Key Points
Question
In a community-based setting, what is the prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) among patients with heart failure, preserved ejection fraction, and ventricular wall thickening?
Findings
In this cohort study, only 16 of 1235 such patients (1.3%; all men) had clinically recognized ATTR-CM. With a systematic screening strategy that incorporated technetium Tc 99m pyrophosphate scintigraphy and reflex testing, 6.3% of 286 patients (10.1% of men and 2.2% of women) had ATTR-CM.
Meaning
These results suggest that systematic screening for ATTR-CM, which has a highly effective therapy, should be considered in older patients (particularly men) with heart failure, preserved ejection fraction, and ventricular wall thickening.
Abstract
Importance
Heart failure (HF) with preserved ejection fraction (HFpEF) is common, is frequently associated with ventricular wall thickening, and has no effective therapy. Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause the HFpEF clinical phenotype, has highly effective therapy, and is believed to be underrecognized.
Objective
To examine the prevalence of ATTR-CM without and with systematic screening in patients with HFpEF and ventricular wall thickening.
Design, Setting, and Participants
This population-based cohort study assessed ATTR-CM prevalence in 1235 consecutive patients in southeastern Minnesota with HFpEF both without (prospectively identified cohort study) and with (consenting subset of cohort study, n = 286) systematic screening.
Key entry criteria included validated HF diagnosis, age of 60 years or older, ejection fraction of 40% or greater, and ventricular wall thickness of 12 mm or greater. In this community cohort of 1235 patients, 884 had no known ATTR-CM, contraindication to technetium Tc 99m pyrophosphate scanning, or other barriers to participation in the screening study. Of these 884 patients, 295 consented and 286 underwent scanning between October 5, 2017, and March 9, 2020 (community screening cohort).
Exposures
Medical record review or technetium Tc 99m pyrophosphate scintigraphy and reflex testing for ATTR-CM diagnosis.
Main Outcomes and Measures
The ATTR-CM prevalence by strategy (clinical diagnosis or systematic screening), age, and sex.
Results
A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 149 [52%] male). In the 1235 patients in the community cohort without screening group, 16 patients (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM. The prevalence was 2.5% (95% CI, 1.4%-4.0%) in men and 0% (95% CI, 0.0%-0.6%) in women. In the 286 patients in the community screening cohort, 18 patients (6.3%; 95% CI, 3.8%-9.8%) had ATTR-CM. Prevalence increased with age from 0% in patients 60 to 69 years of age to 21% in patients 90 years and older (P < .001). Adjusting for age, ATTR-CM prevalence differed by sex, with 15 of 149 men (10.1%; 95% CI, 5.7%-16.1%) and 3 of 137 women (2.2%; 95% CI, 0.4%-6.3%) having ATTR-CM (P = .002).
Conclusions and Relevance
In this cohort study based in a community-based setting, ATTR-CM was present in a substantial number of cases of HFpEF with ventricular wall thickening, particularly in older men. These results suggest that systematic evaluation can increase the diagnosis of ATTR-CM, thereby providing therapeutically relevant phenotyping of HFpEF.
This cohort study examined the prevalence of transthyretin amyloid cardiomyopathy among patients with heart failure, preserved ejection fraction, and ventricular wall thickening who did and did not undergo systematic screening.
Introduction
More than half of patients with heart failure (HF) have preserved ejection fraction (HFpEF),1,2 and approximately half of patients with HFpEF have increased left ventricular wall thickness.3 Increased ventricular wall thickening in patients with HFpEF is usually attributed to hypertension-induced myocardial hypertrophy.4 However, cardiac amyloid fibril infiltration increases ventricular wall thickness and can lead to a similar clinical HFpEF syndrome.5 Light chain amyloid cardiomyopathy occurs in patients with light chain amyloidosis, a hematologic disease with specific hematologic therapies. Hereditary transthyretin (ATTRm) and wild-type transthyretin (ATTRwt) amyloidosis can cause transthyretin amyloid cardiomyopathy (ATTR-CM). Identification of ATTR-CM among the broader population of patients with HFpEF is particularly important because there is now highly effective, specific therapy for ATTR-CM,6 whereas there is no specific therapy for HFpEF of other causes.
Prior estimates of the prevalence of ATTR-CM in patients with HFpEF have varied from 5% to 17%,7,8,9 but the studies providing these estimates were small and subject to referral and ascertainment biases. In the past, endomyocardial biopsy was required for diagnosis of ATTR-CM. Currently, technetium Tc 99m pyrophosphate single-photon emission computed tomography (pyrophosphate scan) enables accurate, noninvasive diagnosis of ATTR-CM when coupled with appropriate clinical and reflex laboratory evaluation to rule out light chain amyloidosis.10,11
We performed a prospective, population-based cohort study to determine the prevalence of ATTR-CM among consecutive patients in southeastern Minnesota who were 60 years or older and who had the HFpEF clinical syndrome and increased left ventricular wall thickness. Prevalence was defined without or with screening using pyrophosphate scans and appropriate reflex testing to exclude light chain amyloidosis.
Methods
The study started on October 5, 2017, and was prematurely closed at 98% enrollment on March 9, 2020, because of concerns related to the COVID-19 pandemic. Participants provided written informed consent, including consent for transfer of blood and urine samples for ATTR-CM biomarker development studies. The medical records of community patients were reviewed if they had provided consent for use of their medical records for research. Any data shared with an external party were deidentified. The study was approved by the Mayo Clinic Institutional Review Board. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Study Setting
This study enrolled residents from a 7-county area in southeastern Minnesota. Olmsted County is the most populous of these counties, and its racial and ethnic makeup is predominantly White12 (90.33% White, 2.68% Black or African American, 0.26% Native American, 4.27% Asian, 0.03% Pacific Islander, 0.92% from other races, and 1.51% from ≥2 races). Only 2.38% of the population was Hispanic or Latino of any race. A previous study13 from this region characterized its ancestry as predominantly northern and central European. The Rochester Epidemiology Project,14 a medical record linkage system, allows the indexing of medical diagnoses and thus captures medical care for most residents in this region.15 Mayo Clinic is the largest provider of this care and has performed pyrophosphate scans for clinical diagnosis of ATTR-CM since 2013.
Identification of Patients and Study Procedures
During the study period, a validated natural language processing algorithm16,17 was used to screen electronic medical record notes on patients from southeastern Minnesota each day for terms consistent with HF (Figure 1). Screening occurred in both the inpatient and outpatient settings. All identified patients who were 60 years or older were entered into the screening log and underwent sequentially more detailed record review by trained nurse abstractors. Patients who had received an echocardiogram within the last year that reported an ejection fraction greater than or equal to 40% were eligible for further consideration. Of these, patients with a midintraventricular septum, midposterior wall, or basal intraventricular septal dimension of 12 mm or greater were eligible for further consideration. In these patients, the HF diagnosis was validated (record review) using prespecified criteria (eTable 1 in the Supplement). Of patients with validated HF, those with a prior ejection fraction less than 40% or HF attributable to mitral valve disease were excluded. The remaining patients comprised the community cohort (Figure 1) in which the prevalence of a clinical diagnosis of ATTR-CM was assessed.
Figure 1. CONSORT Diagram.
aResident of the 7-county region of southeastern Minnesota with a clinical note that contained terms possibly consistent with heart failure on a natural language processing search.
bA middle or basal intraventricular septal and/or posterior wall thickness of 12 mm or greater.
cHeart failure related to mitral valve disease (stenosis or mitral regurgitation).
dFactors that may result in inaccurate pyrophosphate scan (hydroxychloroquine therapy [n = 55], recent myocardial infarction [n = 34], or chest trauma or cardiovascular surgery [n = 18]).
eFactors that limit the ability to consent or participate (cognitive impairment [n = 25], psychiatric conditions [n = 5], critical noncardiac illness [n = 46], hospice [n = 20], or incarceration [n = 1]).
Patients with conditions that may confound pyrophosphate scanning, with barriers to consent or participation, or with known amyloid cardiomyopathy were excluded. All others were invited to participate (Figure 1). In participants, clinical data, including echocardiographic and electrocardiographic data (within 1 year of enrollment), were abstracted. The Charlson Comorbidity Index was calculated using International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes.18 Phlebotomy for measurement of cardiac biomarkers (N-terminal pro–brain-type natriuretic peptide and high-sensitivity cardiac troponin T) and pyrophosphate scans (eMethods in the Supplement) were performed. Patients undergoing imaging comprised the community screening cohort in which enrollment was designed to continue until 150 men and 150 women had enrolled. All pyrophosphate scan–positive patients were evaluated by amyloid specialists, had light chain amyloidosis excluded with appropriate blood and urine tests, and were evaluated for ATTRm vs ATTRwt (eMethods in the Supplement).
Statistical Analysis
The study was powered based on the precision of the CI estimate, whereby, with a hypothesized prevalence of ATTR-CM of 7.0%, 300 participants provided a 99% CI with a precision of ±4.0%. The association of sample size and observed prevalence with the 95% CI of the prevalence estimate is detailed in eTable 2 in the Supplement.
Group comparisons used a 2-sample t test, Wilcoxon rank sum test, Pearson χ2 test, or Fisher exact test, as appropriate. Multivariable least-squares linear regression and multivariable logistic regression models were used to adjust associations with amyloidosis presence for potential confounders. In linear regression analyses, nonnormally distributed continuous variables (by visual inspection) were log transformed.
To assess for the association of potential participation bias with ATTR-CM prevalence,19 we compared the clinical, echocardiographic, and electrocardiographic data between participants and nonparticipants. Furthermore, we constructed a logistic model predictive of ATTR-CM in the community screening cohort (eMethods in the Supplement) to calculate a score and compared the score value (2-sample t test) in nonparticipants and participants. Two-sided P ≤ .05 was considered statistically significant. Analyses were performed using SAS software, version 9.4 and JMP-Pro, version 14 (SAS Institute Inc).
Results
During the study period, 11 650 southeastern Minnesota residents with a possible HF diagnosis were identified (Figure 1), of whom 2409 had qualifying ejection fraction and ventricular wall thickness. A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 149 [52%] male).
Prevalence of Clinical Diagnosis of ATTR-CM in the Community Cohort
Of the 1235 patients who met validation criteria for HFpEF and constituted the community cohort, 16 (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM (Figure 2A). The prevalence was significantly higher in men (2.5%; 95% CI, 1.4%-4.0%) than women (0%; 95% CI, 0.0%-0.6%) (P < .001) (Figure 2B) but did not vary significantly by age (<70 years of age: 0.9%; 70-79 years of age: 0.8%; 80-89 years of age: 1.8%; and ≥90 years of age≥: 1.6%; P = 0.58) (Figure 2C). In addition, 8 patients (0.6%) had light chain cardiac amyloidosis, and 2 (0.2%) had serum amyloid A cardiac amyloidosis.
Figure 2. Prevalence of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in Heart Failure With Preserved Ejection Fraction.
Error bars indicate 95% CIs.
Community Screening Cohort Participants
Of the 884 patients who were eligible to participate in the prospective screening study (Figure 1), 295 consented (33%) and 286 underwent imaging. This community screening cohort included 149 men and 137 women, with 78 patients (27%) identified during an HF hospitalization (vs identified in an outpatient encounter). The comorbidity profile (Table 1) and medication use (eTable 3 in the Supplement) were typical for community-based HFpEF cohorts.16,20 A history of carpal tunnel syndrome (37%) and spinal stenosis (31%) were common. Cardiac biomarker levels were elevated.
Table 1. Clinical Characteristics of the Community Screening Cohorta.
| Characteristic | All (N = 286) | Heart failure with preserved ejection fraction (n = 268) | Transthyretin amyloid cardiomyopathy (n = 18) | P value | Adjusted P valueb |
|---|---|---|---|---|---|
| Age, median (IQR), y | 78 (71-84) | 78 (71-83) | 84 (79-89) | <.001 | NA |
| Male sex | 149 (52) | 134 (50) | 15 (83) | .006 | NA |
| White | 275 (96) | 257 (96) | 18 (100) | .38 | .98 |
| BMI, median (IQR) | 32.9 (29.0-38.6) | 33.1 (29.4-38.9) | 27.4 (25.2-32.0) | .002 | .26 |
| Systolic blood pressure, median (IQR), mm Hg | 130 (117-148) | 130 (116-148) | 133 (117-147) | .77 | .46 |
| Previous heart failure hospitalization | 142 (50) | 133 (50) | 9 (50) | .99 | .94 |
| Charlson Comorbidity Index, median (IQR) | 5.0 (4.0-7.0) | 5.0 (4.0-7.0) | 3.5 (2.0-6.0) | .01 | .03 |
| Obesityc | 189 (67) | 182 (69) | 6 (33) | .002 | .08 |
| Hypertension | 274 (96) | 260 (97) | 14 (78) | <.001 | <.001 |
| Diabetes | 142 (50) | 137 (51) | 5(28) | .06 | .25 |
| Coronary artery disease | 187 (65) | 177 (66) | 10 (56) | .37 | .13 |
| Chronic kidney disease (n = 267)d | 156 (58) | 147 (59) | 8 (53) | .68 | .73 |
| Anemiae | 102 (38) | 99 (40) | 3 (20) | .13 | .13 |
| Chronic obstructive lung disease (n = 285) | 85 (30) | 82 (31) | 3 (17) | .21 | .47 |
| History of atrial fibrillation | 187 (66) | 175 (66) | 12 (67) | .92 | .57 |
| Carpal tunnel syndrome | 105 (37) | 92 (34) | 13 (72) | .001 | .002 |
| Spinal stenosis | 88 (31) | 86 (32) | 2 (12) | .08 | .09 |
| Previous aortic valve replacement | 44 (15) | 42 (16) | 2 (11) | .60 | .36 |
| Severe aortic stenosis | 8 (3) | 8 (3) | 0 | .46 | .97 |
| Creatinine, median (IQR), mg/dL (n = 267) | 1.2 (1.0-1.6) | 1.2 (1.0-1.6) | 1.2 (1.1-1.5) | .58 | .93 |
| Glomerular filtration rate, median (IQR), mL/min/1.73 m2 (n = 267)f | 53 (39-71) | 53 (38-71) | 51 (45-70) | .88 | .99 |
| N-terminal pro–brain-type natriuretic peptide, median (IQR), pg/L | 1451 (585-3153) | 1337 (552-3050) | 2093 (1638-4126) | .01 | .20 |
| High-sensitivity cardiac troponin T, median (IQR), ng/L | 28 (17-50) | 27 (16-45) | 52 (34-66) | <.001 | .04 |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); IQR, interquarile range; NA, not applicable.
SI conversion factors: To convert creatinine to micromoles per liter, multiply by 88.4; N-terminal pro–brain-type natriuretic peptide to nanograms per liter, divide by 1000; and high-sensitivity cardiac troponin T to micrograms per liter, divide by 1000.
Data are presented as number (percentage) of patients unless otherwise indicated.
Adjusted for age and sex.
Obesity defined as a BMI greater than 30.
Chronic kidney disease defined as glomerular filtration rate less than 60 mL/min/1.73 m2.
Anemia defined as a hemoglobin level less than 12 g/dL in men or less than 11 g/dL in women.
Estimated from the creatinine level using the Modification of Diet in Renal Disease formula.
Median ejection fraction was 60% (Table 2). Midintraventricular septal wall thickening (median, 12 mm) was present in 223 participants (78%) (with or without posterior wall or basal intraventricular septal wall thickening), whereas only the posterior wall (median, 12 mm) and/or the basal intraventricular septal wall thickness (median, 16 mm) were increased in 62 participants (22%). Echocardiographic variables were suggestive of impaired myocardial relaxation, elevated left ventricular filling pressures, left atrial enlargement, and pulmonary hypertension.
Table 2. Echocardiogram and Electrocardiogram Parameters of the Community Screening Cohort.
| Parameter | Median (IQR) | P value | Adjusted P valuea | ||
|---|---|---|---|---|---|
| All (N = 286) | Heart failure with preserved ejection fraction (n = 268) | Transthyretin amyloid cardiomyopathy (n = 18) | |||
| Echocardiogram | |||||
| Ejection fraction, % | 60 (55-64) | 60 (55-64) | 57 (50-63) | .20 | .33 |
| Stroke volume index, mL/m2 (n = 262)b | 43 (35-49) | 43 (36-50) | 36 (32-44) | .02 | .01 |
| Left ventricular end diastolic diameter, mm | 50 (46-55) | 51 (46-55) | 46 (41-50) | .002 | <.001 |
| Septal wall thickness, mm | 12 (12-14) | 12 (12-13) | 14 (13-17) | <.001 | <.001 |
| Posterior wall thickness, mm | 12 (10-13) | 12 (10-13) | 13 (12-15) | <.001 | <.001 |
| Basal septal wall thickness, mm (n = 47) | 16 (14-18) | 16 (14-18) | 18 (18-19) | .12 | .28 |
| Relative wall thicknessc | 0.47 (0.43-0.54) | 0.47 (0.42-0.53) | 0.57 (0.52-0.78) | <.001 | <.001 |
| Left ventricular mass index, g/m2d | 115 (98-134) | 114 (97-133) | 125 (113-140) | .06 | .38 |
| Left ventricular hypertrophy, No. (%) (n = 278)e | 181 (65) | 167 (64) | 14 (82) | .12 | .04 |
| Medial e′, m/s (n = 254) | 0.06 (0.04-0.07) | 0.06 (0.04-0.07) | 0.05 (0.03-0.07) | .20 | .14 |
| Medial E/e′ (n = 244) | 16 (12-20) | 16 (12-20) | 19 (15-26) | .14 | .17 |
| Left atrial volume index, mL/m2 (n = 245)f | 46 (38-57) | 46 (37-56) | 49 (44-57) | .22 | .84 |
| Pulmonary artery systolic pressure, mm Hg (n = 252) | 41 (34-52) | 41 (34-51) | 47 (42-56) | .05 | .27 |
| Pericardial effusion, No. (%) (n = 278) | 46 (16) | 40 (15) | 6 (35) | .03 | .03 |
| Electrocardiogram | |||||
| PR interval, ms (n = 152) | 183 (158-213) | 182 (158-212) | 226 (176-304) | .09 | .15 |
| QRS interval, ms (n = 236) | 96 (86-120) | 96 (86-116) | 122 (110-132) | .009 | .07 |
| Low-voltage criteria (n = 236)g | 24 (10) | 20 (9) | 4 (31) | .01 | .03 |
| Pseudomyocardial infarction pattern (n = 236)g | 16 (7) | 14 (6) | 2 (15) | .20 | .23 |
Abbreviation: IQR, interquartile range.
Adjusted for age and sex.
Stroke volume divided by body surface area.
Sum of septal and posterior wall thickness divided by left ventricular end diastolic diameter.
Left ventricular mass divided by body surface area.
Defined as left ventricular mass index greater than 115 g/m2 in men and 95 g/m2 in women.
Defined as left atrial volume/body surface area.
Defined as outlined in the eMethods in the Supplement.
Patients who qualified for but did not participate in the prospective screening study were slightly older than participants but otherwise had similar clinical characteristics (eTable 4 in the Supplement) without significant differences in sex distribution, body mass index, comorbidities, cardiac biomarker levels, and echocardiogram or electrocardiogram parameters. The logistic regression model had good predictive characteristics for a positive pyrophosphate scan in the community screening cohort (area under the curve = 0.92) (eTable 5 in the Supplement). The score value calculated from the logistic regression model did not differ significantly between participants and nonparticipants, suggesting that participation bias was minimal and did not impact prevalence estimates.
Prevalence of ATTR-CM in the Community Screening Cohort
Overall, 18 of the 286 patients (6.3%; 95% CI, 3.8%-9.8%) who underwent imaging had ATTR-CM (Figure 2A) by imaging and comprehensive amyloid clinical and laboratory evaluation (eTable 6 in the Supplement). Prevalence increased notably with age from 0% in patients in their 60s to 21% in patients 90 years and older (P < .001) (Figure 2C) and, adjusting for age, differed significantly by sex, with 15 of 149 men (10.1%; 95% CI, 5.7%-16.1%) and 3 of 137 women (2.2%; 95% CI, 0.4%-6.3%) having ATTR-CM (P = .002) (Figure 2B). After age and sex were adjusted for, prevalence did not differ according to inpatient or outpatient status at the care episode when potential HF was identified or by ejection fraction but did increase with increasing relative wall thickness. None of the patients with only posterior and/or basal ventricular septal thickening (n = 62) had ATTR-CM.
Patients With HFpEF With or Without ATTR-CM
After adjustment for age and sex, there were no significant differences in body mass index, blood pressure, or frequency of previous HF hospitalization between the community screening cohort patients without or with ATTR-CM (Table 1). The patients with ATTR-CM had lower Charlson Comorbidity Indexes and prevalence of hypertension and had a higher prevalence of carpal tunnel syndrome but had no major differences in the prevalence of other comorbidities (Table 1). High-sensitivity cardiac troponin T levels were higher in patients with ATTR-CM, but creatinine, glomerular filtration rate, and N-terminal pro–brain-type natriuretic peptide concentrations were not different (Table 1).
After adjustment for age and sex, stroke volume index and ventricular diastolic dimension were lower, whereas septal and posterior wall thicknesses, relative wall thickness, and prevalence of pericardial effusion were higher in patients with ATTR-CM (Table 2). No major differences were found in ventricular mass, ejection fraction, left atrial volume index, pulmonary artery pressure, or diastolic function parameters (Table 2). The patients with ATTR-CM had a higher prevalence of low voltage but not pseudo-infarct pattern on the electrocardiogram (Table 2).
Discussion
To our knowledge, this is the first prospective, population-based cohort study of ATTR-CM prevalence. In 1235 consecutively enrolled ambulatory or hospitalized patients with a validated HF diagnosis and at increased risk for ATTR-CM because of their age, preserved ejection fraction, and increased ventricular wall thickness, the prevalence of clinically recognized ATTR-CM was only 1.3% (95% CI, 0.7%-2.1%) but was approximately 6-fold higher (6.3%; 95% CI, 3.8%-9.8%) in the sample of the cohort who underwent systematic screening for ATTR-CM. The prevalence of ATTR-CM was greater in older persons and in men, with 10.1% (95% CI, 5.7%-16.1%) of male HFpEF patients having ATTR-CM. In this predominantly White, community-based sample, affected women with ATTR-CM were not diagnosed without systematic screening. Compared with patients with HFpEF without ATTR-CM, patients with ATTR-CM had slightly less comorbidity; were more likely to have a history of carpal tunnel syndrome, low voltage on electrocardiogram, or a pericardial effusion; and had smaller left ventricular cavities and thicker left ventricular walls.
In an autopsy study7 of patients with an antemortem diagnosis of HFpEF, 17% of patients had ventricular ATTRwt deposition. However, moderate or severe deposition (definitive for ATTR-CM) was present in only 5% of patients, with the other 12% showing mild interstitial and/or variable severity of intramural coronary vascular deposition. Of importance, the autopsy study was not exclusively community based and was subject to potential ascertainment bias (autopsy). A study8 from a Spanish referral hospital performed technetium Tc 99m scintigraphy on 120 consecutive hospitalized patients with the same entry criteria as our study and reported positive technetium Tc 99m scintigraphy in 16 (13%). Despite the southern European study setting where certain ATTRm prevalence may be higher, all cases of ATTR-CM were attributable to ATTRwt. Most recently, in 108 patients referred to a tertiary referral HFpEF clinic (mean age, 66 years; 57% Black) and who (irrespective of wall thickness) consented to undergo research endomyocardial biopsies, 11 (10%) had ATTR-CM on biopsy, including 7 with ATTRwt and 2 with the Val122Ile form of ATTRm.9
For unclear reasons, ATTR-CM attributable to ATTRwt is more common in men, and its prevalence increases with age.5 These associations were readily apparent in our study. As above, Black Americans and persons of some European ancestries have higher rates of ATTRm.5 This finding is most striking for the high prevalence of Val122Ile in Black individuals and the Val30Met variant, which causes neurologic and cardiac (late-onset) manifestations, particularly in Sweden and some southern European countries.5,21,22 The well-defined population structure of our study setting is both a strength and a limitation. Being predominantly White and not of southern European ancestry, our population allows interpretation of the observed absence of ATTRm. Our population is well suited to address the prevalence of ATTR-CM attributable to ATTRwt because racial or ethnic variation in the prevalence of ATTRwt has not been described. We anticipate a higher prevalence of ATTR-CM in regions with higher proportions of Black people and persons of southern European descent in whom ATTRm could contribute more to ATTR-CM prevalence. A study23 screening for ATTR-CM among minority populations with HF is currently underway and will provide crucial context to our findings. Arguably, given the prevalence of ATTRwt-CM in White people demonstrated in this study and the known association among the Val122Ile transthyretin variant, Black race, and ATTR-CM, the need for systematic screening in older White men and Black persons with HFpEF and increased wall thickness seems clear. The lower prevalence of ATTR-CM in women despite using the same wall thickness entry criteria as in men is of note. Normal ventricular wall thickness is lower in women; thus, our entry criteria should have enriched for ATTR-CM in women.
In the context of clinical HFpEF management and HFpEF clinical trials, one must phenotype patients with HFpEF appropriately by recognizing conditions with specific therapies, including coronary vascular, valvular, pericardial, inflammatory, deposition, genetic, and (as studied here) infiltrative diseases. Highly effective therapy is available for patients with ATTR-CM,6 and in older patients with wall thickening, our (possibly conservative) estimate of up to 9.8% prevalence in the community and up to 16.1% in men supports systematic evaluation in this specific HFpEF phenotype (≥60 years of age with wall thickening) in clinical practice and clinical trials, at least in men. However, our findings also suggest the potential for risk scores (beyond age and wall thickness) to better stratify the risk of ATTR-CM and reduce the number of pyrophosphate scans needed. Current guidelines emphasize that multiple features should suggest the diagnosis,24 but a simple score with well-defined predictive characteristics and suitable for generalized use is needed.
Strengths and Limitations
Our study has several strengths, including the prospective epidemiologic study design using the resources of the Rochester Epidemiology Project, careful validation of HF diagnosis, characterization of both current clinical diagnosis rate and true (systematic screening) prevalence estimates in the community, and careful evaluation of potential participation bias. Of importance, we did not rely solely on the pyrophosphate scan for a diagnosis of ATTR-CM, and all scan-positive patients underwent careful evaluation. Our well-characterized population structure is a both a strength and a limitation but allows clear interpretation of our findings. Our consent rate (32.4%) was lower than that in a population-based (mail-in) questionnaire study19 that targeted patients with HF (43%) or a general population imaging survey25 that targeted a sample of all community residents 45 years or older (47%). We believe this finding reflects the difficulty of enrolling older and sicker individuals for our more involved study protocol. Although nonparticipants were slightly older than participants, their otherwise similar clinical profile increases confidence in the accuracy of the prevalence estimate. An additional limitation to our study is the high prevalence of White participants, which does not reflect the demographic characteristics of the larger US population; thus, the prevalence of ATTR-CM is likely an underestimate of the more diverse general US population and may not be applicable to more typical urban-dwelling, multiethnic communities. Finally, our study is not able to determine the cost-effectiveness of our systematic screening strategy or the treatment of those participants ultimately diagnosed with ATTR-CM, particularly given the high cost of tafamidis, the only currently approved therapy for ATTR-CM.
Conclusions
In a community-based setting, ATTR-CM was present in a substantial number of cases of HFpEF and ventricular wall thickening, especially in older men. Systematic evaluation for ATTR-CM may significantly increase its diagnosis and offer therapeutically relevant phenotyping of HFpEF.
eMethods. Supplemental Methods
eTable 1. Heart Failure Validation Criteria
eTable 2. Effect of Sample Size and Observed Prevalence on Precision of the Prevalence Estimates
eTable 3. Medication Use in the Community Screening Cohort
eTable 4. Participants vs Non-participants
eTable 5. Model Predictive of Transthyretin Amyloid Cardiomyopathy
eTable 6. Amyloidosis Work-up of Pyrophosphate Scan Positive Subjects
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Supplemental Methods
eTable 1. Heart Failure Validation Criteria
eTable 2. Effect of Sample Size and Observed Prevalence on Precision of the Prevalence Estimates
eTable 3. Medication Use in the Community Screening Cohort
eTable 4. Participants vs Non-participants
eTable 5. Model Predictive of Transthyretin Amyloid Cardiomyopathy
eTable 6. Amyloidosis Work-up of Pyrophosphate Scan Positive Subjects