A Unique High‐Output Cardiac Hypertrophy Phenotype Arising From Low Systemic Vascular Resistance in Cantu Syndrome

Figures

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  Figure 1. Structural remodeling in the CS heart. LVEDV Z score (A) and LVMI (B) are increased in subjects with CS compared with the control group. C, RWT1 is normal in subjects with CS. P values from Wilcoxon rank sum tests are shown. P<0.05 indicates a statistically significant difference between control and CS cohorts. D, Representative 4C (above) and M‐mode (below) echocardiographic images of a control (male sex, 64 kg, ages 15 years [left]) and CS (male sex, 77 kg, aged 16 years [right]) subjects. 4C end‐diastolic volumes were 116 mL (Z=−0.5) and 389 mL (Z=8.1), and ejection fractions were 59% and 70%, for the control and subject with CS, respectively. M‐mode dimensions were diastolic 5.1 cm (Z=0.4) and 7.6 cm (Z=5.8), systolic 3.4 cm (Z=0.4) and 4.8 cm (Z=3.6), and shortening fraction was 33% and 37%, respectively. CS indicates Cantu syndrome; LVEDD, left ventricular end diastolic dimension; LVEDV, left ventricular end‐diastolic volume; LVESD, left ventricular end systolic dimension; LVMI, left ventricular mass index; and RWTI, relative wall thickness.

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  Figure 2. Enhanced left ventricular function in CS. Left ventricular FS (%) (A) and EF (%) (B) are increased in subjects with CS compared with the control group. LV GS Long overall (C), LV GSRs Long (D), and LV GSRe Long (E) are increased in subjects with CS. F, E'/A' is decreased in subjects with CS. P values from Wilcoxon rank sum tests are shown. P<0.05 indicates a statistically significant difference between the control and CS cohorts. A' indicates late diastolic velocity of mitral annulus; CS, Cantu syndrome; E', early diastolic velocity of mitral annulus; E'/A', ratio of E' over A'; EF, ejection fraction; FS, fractional shortening; LV, left ventricle; LV GS Long overall, LV global longitudinal systolic strain; LV GSRe Long, LV diastolic global strain rate; and LV GSRs Long, LV systolic global strain rate.

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  Figure 3. Hemodynamic metrics in subjects with CS. Cardiac index (cardiac output normalized to body surface area) (A) and vascular compliance (as measured by Young's elastic modulus) (B) are increased in subjects with CS. P values from Wilcoxon rank sum tests are shown. P<0.05 indicates a statistically significant difference between the control and CS cohorts. CS indicates Cantu syndrome.

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  Figure 4. Longitudinal assessment of left ventricle dimension. LVEDV Z score was determined in the cohort of subjects with CS over up to 7 years. A trend toward increasing LVEDV Z scores was observed for all subjects with CS (A), and this was more pronounced for younger subjects (first visit at age <18 years [B]) than older subjects (first visit at age >18 years [C]). Data are shown as median Z score value for the CS cohort per visit (blue circles with 95% CIs; linear regression fits in black; slope=0.26, P=0.0609 [A]; slope=0.39, P=0.0208 [B]; slope=0.15, P=0.3652 [C]). Number of subjects at each visit is shown above data points. Data were fit with a mixed random‐effects repeated measures model to test whether changes across time were significant. *P<0.05 for any visit compared with visit 1. CS indicates Cantu syndrome; LV, left ventricular; and LVEDV, left ventricular end diastolic volume.

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  Figure 5. Longitudinal assessment of ventricular function and vascular elasticity. A and B, Both left ventricular ejection fraction (A) and LV GS Long overall (B) remained stable over repeated annual visits for subjects with CS. Number of subjects included in each repeat visit is indicated. Data are shown as median Z score value for the CS cohort per visit (blue circles with 95% CIs; linear regression fit shown in black; slope=0.85, P=0.06 [A]; slope=0.14, P=0.34 [B]). C, Young's elastic modulus did not significantly change over repeated annual visits for subjects with CS. Data are shown as median Z score value for the CS cohort per visit (blue circles with 95% CIs; linear regression fit shown in black; slope=−0.25, P=0.8755). Data were fit with a mixed random‐effects repeated measures model that showed there were no statistically significant differences in values over time. CS indicates Cantu syndrome; LV, left ventricular; and LV GS, left ventricular systolic global strain rate.

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  Figure 6. Mechanism of cardiovascular pathophysiology in CS. (Top left) KATP channel composed of Kir6.1 (KCNJ8) and SUR2 (ABCC9) is expressed in the plasma membrane of smooth muscle cells, including VSM. CS‐associated ABCC9 or KCNJ8 variants cause gain‐of‐function of KATP channels in VSM, driving hyperpolarization of the membrane potential. (Top right) VSM membrane potential hyperpolarization is predicted to result in chronic vasodilation in CS, as reflected by marked decreases in SVR. (Bottom) Cardiac remodeling to high‐output hypertrophic state arises secondary to chronically lowered SVR, resulting in elevated cardiac mass, contractility, and output in subjects with CS. This progresses to HOHF in older subjects. CS indicates Cantu syndrome; EF, ejection fraction; HOHF, high‐output heart failure; KATP, ATP‐sensitive potassium; LVMI, left ventricular mass index; SVR, systemic vascular resistance; and VSM, vascular smooth muscle.