Echocardiographic Analysis of Predictors of Cardiac Dysfunction in Patients With Hereditary Hemochromatosis

Introduction: Hereditary hemochromatosis (HH) is a heterogenous genetic disorder of excess body iron storages caused by unregulated intestinal iron absorption. Approximately 15% of patients with HH have cardiac involvement with 0.9 to 3.0% classically developing an infiltrative, restrictive cardiomyopathy. We described the correlation between echocardiographic findings and cardiac dysfunction in patients with HH. Methods: In this retrospective study, we included patients with HH who underwent transthoracic echocardiography at a tertiary care center between August 2000 and July 2022. We defined 3 primary outcomes for cardiac dysfunction: 1) left ventricular ejection fraction (LVEF) < 55 %, 2) ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) > 15, and 3) global longitudinal strain (GLS) > -18. Multivariable logistic regression was used to identify predictors for cardiac dysfunction. Results: 582 patients (median age 57 years, 61.2% male) were included. The frequency of LVEF < 55%, E/e’ > 15 and GLS > -18 were 9.0% (52/580), 9.6% (51/534) and 20.2% (25/124), respectively. Table 1 In multivariable analysis, non-White race (OR 4.36, P=0.007), and C282Y/H36D genetic mutation (OR 0.10, P=0.034) were associated with E/e’ > 15. No specific HFE genetic mutation was associated with LVEF < 55%. A history of myocardial infarction was strongly associated with both LVEF < 55% and E/e’ > 15. Patients with C282Y/H63D had a higher frequency of myocardial infarction. Smoking and alcohol use were significantly associated with GLS > -18 in unadjusted analysis. Conclusion: To our knowledge, this is the largest study to summarize the echocardiographic findings in patients with HH and the only to determine risk factors and the effects of HFE genetic mutations on cardiac dysfunction. We found the traditional risk factors of male sex, and history of myocardial infarction or heart failure, were associated with a reduced LVEF, irrespective of the underlying HFE genetic mutation. We found patients with a C282Y/H63D genetic mutation had a higher frequency of myocardial infarction, yet this mutation was associated with reduced odds of diastolic dysfunction compared to other genetic mutations. Our findings reinforce the usefulness of echocardiography as a screening test in HH. A potential application of our findings is the derivation of a risk score to predict cardiac dysfunction in patients with HH (Figure 1).Figure 1.: Transthoracic Echocardiography of Reduced Left Ventricular Ejection Fraction. Panels A and D show diastole and Panels B and C shows systole. Panels A and C show the apical 4 chamber view. Panels B and D show the parasternal long axis. LV, left ventricle, RV, right ventricle. Table 1. - Comparison of echocardiogram, laboratory, ECG, and CMR information according to HFE genetics Median (minimum, maximum) or No. (%) of patients Variable N C282Y/H63D or C282Y/C282Y patients (N=178) C282Y/H63D patients (N=56) C282Y/C282Y patients (N=122) Other patients (N=201) P-value Echocardiogram information 379 Primary outcomes LVEF 377 63 (23, 77) 63 (45, 75) 63 (23, 77) 63 (30, 80) 0.70 Cardiac dysfunction defined by LVEF < 55% 377 15 (8.5%) 6 (10.9%) 9 (7.4%) 18 (9.0%) 0.72 E/e’ 348 8.9 (4.5, 25.0) 8.6 (4.5, 21.4) 8.9 (5.0, 25.0) 10.0 (0.1, 25.0) 0.53 Cardiac dysfunction defined by E/e’ > 15 348 9 (5.6%) 1 (2.0%) 8 (7.1%) 21 (11.2%) 0.088 Global longitudinal strain (GLS) 110 -19 (-24, -12) -19 (-23, -12) -20 (-24, -14) -19.5 (-26, -16) 0.32 Cardiac dysfunction defined by GLS > -18 110 14 (20.6%) 6 (28.6%) 8 (17.0%) 8 (19.0%) 0.62 Secondary outcomes LVEDD 375 45 (27, 66) 47 (35, 65) 45 (27, 66) 46.5 (30, 70) 0.030 LVESD 366 29 (16, 56) 30 (20, 49) 29 (16, 56) 30 (2, 52) 0.34 LV mass index 374 79 (37, 134) 87 (50, 134) 75.5 (37, 134) 83 (40, 233) 0.077 LVESV 145 35 (11, 82) 32 (11, 81) 35.5 (14, 82) 38 (16, 130) 0.20 LVEDV 145 92 (53, 197) 91 (55, 197) 98.5 (53, 169) 103 (52, 201) 0.25 LVEF thru volume 145 62 (22, 75) 65.5 (43, 75) 61.5 (22, 75) 64 (35, 76) 0.11 LA volume index 350 25 (10, 61) 22 (10, 44) 25 (13, 61) 25 (8, 70) 0.027 Diastolic dysfunction grade 82 0.34 1 38 (95.0%) 11 (91.7%) 27 (96.4%) 36 (85.7%) 2 2 (5.0%) 1 (8.3%) 1 (3.6%) 6 (14.3%) 3 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) RV size measurements 189 27 (14, 50) 27 (16, 34) 28 (14, 50) 28 (9, 41) 0.63 TAPSE 179 22 (15, 35) 21 (17, 29) 23 (15, 35) 22 (0, 33) 0.36 RVSP 206 27 (15, 82) 27 (21, 65) 27 (15, 82) 29 (14, 69) 0.16 Estimated RA pressure 275 5 (4, 15) 5 (5, 10) 5 (4, 15) 5 (5, 15) 0.27 Laboratory values 301 Troponin 35 3 (0, 49) 6 (0, 49) 0 (0, 42) 0 (0, 118) 0.56 Sodium 275 139 (126, 145) 139 (130, 144) 140 (126, 145) 139 (126, 152) 0.17 Creatinine 279 0.9 (0.4, 2.7) 0.9 (0.5, 2.7) 0.8 (0.4, 2.0) 0.9 (0.5, 9.9) 0.016 GFR 271 64.5 (17.0, 131.4) 67.5 (17.0, 131.4) 60.0 (36.0, 90.0) 60.0 (5.0, 90.0) 0.022 Ferritin 113 72.0 (4.9, 972.0) 375.5 (19.0, 639.0) 72.0 (4.9, 972.0) 156.5 (8.0, 962.0) 0.021 ECG information 352 AI probability of atrial fibrillation 336 1.4 (0.0, 98.6) 1.9 (0.0, 85.5) 1.2 (0.0, 98.6) 1.8 (0.0, 95.5) 0.60 AI probability of HCM 352 0.1 (0.0, 52.4) 0.1 (0.0, 18.2) 0.1 (0.0, 52.4) 0.1 (0.0, 600.0) 0.83 AI probability of LV dysfunction 351 0.8 (0.1, 90.9) 0.8 (0.1, 39.8) 0.8 (0.1, 90.9) 1.1 (0.1, 94.9) 0.011 LVH 349 6 (3.7%) 4 (7.8%) 2 (1.8%) 15 (8.1%) 0.046 CMR information 32 LVESV 32 39.0 (16.0, 75.1) 48.0 (16.0, 75.1) 30.0 (19.0, 72.0) 42.5 (19.0, 129.0) 0.62 LVEDV 32 92 (42, 147) 105 (50, 147) 75 (42, 112) 75 (46, 237) 0.40 LVEF 31 58.5 (27.0, 68.0) 60.0 (37.5, 68.0) 54.0 (27.0, 65.0) 56.0 (15.0, 68.0) 0.66 LVEF=left ventricular ejection fraction=E/e’=early mitral inflow velocity and mitral annular early diastolic velocity; GLS=global longitudinal strain; LVEDD=left ventricular end-diastolic diameter; LVESD=left ventricular end-systolic diameter; LV=left ventricle; LVESV=left ventricle end-systolic volume; LVEDV=left ventricle end-diastolic volume; LA=left atrium; RV=right ventricle; TAPSE=tricuspid annular plane systolic excursion; RVSP=right ventricular systolic pressure; RA=right atrium; ECG=electrocardiogram; AI=artificial intelligence; HCM=hypertrophic obstructive cardiomyopathy; LVH; left ventricular hypertrophy; CMR=cardiac magnetic resonance imaging. P-values result from a Kruskal-Wallis rank sum test (continuous and ordinal variables) or Fisher’s exact test (categorical variables) comparing characteristics between the 3 groups of C282Y/H36D patients, C282Y/C282Y patients, and other patients.