

Impact of Donor Hemodynamics on Recipient Survival in Heart Transplantation.

BACKGROUND: Heart transplantation is the gold-standard therapy for end-stage heart failure, but rates of donor-heart use remain low due to various factors that are often not evidence based. The impact of donor hemodynamics obtained via right-heart catheterization on recipient survival remains unclear. METHODS: The United Network for Organ Sharing registry was used to identify donors and recipients from September 1999-December 2019. Donor hemodynamics data were obtained and analyzed using univariate and multivariable logistical regression, with the primary endpoints being 1- and 5-year post-transplant survival. RESULTS: Of the 85,333 donors who consented to heart transplantation during the study period, 6573 (7.7%) underwent right-heart catheterization, of whom 5531 eventually underwent procurement and transplantation. Donors were more likely to undergo right-heart catheterization if they had high-risk criteria. Recipients who had donor hemodynamic assessment had 1- and 5-year survival rates similar to those without donor hemodynamic assessment (87% vs 86%, 1 year). Abnormal hemodynamics were common in donor hearts but did not impact recipient survival rates, even when risk-adjusted in multivariable analysis. CONCLUSIONS: Donors with abnormal hemodynamics may represent an opportunity to expand the pool of viable donor hearts.

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.

Pathophysiology and Therapeutic Approaches to Cardiac Amyloidosis.

Often considered a rare disease, cardiac amyloidosis is increasingly recognized by practicing clinicians. The increased rate of diagnosis is in part due the aging of the population and increasing incidence and prevalence of cardiac amyloidosis with advancing age, as well as the advent of noninvasive methods using nuclear scintigraphy to diagnose transthyretin cardiac amyloidosis due to either variant or wild type transthyretin without a biopsy. Perhaps the most important driver of the increased awareness is the elucidation of the biologic mechanisms underlying the pathogenesis of cardiac amyloidosis which have led to the development of several effective therapies with differing mechanisms of actions. In this review, the mechanisms underlying the pathogenesis of cardiac amyloidosis due to light chain (AL) or transthyretin (ATTR) amyloidosis are delineated as well as the rapidly evolving therapeutic landscape that has emerged from a better pathophysiologic understanding of disease development.

Prevalence and significance of extracardiac uptake on pyrophosphate imaging in the SCAN-MP study: the first 379 cases.

INTRODUCTION: Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings. METHODS: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects. RESULTS: Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings. CONCLUSION: Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases.

Racial Differences in Val122Ile-Associated Transthyretin Cardiac Amyloidosis.

BACKGROUND: The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the United States, affecting primarily individuals of African descent. This variant has been identified recently in a cluster of white individuals in Italy. METHODS AND RESULTS: Clinical phenotype and chamber performance of Black and white individuals with Val122Ile TTR cardiac amyloidosis (ATTR-CA) were compared. Compared to white patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs 131 mmHg, <0.001), reduced pulse pressures (41 vs 58 mmHg; P < 0.001), and impaired renal function (eGFR 46 vs 67 mL/min/1.73m2; P < 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had end-diastolic pressure-volume relationships that were shifted upward and leftward relative to those of white patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black than in white individuals (8055 mmHg/mL vs 11,538 mmHg/mL; P = 0.008). CONCLUSION: Despite presenting at ages similar to those of white patients, Black individuals with Val122Ile-associated ATTR-CA had a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study.

Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

COVID-19 and Cardiovascular Disease.

Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction. In the United States, the valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant. Data on sex differences in presentation and outcomes of Val122Ile associated ATTR-CA are lacking. METHODS AND RESULTS: In a retrospective, single-center study of 73 patients diagnosed with Val122Ile associated ATTR-CA between 2001 and 2018, sex differences in clinical and echocardiographic data at the time of diagnosis were evaluated. Pressure-volume analysis using noninvasive single beat techniques was used to compare chamber performance. Compared with men (n = 46), women (n = 27) were significantly older at diagnosis, 76 years vs 69 years; P < .001. The end-systolic pressure-volume relationship, 5.1 mm Hg*m2/mL vs 4.3 mm Hg*m2/mL; P = .27, arterial elastance, 5.5 mm Hg*m2/mL vs 5.7 mm Hg*m2/mL; P = .62, and left ventricular capacitance were similar between sexes as was pressure-volume areas indexed to a left ventricular end-diastolic pressure of 30 mm Hg, a measure of overall pump function. The 3-year mortality rates were also similar, 34% vs 43%; P = .64. CONCLUSIONS: Despite being significantly older at time of diagnosis with Val122Ile associated ATTR-CA, women have similar overall cardiac chamber function and rates of mortality to men, suggesting a less aggressive disease trajectory. These findings should be confirmed with longitudinal studies.

Management of Cardiac Sarcoidosis Using Mycophenolate Mofetil as a Steroid-Sparing Agent.

BACKGROUND: Cardiac sarcoidosis (CS) is a major cause of morbidity and mortality in patients with systemic sarcoidosis. Steroid-sparing agents are increasingly used, despite a lack of randomized trials or published guidelines to direct treatment. METHODS AND RESULTS: This retrospective study included 77 patients with CS treated with prednisone monotherapy (n = 32) or a combination with mycophenolate mofetil (n = 45) between 2003 and 2018. Baseline characteristics and clinical outcomes were evaluated. The mean patient age was 53 ± 11 years at CS diagnosis, 66.2% were male, and 35.1% were Black. The total exposure to maximum prednisone dose (initial prednisone dose × days at dose) was lower in the combination therapy group (1440 mg [interquartile range (IQR), 1200-2760 mg] vs 2710 mg [IQR, 1200-5080 mg]; P = .06). On 18F-fluorodeoxyglucose positron emission tomography scans, both groups demonstrated a significant decrease in the cardiac maximum standardized uptake value after treatment: a median decrease of 3.9 (IQR 2.7-9.0, P = .002) and 2.9 (IQR 0-5.0, P = .001) for prednisone monotherapy and combination therapy, respectively. Most patients experienced improvement or complete resolution in qualitative cardiac 18F-fluorodeoxyglucose uptake (92.3% and 70.4% for the prednisone and combination therapy groups, respectively). Mycophenolate mofetil was well tolerated. CONCLUSIONS: Mycophenolate mofetil in combination with prednisone for the treatment of CS may minimize corticosteroid exposure and decrease cardiac inflammation without significant adverse effects.

Clinical and Imaging Response to Tumor Necrosis Factor Alpha Inhibitors in Treatment of Cardiac Sarcoidosis: A Multicenter Experience.

BACKGROUND: Cardiac sarcoidosis (CS) is an increasingly recognized cause of cardiomyopathy; however, data on immunosuppressive strategies are limited. Treatment with tumor necrosis factor (TNF) alpha inhibitors is not well described; moreover, there may be heart failure-related safety concerns. METHODS: Retrospective multicenter study of patients with CS treated with TNF alpha inhibitors. Baseline characteristics, treatments, and outcomes were adjudicated. RESULTS: Thirty-eight patients with CS (mean age 49.9 years, 42% women, 53% African American) were treated with TNF alpha inhibitor (30 infliximab, 8 adalimumab). Prednisone dose decreased from time of TNF alpha inhibitor initiation (21.7 ± 17.5 mg) to 6 months (10.4 ± 6.1 mg, P = .001) and 12 months (7.3 ± 7.3 mg, P = .002) after treatment. On pre-TNF alpha inhibitor treatment positron emission tomography with 18-flourodoxyglucose (FDG-PET), 84% of patients had cardiac FDG uptake. After treatment, there was a significant decrease in number of segments involved (3.5 ± 3.8 to 1.0 ± 2.5, P = .008) and maximum standardized uptake value (3.59 ± 3.70 to 0.57 ± 1.60, P = .0005), with 73% of patients demonstrating complete resolution or improvement of cardiac FDG uptake. The left ventricular ejection fraction remained stable (45.0 ± 16.5% to 47.0 ± 15.0%, P = .10). Four patients required inpatient heart failure treatment, and 8 had infections; 2 required treatment cessation. CONCLUSIONS: TNF alpha inhibitor treatment guided by FDG-PET imaging may minimize corticosteroid use and effectively reduce cardiac inflammation without significant adverse effect on cardiac function. However, infections were common, some of which were serious, and therefore patients require close monitoring for both infection and cardiac symptoms.

Clozapine-Associated Myocarditis: A Protocol for Monitoring Upon Clozapine Initiation and Recommendations for How to Conduct a Clozapine Rechallenge.

BACKGROUND: Clozapine is the only medication with Food and Drug Administration approval for treatment-resistant schizophrenia. However, it is underutilized in the United States because of several life-threatening adverse effects, including clozapine-associated myocarditis (CAM), and a limited understanding of how to manage these complications. To date, recommendations for rechallenging patients with CAM that incorporate the cardiac literature or cardioprotective medications have not been developed. FINDINGS: In this article, we outline a protocol developed with cardiologists and guided by the cardiac literature that provides direction on how to monitor for the initial development of CAM and how to rechallenge patients with CAM. Furthermore, we present 2 successful cases of clozapine rechallenge that were managed using this protocol. CONCLUSIONS: In both cases, the patients showed marked improvement in their psychiatric symptoms and functioning, demonstrating the importance of considering rechallenge in patients after CAM.

How can we better inform our patients about post-heart transplantation survival? A conditional survival analysis.

BACKGROUND: Conditional survival (CS) is a dynamic method of survival analysis that provides an estimate of how an individual's future survival probability changes based on time post-transplant, individual characteristics, and post-transplant events. This study sought to provide post-transplant CS probabilities for heart transplant recipients based on different prognostic variables and provide a discussion tool for the providers and the patients. METHODS: Adult heart transplant recipients from January 1, 2004, through October 18, 2018, were identified in the UNOS registry. CS probabilities were calculated using data from Kaplan-Meier survival estimates. RESULTS: CS probability exceeded actuarial survival probability at all times post-transplant. Women had similar short-term, but greater long-term CS than men at all times post-transplant (10-year CS 1.8-11.5% greater [95% CI 1.2-12.9]). Patients with ECMO or a surgical BiVAD had decreased survival at the time of transplant, but their CS was indistinguishable from all others by 1-year post-transplant. Rejection and infection requiring hospitalization during the first year were associated with a persistently decreased CS probability. CONCLUSIONS: In this study, we report differential conditional survival outcomes based on time, patient characteristics, and clinical events post-transplant, providing a dynamic assessment of survival. The survival probabilities will better inform patients and clinicians of future outcomes.

Extracorporeal photopheresis and its role in heart transplant rejection: prophylaxis and treatment.

Heart transplantation is the gold standard therapeutic option for select patients with end-stage heart failure. Unfortunately, successful long-term outcomes of heart transplantation can be hindered by immune-mediated rejection of the cardiac allograft, specifically acute cellular rejection, antibody-mediated rejection, and cardiac allograft vasculopathy. Extracorporeal photopheresis is a cellular immunotherapy that involves the collection and treatment of white blood cells contained in the buffy coat with a photoactive psoralen compound, 8-methoxy psoralen, and subsequent irradiation with ultraviolet A light. This process is thought to cause DNA and RNA crosslinking, ultimately leading to cell destruction. The true mechanism of therapeutic action remains unknown. In the last three decades, extracorporeal photopheresis has shown promising results and is indicated for a variety of conditions. The American Society for Apheresis currently recommends the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma, scleroderma, psoriasis, pemphigus vulgaris, atopic dermatitis, graft-versus-host disease, Crohn's disease, nephrogenic systemic fibrosis, and solid organ rejection in heart, lung, and liver transplantation. In this review, we aim to explore the proposed effects of extracorporeal photopheresis and to summarize published data on its use as a prophylactic and therapy in heart transplant rejection.

Higher Prevalence of Concurrent Thrombocytopenia in Patients Receiving Continuous Renal Replacement Therapy in the Cardiac Intensive Care Unit.

INTRODUCTION: Thrombocytopenia (TCP) is a common finding in patients receiving continuous renal replacement therapy (CRRT). OBJECTIVE: The purpose of this study was to assess the nature of TCP in patients receiving CRRT. METHODS: This is a single-center case-control observational study of 795 patients involving over 166,950 h of delivered CRRT at Johns Hopkins Hospital. Concurrent TCP in patients receiving CRRT was defined as a decrease in platelet count of ≥50% any time within 72 h of initiation of CRRT with strict exclusion criteria. RESULTS: There was a higher incidence of TCP in the cardiac intensive care unit (CICU) (22.5%) compared to medical ICU (MICU) (13.1%). Using logistic regression, the odds of developing concurrent TCP in patients receiving CRRT was 2.46 (95% CI 1.32-3.57, p < 0.05) times higher in the CICU compared with the MICU. There was no difference in the incidence of severe or profound TCP or timing of acute TCP between the CICU and MICU. CONCLUSION: Safe delivery of dialysis care in the ICU is paramount and creating awareness of potential risks such as concurrent TCP in patients receiving CRRT should be part of this care.

Comparing outcomes for infiltrative and restrictive cardiomyopathies under the new heart transplant allocation system.

The new heart transplantation (HT) allocation policy was introduced on 10/18/2018. Using the UNOS registry, we examined early outcomes following HT for restrictive cardiomyopathy, hypertrophic cardiomyopathy, cardiac sarcoidosis, or cardiac amyloidosis compared to the old system. Those listed who had an event (transplant, death, or waitlist removal) prior to 10/17/2018 were in Era 1, and those listed on or after 10/18/2018 were in Era 2. The primary endpoint was death on the waitlist or delisting due to clinical deterioration. A total of 1232 HT candidates were included, 855 (69.4%) in Era 1 and 377 (30.6%) in Era 2. In Era 2, there was a significant increase in the use of temporary mechanical circulatory support and a reduction in the primary endpoint, (20.9 events per 100 PY (Era 1) vs. 18.6 events per 100 PY (Era 2), OR 1.98, p = .005). Median waitlist time decreased (91 vs. 58 days, p < .001), and transplantation rate increased (119.0 to 204.7 transplants/100 PY for Era 1 vs Era 2). Under the new policy, there has been a decrease in waitlist time and waitlist mortality/delisting due to clinical deterioration, and an increase in transplantation rates for patients with infiltrative, hypertrophic, and restrictive cardiomyopathies without any effect on post-transplant 6-month survival.

United network for organ sharing outcomes after heart transplantation for al compared to ATTR cardiac amyloidosis.

Light-chain (AL) cardiac amyloidosis (CA) has a worse prognosis than transthyretin (ATTR) CA. In this single-center study, we compared post-heart transplant (OHT, orthotopic heart transplantation) survival for AL and ATTR amyloidosis, hypothesizing that these differences would persist post-OHT. Thirty-nine patients with CA (AL, n = 18; ATTR, n = 21) and 1023 non-amyloidosis subjects undergoing OHT were included. Cox proportional hazards modeling was used to evaluate the impact of amyloid subtype and era (early era: from 2001 to 2007; late era: from 2008 to 2018) on survival post-OHT. Survival for non-amyloid patients was greater than ATTR (P = .034) and AL (P < .001) patients in the early era. One, 3-, and 5-year survival rates were higher for ATTR patients than AL patients in the early era (100% vs 75%, 67% vs 50%, and 67% vs 33%, respectively, for ATTR and AL patients). Survival in the non-amyloid cohort was 87% at 1 year, 81% at 3 years, and 76% at 5 years post-OHT. In the late era, AL and ATTR patients had unadjusted 1-year, 3-year, and 5-year survival rates of 100%, which was comparable to non-amyloid patients (90% vs 84% vs 81%). Overall, these findings demonstrate that in the current era, differences in post-OHT survival for AL compared to ATTR are diminishing; OHT outcomes for selected patients with CA do not differ from non-amyloidosis patients.

Right Ventricular Contractility and Pulmonary Arterial Coupling After Less Invasive Left Ventricular Assist Device Implantation.

Right ventricular failure contributes significantly to morbidity and mortality after left ventricular assist device implantation. Recent data suggest a less invasive strategy (LIS) via thoracotomy may be associated with less right ventricular failure than conventional median sternotomy (CMS). However, the impact of these approaches on load-independent right ventricular (RV) contractility and RV-pulmonary arterial (RV-PA) coupling remains uncertain. We hypothesized that the LIS approach would be associated with preserved RV contractility and improved RV-PA coupling compared with CMS. We performed a retrospective study of patients who underwent durable, centrifugal left ventricular assist device implantation and had paired hemodynamic assessments before and after implantation. RV contractility (end-systolic elastance [Ees]), RV afterload (pulmonary effective arterial elastance [Ea]), and RV-PA coupling (Ees/Ea) were determined using digitized RV pressure waveforms. Forty-two CMS and 21 LIS patients were identified. Preimplant measures of Ees, Ea, and Ees/Ea were similar between groups. After implantation, Ees declined significantly in the CMS group (0.60-0.40, p = 0.008) but not in the LIS group (0.67-0.58, p = 0.28). Coupling (Ees/Ea) was unchanged in CMS group (0.54-0.59, p = 0.80) but improved significantly in the LIS group (0.58-0.71, p = 0.008). LIS implantation techniques may better preserve RV contractility and improve RV-PA coupling compared with CMS.

Effect of patisiran on stroke volume in hereditary transthyretin-mediated amyloidosis: insights from pressure-volume analysis of the APOLLO study.

AIMS: Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study. METHODS AND RESULTS: Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran. CONCLUSIONS: Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.