Clinical Context

Markers of cardiac disease can be critical among patients with suspected conditions such as acute ischemia or heart failure, but patient factors also can produce variability in these laboratory values. The authors of the current study provide a review of this phenomenon, with an emphasis on sex-based differences in cardiac biomarkers.

Women generally have lower levels of high-sensitivity cardiac troponin (hs-cTn) compared with men, although the clinical significance of this difference is controversial. In contrast, levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are higher among women vs men, and this difference is maintained regardless of the presence of cardiac disease. Age is positively associated with higher NT-proBNP levels, whereas body mass index is inversely related to NT-proBNP.

What should clinicians do regarding making adjustments for hs-cTn and NT-proBNP values among transgender adults, particularly those who are using gender-affirming therapy? The current study addresses this question.

Study Synopsis and Perspective

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas NT-proBNP concentrations are higher in females than males across all ages after puberty.

"That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state," study author Dina M. Greene, PhD, University of Washington, Seattle, told theheart.org | Medscape Cardiology.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is "currently absent."

The American Heart Association's recent scientific statement on the cardiovascular (CV) health of transgender and gender diverse (TGD) people, says that mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan.^[1] "In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory."

For the present study, Dr Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle, Washington, and Iowa City, Iowa, to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT and ACCESS high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay, and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women.^[2] The pattern was consistent across the 2 other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

"It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth," Dr. Greene said.

The observed differences in hs-cTn concentrations "are likely physiological and not pathological," given that concentrations between healthy cisgender people are also apparent and are not thought to portend adverse events, the authors note.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits (URLs) for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they add. "Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks."

Dr Greene pointed out that the study was not powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

"It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements," Dr Greene said. "Within this population, it's very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they're non-sex-specific are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn't been a change over time."

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. "For NT-proBNP, it's not as important. People don't usually have a little bit of heart failure, they have heart failure, where people have small MIs."

Dr Greene said that she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy, but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

"The sample sizes are never going to be as big as we get for cisgender people for a number of reasons, but ensuring that it's something that's being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease," Dr Greene said. "And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it's such a political issue."

The study was supported in part by the University of Washington, Department of Laboratory Medicine; the University of Iowa, Department of Pathology; and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. Coauthor Robert H. Christenson, PhD, reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other financial relationships were reported.

JAMA Cardiol. Published online October 5, 2022.

Clinical Implications

• Cisgender women generally have lower levels of hs-cTn and higher levels of NT-proBNP compared with cisgender men.
• The current study finds that hs-cTN and NT-proBNP levels among transgender women and men mirror those of cisgender adults of their transition gender.
• Implications for the healthcare team: The healthcare team should evaluate transgender women and men using gender-affirming hormone therapy, applying cardiac biomarker norms for cisgender women and men.

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