Optimizing Cascade Testing to Advance Health Equity in Cardiac Amyloidosis

Hereditary transthyretin cardiac amyloidosis (ATTR-CM) is a progressive cardiomyopathy that is increasingly recognized as an important cause of heart failure with preserved ejection fraction (HFpEF).¹ Over 130 pathogenic variants in TTR have been identified with V142I (also known as V122I) as the most common variant in the US; V142I is enriched in individuals of West African ancestry with a frequency of nearly 4%.² Patients who identify as Black are also more likely to be diagnosed after end-organ dysfunction; there is an estimated loss of ~1 million years of life in the US Black population due to V142I.² Later-stage at diagnosis and delayed initiation of treatment results in limited effectiveness of disease-modifying therapies and worse outcomes in ATTR-CM.³

The proliferation of genetic testing offers a timely opportunity to identify at-risk individuals, promote earlier diagnosis, and improve outcomes for ATTR-CM (and other inherited cardiovascular conditions, such as familial hyperlipidemia (FH), cardiomyopathies, inherited arrhythmias, and aortopathies). Despite the well-established utility of first-degree relatives (FDRs) undergoing genetic testing to identify those at risk, called cascade testing, this approach has limited uptake in ATTR-CM for a variety of reasons including incomplete and age-dependent penetrance.^3,4 Improving rates of cascade testing may offer an opportunity to advance health equity in ATTR-CM as historically underrepresented groups have greater disease burden (attributable to the high prevalence of V142I in individuals of West African ancestry), higher rate of under diagnosis or late-stage diagnosis, and higher rates of undertreatment with disease-modifying therapies.²

The 2023 ACC Expert Consensus Decision Pathway on Cardiac Amyloidosis recommended cascade testing of FDRs after a proband with a pathogenic (P) or likely pathogenic (LP) TTR variant is identified (and suggests this testing would have the most relevance for siblings than younger at-risk offspring).¹ In this viewpoint, we consider barriers for cascade testing of FDRs, lessons learned from hereditary cancer syndromes and other inherited cardiovascular conditions, and opportunities to promote health equity with genomic testing, specifically leading to earlier identification of V1421+ (genotype+/phenotype-) and ATTR-CM diagnosis (genotype+/phenotype+). These lessons from hereditary cancer syndromes may also more broadly inform how to optimize cascade testing in inherited cardiovascular diseases beyond ATTR-CM.

Barriers in Cascade Testing of First-Degree Relatives

Cascade testing is currently underutilized in a variety of inherited cardiovascular diseases. Factors that influence uptake in genetic testing include limited genomics knowledge, lack of access to genetic services, fear of genetic discrimination, and high cost of testing. Several additional barriers in minoritized populations include, but are not limited to, cultural influence, distrust, and language and geographic barriers. In addition, minoritized patients are less likely to be referred for genetic services.⁵ A recent scoping review identified limited genomic knowledge and suboptimal proband-driven communication as barriers. Choice of direct communication by the healthcare team opposed to proband-driven communication may improve uptake and minimize psychosocial stress related disclosure.⁴

Insights from Hereditary Cancer Syndromes and Familial Hypercholesterolemia

Genomic testing to identify at-risk individuals has better uptake in oncology and there are some additional studies in FH that may offer helpful insights. A recent study demonstrated that facilitated cascade testing for BRCA variants with provider-driven disclosure followed by telephone genetic counseling with mailed salvia kits led to testing of at-risk relatives to 58%, compared with less than 30% in other studies with proband-driven communication.⁶ While this method of cascade testing was shown to increase uptake, disclosure to family members is currently limited by privacy laws that require consent from proband. Cascade testing in FH may have greater uptake due to straightforward testing of phenotype (e.g., cholesterol) and medical interventions (e.g., statins) to those at-risk. A study of FH probands tested additional cascade testing interventions, including chatbots and direct family contact and did identify higher uptake using these different strategies.⁷

A systematic review on culturally-tailored genetic counseling materials found the most promising strategies were designed by members of the impacted minoritized communities in conjunction with healthcare professionals and emphasized the importance of culturally-tailored educational resources combined with the use of telehealth and digital platforms.⁸ Culturally-tailored educational interventions that include visual and video aids centering members of the community, help improve attitudes toward genetic testing. Testimonials and storytelling from individuals from similar cultural backgrounds have also been suggested to enhance pre-test counseling. Importantly, these cascade testing strategies can be applied in all inherited cardiovascular disease.

Proposed Framework for Cascade Testing in FDRs

Developing a sustainable cascade testing program specifically for V1421, and more broadly for all inherited cardiovascular disease, should be a priority. Herein we propose a potential multi-tiered approach that considers clinical workflow integration, healthcare delivery models, culturally-competent education, and healthcare costs (FIGURE). The current system requires proband-driven communication to recommend cascade testing, which introduces barriers. An alternative approach would offer direct communication by the healthcare team following proband consent. This alternative strategy would also require increased clinician knowledge of genetic testing, which can be successfully achieved through online resources (e.g., https://education.clinical.jax.org/page/cardiovascular-genetics-education). Enhancing access and ease for ordering genomic testing for cardiologists is also needed. Second, broader access to genetic counselors for delivery of genetic counseling is needed, which requires policy-level changes to facilitate intrastate telehealth delivery of care. Third, culturally adapted interventions should be developed in partnership with affected communities to ensure cultural relevance, concordance with preferred language, and appropriate level of health literacy. These may include educational aids such as testimonials, narrative videos, and other resources. Fourth, a patient navigator could support contact of FDRs via phone or video visit. Lastly, genetic counseling could be also be provided in group sessions, involving family members and community leaders, with telehealth options to augment accessibility.

Figure.

Pillars to Advance Equity in Cascade Testing for Inherited Cardiovascular Conditions

However, advocating for broader cascade testing will not advance equity without integration of care, including surveillance for onset of symptoms and earlier treatment. The ultimate goal of this framework is to decrease negative clinical outcomes for at-risk individuals with inherited cardiovascular disease. For ATTR-CM, this may be further limited by the very high cost of targeted therapies that exceed usual willingness to pay with an incremental cost effectiveness ratio of $880,000 per QALY gained.⁹ Without reduction in pricing of these therapies, barriers will remain in equitably improving health outcomes in ATTR-CM even with improved cascade testing.

Conclusion

Cascade testing in FDRs of probands with ATTR-CM has the potential to promote earlier diagnosis and earlier treatment, particularly among patients with West African ancestry who have a much higher population frequency of the V142I pathogenic variant. Testing for hereditary cancer syndromes in racially and ethnically diverse groups demonstrates the importance of culturally tailored outreach, asynchronous online education materials, and telehealth genetic counseling to improve attitudes about and uptake of genetic testing. However, several critical research gaps for ATTR-CM remain beyond identification of at-risk individuals for genetic testing, including generating evidence for downstream strategies for clinical screening and interventions that modify risk in the pre-clinical phase. While identifying genotype+/phenotype- FDRs is an important first step in improving outcomes in ATTR-CM, and, more broadly, in inherited cardiovascular diseases, ultimately, we need evidence-based and cost-effective strategies that equitably improve outcomes.