Ronald Witteles, MD, is a professor of cardiovascular medicine at Stanford University and co-director of the Stanford Amyloid Center and the Stanford Multidisciplinary Sarcoidosis Program

Ronald Witteles, MD

The panel focuses on recognizing extra-cardiac manifestations that often precede cardiac symptoms in ATTR-CM. Orthopedic signs—such as bilateral carpal tunnel syndrome, cervical or lumbar spinal stenosis, biceps tendon rupture, trigger finger, and recurrent joint replacements—may occur five to ten years before cardiac involvement. Neurologic and autonomic features, including peripheral neuropathy, orthostatic hypotension, constipation, diarrhea, urinary retention, and erectile dysfunction, also serve as early clues, though frequently attributed to aging or unrelated conditions. The discussion emphasizes the importance of educating clinicians across specialties to identify these signals and consider amyloidosis when patterns cluster. The panel notes that orthopedic surgeons, neurologists, primary care physicians, and geriatricians play key roles in spotting early presentations. Advanced practice providers can also help bridge communication and referral pathways. Rather than screening every patient with common conditions, the group recommends viewing these findings as risk indicators and prompting coordinated evaluation to facilitate earlier diagnosis and treatment.

Extra-Cardiac Clues and Care Team Integration for Earlier ATTR-CM Detection

The panel focuses on recognizing extra-cardiac manifestations that often precede cardiac symptoms in ATTR-CM. Orthopedic signs—such as bilateral carpal tunnel syndrome, cervical or lumbar spinal stenosis, biceps tendon rupture, trigger finger, and recurrent joint replacements—may occur five to ten years before cardiac involvement. Neurologic and autonomic features, including peripheral neuropathy, orthostatic hypotension, constipation, diarrhea, urinary retention, and erectile dysfunction, also serve as early clues, though frequently attributed to aging or unrelated conditions. The discussion emphasizes the importance of educating clinicians across specialties to identify these signals and consider amyloidosis when patterns cluster.

The panel notes that orthopedic surgeons, neurologists, primary care physicians, and geriatricians play key roles in spotting early presentations. Advanced practice providers can also help bridge communication and referral pathways. Rather than screening every patient with common conditions, the group recommends viewing these findings as risk indicators and prompting coordinated evaluation to facilitate earlier diagnosis and treatment.

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The panel focuses on recognizing extra-cardiac manifestations that often precede cardiac symptoms in ATTR-CM. Orthopedic signs—such as bilateral carpal tunnel syndrome, cervical or lumbar spinal stenosis, biceps tendon rupture, trigger finger, and recurrent joint replacements—may occur five to ten years before cardiac involvement. Neurologic and autonomic features, including peripheral neuropathy, orthostatic hypotension, constipation, diarrhea, urinary retention, and erectile dysfunction, also serve as early clues, though frequently attributed to aging or unrelated conditions. The discussion emphasizes the importance of educating clinicians across specialties to identify these signals and consider amyloidosis when patterns cluster.
The panel notes that orthopedic surgeons, neurologists, primary care physicians, and geriatricians play key roles in spotting early presentations. Advanced practice providers can also help bridge communication and referral pathways. Rather than screening every patient with common conditions, the group recommends viewing these findings as risk indicators and prompting coordinated evaluation to facilitate earlier diagnosis and treatment.


The panel opens by outlining the significant clinical burden of ATTR-CM. Patients often initially present with atrial arrhythmias or conduction abnormalities before developing heart failure, which commonly manifests first as exercise intolerance. Without treatment, the disease follows a progressive course that impacts both patients and caregivers, many of whom are unfamiliar with amyloidosis at diagnosis. The discussion highlights notable delays in identifying hereditary ATTR-CM, particularly among Black and Caribbean patients with the V142I variant, emphasizing the need for improved community and provider awareness. The conversation then shifts to trends in diagnosis. While recognition of ATTR-CM has increased and patients are being diagnosed earlier—with outcomes improving when therapy is initiated sooner—significant barriers remain. A major challenge is persistent misperception of ATTR-CM as rare. The panel stresses reframing heart failure with preserved ejection fraction as a syndrome requiring etiologic evaluation and encourages clinicians to consider ATTR-CM in older patients with increased ventricular wall thickness, prompting timely, appropriate diagnostic workup.

Clinical Burden and Barriers to Early Diagnosis in Transthyretin Amyloid Cardiomyopathy (ATTR-CM)

The panel opens by outlining the significant clinical burden of ATTR-CM. Patients often initially present with atrial arrhythmias or conduction abnormalities before developing heart failure, which commonly manifests first as exercise intolerance. Without treatment, the disease follows a progressive course that impacts both patients and caregivers, many of whom are unfamiliar with amyloidosis at diagnosis. The discussion highlights notable delays in identifying hereditary ATTR-CM, particularly among Black and Caribbean patients with the V142I variant, emphasizing the need for improved community and provider awareness.

The conversation then shifts to trends in diagnosis. While recognition of ATTR-CM has increased and patients are being diagnosed earlier—with outcomes improving when therapy is initiated sooner—significant barriers remain. A major challenge is persistent misperception of ATTR-CM as rare. The panel stresses reframing heart failure with preserved ejection fraction as a syndrome requiring etiologic evaluation and encourages clinicians to consider ATTR-CM in older patients with increased ventricular wall thickness, prompting timely, appropriate diagnostic workup.

The panel opens by outlining the significant clinical burden of ATTR-CM. Patients often initially present with atrial arrhythmias or conduction abnormalities before developing heart failure, which commonly manifests first as exercise intolerance. Without treatment, the disease follows a progressive course that impacts both patients and caregivers, many of whom are unfamiliar with amyloidosis at diagnosis. The discussion highlights notable delays in identifying hereditary ATTR-CM, particularly among Black and Caribbean patients with the V142I variant, emphasizing the need for improved community and provider awareness.
The conversation then shifts to trends in diagnosis. While recognition of ATTR-CM has increased and patients are being diagnosed earlier—with outcomes improving when therapy is initiated sooner—significant barriers remain. A major challenge is persistent misperception of ATTR-CM as rare. The panel stresses reframing heart failure with preserved ejection fraction as a syndrome requiring etiologic evaluation and encourages clinicians to consider ATTR-CM in older patients with increased ventricular wall thickness, prompting timely, appropriate diagnostic workup.


Clinical Burden and Barriers to Early Diagnosis in Transthyretin Amyloid Cardiomyopathy (ATTR-CM)”

HELIOS-B: Open-Label Extension Proves Vutrisiran’s Long-Term Efficacy, With Ronald Witteles, MD

Vutrisiran has demonstrated significant clinical benefit in patients with 

transthyretin amyloidosis with cardiomyopathy (ATTR-CM)

 compared to placebo, based on 12-month data from an open-label extension of the HELIOS-B trial presented at the 

Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025

ATTR-CM is a progressive and frequently fatal disease, characterized by deposition of misfolded transthyretin protein in the heart. Vutrisiran inhibits hepatic transthyretin production, leading to rapid knockdown of the pathogenic protein. In the HELIOS-B trial, the subcutaneously administered RNA interface therapy was shown to lower the risk of the primary composite endpoint of all-cause mortality (ACM) and recurrent cardiovascular (CV) events compared to placebo.

 sat down with Ronald Witteles, MD, co-director of the Stanford Amyloid Center and the Stanford Multidisciplinary Sarcoidosis Program at the Stanford University School of Medicine, to discuss the study and his thoughts on vutrisiran fitting into the broader ATTR-CM treatment landscape.

“We wanted to look at people who had followed for up to 12 months of open-label extension data,” Witteles told 

. “The takeaway from all of that was that vutrisiran works, it works well, and the longer that patients are on it, you will have further separation of the curves. We can also see that patients who started on placebo and then switched to the open-label extension clearly had disease progression by several markers: quality of life, cardiac biomarkers, et cetera.”

HELIOS-B was a phase 3 interventional global trial, during which 655 patients were tested across 79 locations. The trial comprised a 33-36-month double-blind period, followed by a 2-year open-label extension. Investigators included 2 arms receiving vutrisiran; the first had been taking tafamidis on baseline, and the second had not. The latter was measured separately as the monotherapy population.

To be included, patients were required to have a documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR (hATTR) amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis. Additionally, patients were required to exhibit a medical history of 

 with ≥1 before hospitalization for heart failure or clinical evidence of heart failure.

Patients were excluded from the study if they had known primary amyloidosis or leptomeningeal amyloidosis, if they had New York Heart Association Class IV heart failure or Class III heart failure and were at risk based on prespecified criteria, or had a polyneuropathy disability, among other conditions.

Primary outcomes included a composite endpoint of ACM and recurrent CV events, as well as hospitalizations and urgent heart failure visits. Secondary outcomes included change from baseline in 6-minute walk test and change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary, among others.

Patients receiving vutrisiran in the first phase of HELIOS-3 exhibited reduced risk of the primary composite endpoint in both the overall population and the monotherapy population. Patients who completed this period were eligible to enter the extension, which saw all patients receive vutrisiran 25mg Q3M. During this study, Witteles and colleagues measured mortality and CV events to determine the long-term efficacy of the drug.

Ultimately, the 466 patients in the extension study exhibited sustained improvement across key measures of disease progression through the first 12 months of the study. The long-term safety and tolerability profile was also consistent with vutrisiran’s established profile.

“If you look at the subjects who started and ended on vutrisiran, their average troponin level was a little lower all the way out at 48 months than it was at baseline. So that tells us something as well,” Witteles said. “The big take-home message is that you don’t want to wait to start therapy. That is lost functional status, it’s lost progression of disease.”

Editor's Note: Witteles reports disclosures with Alexion, Alnylam, AstraZeneca, BridgeBio, Novo Nordisk, and Pfizer.

Garcia-Pavia P, Witteles R, Morbach C, et al. HELIOS-B: 12-Month Results From the Open-Label Extension Period of Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

Alnylam Pharmaceuticals. HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. ClinicalTrials.gov identifier: NCT04153149. Updated May 13, 2025. Accessed October 16, 2025. 

https://clinicaltrials.gov/study/NCT04153149

Alnylam Pharmaceuticals. New Data from Landmark HELIOS-B Phase 3 Study Presented at ESC Congress 2025 Demonstrate Vutrisiran’s Long-Term Cardiovascular Benefit in ATTR-CM. August 31, 2025. Accessed October 16, 2025. 

https://investors.alnylam.com/press-release?id=29256

Witteles highlights the uniform improvement after the tafamidis and vutrisiran arms were both moved to the same vutrisiran dose.

Expert Perspectives: Top News in Heart Failure from HFSA Annual Scientific Meeting 2025

The Heart Failure Society of America Annual Scientific Meeting 2025,

 incorporating over 50 scientific sessions and hundreds of abstract presentations from leading researchers, saw a slew of exciting trial updates and insights from some of the best minds in cardiology.

During the conference, the editorial team at 

 sat down with several of these experts, collecting their thoughts on the most significant developments in 

’s approval of finerenone, the upcoming decision on aficamten, and the recent VICTOR, SUMMIT, and MAPLE- and ODYSSEY-HCM trials were highlighted.

The clinicians included in this summary are:

Ronald Witteles, MD, professor of cardiovascular medicine at Stanford University and co-director of the Stanford Amyloid Center and the Stanford Multidisciplinary Sarcoidosis Program

Barry Borlaug, MD, professor of cardiology at Mayo Clinic

Justin Ezekowitz, MD, professor of medicine at University of Alberta and cardiologist at the University of Alberta Hospital and Mazankowski Alberta Heart Institute

Ahmad Masri, MD, director of the Oregon Health & Science University Hypertrophic Cardiomyopathy Center and Knight Cardiovascular Institute Cardiac Amyloidosis Program

Javed Butler, MD, MPH, professor and chair of the department of medicine and Patrick H. Lehan Chair of Cardiovascular Research at the University of Mississippi Medical Center

Benjamin Hansen, MD, postdoctoral research fellow at the Department of Intensive Care at Copenhagen University Hospital - Rigshospitalet

Henri Roukoz, MD, associate professor of medicine, cardiovascular division, and section chief of electrophysiology, director of complex and congenital ablation at the University of Minnesota

Petra Mamic, MD, instructor of cardiovascular medicine at Stanford University Medicine

Stephen Greene, MD, cardiovascular disease fellow at Duke University Medical Center

Viet Le, DMSc, PA-C, associate professor of research at Intermountain Health

Milind Desai, MD, director of the center for hypertrophic cardiomyopathy and vice chair of education of the Heart Vascular Thoracic Institute at the Cleveland Clinic

I may be biased, but to me, ATTR amyloidosis is still the biggest story in heart failure. You’re talking about a disease that, a decade ago, most people hadn’t heard of. Maybe there would be one session every few years at the meetings, which was sparsely attended, but there was little interest, it was wildly underdiagnosed, and there were no therapies for it. Now we’re in an era where we realize this disease is not that rare, that if you look at the right patient populations, particularly older men with heart failure, thick hearts, and atrial fibrillation, you will pick up a lot of this. And it’s easy to diagnose; most patients can be diagnosed non-invasively. And now we have 3 FDA-approved treatments for ATTR 

, we have multiple other treatments approved for ATTR polyneuropathy, and multiple other agents in phase 3 trials. It is a super dynamic area, and it’s one that I think is particularly gratifying because it went from a fundamental understanding of the pathophysiology of the disease that led directly to the therapies. In the world of ATTR amyloidosis, the therapies have been designed to do exactly what they do, and in a rare thing in medicine, they pretty much all work.


The SUMMIT trial is probably the biggest news. It wasn’t a lot of events, it wasn’t a big trial, but it was a statistically significant improvement with a drug that was developed for weight loss, and it’s really ushering in a new era. HFpEF is a disease that’s driven by adiposity and everything that comes with that, such as visceral adiposity, pro-inflammatory and profibrotic effects, and many others. It’s opening the door for a lot of different drugs and potentially even devices that can target this cardiometabolic axis.


 2025 has been a pretty banner year for some trials: the VICTOR trial, being the largest recent clinical trial, has been quite important; the completion of DAPA-ACT, being the last real SGLT2 trial, showing that, when in combination with the meta-analysis, there is an advantage to starting those drugs early on. I think seeing the secondary analysis from some trials, such as the SUMMIT trial and the MRI of adipose tissue, is really interesting because it shows there’s a change in the structure and function of the myocardium that really is interesting. We’ve had so many great smaller trials as well, though, so it’s hard to pick one. There’s so much good stuff going on.


 Focusing on hypertrophic cardiomyopathy specifically, I think the 2 recent trials that were published, MAPLE-HCM and ODYSSEY-HCM, are really important findings in this space. MAPLE-HCM showed that beta blockers, as represented by metoprolol, are detrimental to patients with obstructive hypertrophic cardiomyopathy. This challenges a practice of 60-plus years of using beta blockers as first-line therapy. You don’t see reversals in approach frequently, because you don’t see these first-time agents challenged frequently. ODYSSEY-HCM, on the other hand, while it wasn’t a positive trial, showed that you have to be careful in your evaluation of patients with hypertrophic cardiomyopathy. You have to be mindful that you can’t just use 1 trial in a specific population and expand the drug treatment to other populations without investigation. This is a drug that was successful in obstructive hypertrophic cardiomyopathy with some safety issues that were managed and dealt with that wasn’t successful in non-obstructive HCM, and the safety signal was much worse. The trial wasn’t positive, but it reminded us that we have to be really careful when applying an extension of the current use of drugs, and we have to strive to stay with evidence-based medicine as much as we can with our newer therapies.


 The biggest story so far is that the field continues to move forward. We had a lot of positive data that has come out of either smaller primary studies or secondary analyses of larger studies with the obesity trials. That is becoming the solid, certified data that evidence generation needs, which has led to a lot of ongoing studies. The other is smaller studies that have shown that aldosterone modulation in ways other than MRA, like aldosterone synthase inhibitors, may be very helpful. And third, there’s a lot of compelling data that has come out about prevention of heart failure in high-risk populations.


 If I were to call out just one big news, it’s the role of vericiguat. I think that’s something of a hot topic right now, so I guess that’s something we really need to look further into to see its role in this population of well-treated outpatients with difficult-to-treat or advanced heart failure.


I would say how widely the SGLT2 inhibitors are being used and the increase in the indication to cover HFpEF patients. The second part is rhythm control and afib in heart failure, which is still a dominant thing from the EP standpoint.


This past year, we’ve had incredible studies published about gut microbiome in the context of heart failure, which have really put certain gut microbial metabolites on the map for their roles in heart failure. I think where we have come from 2024 to 2025 has really informed my research in a huge way.


There’s some things to pick from, but one thing that’s very notable is the FDA approval of finerenone as an evidence-based treatment for HFpEF, not just diabetic kidney disease anymore. The FINEARTS trial was presented last year, but FDA approval now really solidifies this in my mind that we have another pillar for HFpEF. SGLT2 inhibitors were the first definitively proven therapy for patients with HFpEF, and despite making up more than half of our heart failure population, we had no evidence-based therapy, no disease-modifying therapy to offer them. Now we have another therapy that I would argue strongly is definitively proven for improving hard clinical outcomes. I think we need to embrace that.

I’d also like to encourage people to think that it’s not an either-or when we talk about the “pillars of therapy,” and I don’t want to make the same mistakes that we made in HFrEF. We have multiple evidence-based therapies; you need to be willing to initiate them simultaneously and not get distracted with this specific medication sequence. People need both for prognosis comparable to cancer, not either-or.


GLP-1s are one of these unifying therapies across multiple diseases, and I think as we think back to 2025, we’re just having this confluence of heart failure from the diabetic space. Everyone is reporting clinical data trending towards benefit with GLP-1s. I think this is such a great jump-off point. So many different industry partners are looking into this, and before 2025, they were thinking about it. But now I think the community is much more aware. I look forward to seeing where those fit in the space of heart failure, but also in cardiovascular, kidney, and metabolic health.


I think the continued evolution of high-quality randomized controlled trial data in the context of cardiomyopathy, not just hypertrophic obstructive cardiomyopathy. Gene therapy is rapidly evolving, and you’re going to hear a lot about it. The other important thing is the utilization of novel artificial intelligence techniques to make early and precise diagnoses in these spaces. A rising tide lifts all boats, so they say; there’s a major tide that is lifting a lot of boats right now.

The quotes contained in this video summary were edited for clarity.

Editor's Note: Le reports disclosures with Pfizer, Novartis, Janssen, Idorsia, Amarin, and Lexicon. Greene reports disclosures with Amgen, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, Corcept, and others. Butler reports disclosures with Abbott Laboratories, Amgen, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, and others. Masri reports disclosures with Pfizer, Ionis Pharmaceuticals, AstraZeneca, Cytokinetics, BioMarin, Akros, and others. Desai reports disclosures with Bristol-Myers Squibb, Medtronic, Cytokinetics, Edgewise, Viz-Al, and Tenaya Therapeutics. Borlaug reports disclosures with Amgen, Novo Nordisk, Eli Lilly, Edwards LifeSciences, Boehringer Ingelheim, AstraZeneca, and others. Witteles reports disclosures with Pfizer, Alnylam Pharmaceuticals, Bridge Bio, Janssen, AstraZeneca, and Alexian Pharmaceuticals. Roukoz, Hansen, Mamic, and Ezekowitz report no disclosures.

US FDA Approves KERENDIA (finerenone) to Treat Patients with Heart Failure with Left Ventricular Ejection Fraction ≥40% Following Priority Review. Bayer. July 14, 2025. Accessed October 3, 2025. 

https://www.bayer.com/en/us/news-stories/fda-approves-kerendia

Reddy YNV, Butler J, Anstrom KJ, et al. Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial. Eur J Heart Fail. 2025;27(2):209-218. 

Packer M, Zile MR, Kramer CM, et al. Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity: The SUMMIT Trial. J Am Coll Cardiol. 2025;85(18):1721-1735. 

Hegde SM, Wang X, Garcia-Pavia P, et al. Effect of Aficamten Compared With Metoprolol on Echocardiographic Measures in Symptomatic Obstructive Hypertrophic Cardiomyopathy: MAPLE-HCM. J Am Coll Cardiol. Published online August 27, 2025. 

Desai MY, Olivotto I, Abraham T, et al. Effects of Mavacamten on Cardiac Biomarkers in Nonobstructive Hypertrophic Cardiomyopathy: Insights From the ODYSSEY-HCM Trial. J Am Coll Cardiol. Published online August 25, 2025. 

This set of interviews collects perspectives from 11 leading clinicians in the heart failure field, cataloguing the biggest news from 2025.

Ronald Witteles, MD

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