Woo, Anna

Importance Current risk prediction guidelines for hypertrophic cardiomyopathy predict only sudden cardiac death and are imperfect, leading to avoidable deaths and unnecessary implantable cardioverter defibrillators. Objective To combine prospectively collected clinical history, imaging, genetic, and biomarker data to improve risk prediction of adverse events in hypertrophic cardiomyopathy. Design, Setting, and Participants A total of 2750 patients with hypertrophic cardiomyopathy were prospectively enrolled in the registry-based study from 44 sites in North America and Europe with expertise in hypertrophic cardiomyopathy and cardiac magnetic resonance (CMR) imaging. Participants were enrolled from April 1, 2014, to April 7, 2017. Exposures Patients underwent a health history questionnaire, blood sampling for biomarkers and genotyping, and contrast-enhanced CMR. Patients were followed up yearly by telephone and through records review regarding event documentation. Main Outcomes and Measures The predefined composite adjudicated primary end point was time to first event for hypertrophic cardiomyopathy–related deaths; nonfatal sustained ventricular arrhythmias (VAs) requiring cardioversion or defibrillation; and left ventricular (LV) assist device implant or heart transplant. A secondary end point was a composite of sudden cardiac death and nonfatal VA events. The elastic-net method identified the most important predictors. Cox proportional hazards regression assessed associations with time to the first end point. Results Of the 2750 prospectively enrolled patients, 2698 (98%) had analyzable data after 9 were excluded because they had hypertrophic cardiomyopathy phenocopies and 43 withdrew. Of these remaining patients, 1919 (71%) were male, mean age was 50 years (SD, 11 years), and 423 (16%) were from underrepresented racial and minority groups. The mean follow-up was 6.9 years (SD, 2.1 years). The primary event model in 104 patients included LV scar as a percentage of LV mass by late gadolinium enhancement (LGE%; hazard ratio [HR], 1.86; 95% CI, 1.58-2.20; P < .001), LV mass index (HR, 1.09; 95% CI, 1.01-1.17; P = .03), LV end-systolic volume index (HR, 1.28; 95% CI, 1.12-1.46; P < .001 ), all per 10-unit increase, history of heart failure at study entry (HR, 2.89; 95% CI, 1.75-4.77; P < .001), and log N-terminal pro–B-type natriuretic peptide (NT-proBNP; HR, 1.41; 95% CI, 1.17-1.70; P < .001) level per log unit, (C index for all, 0.77). An LGE percentage of the LV mass of 9% or higher substantially increased the primary composite event rate ( P = .001). The secondary sudden cardiac death and VA risk factor model (in 69 patients) included LGE%, LV mass index, LV ejection fraction, and log(NT-proBNP) (C index, 0.76). Conclusions and Relevance These results provide prospective evidence for incorporating cardiac magnetic resonance and NT-proBNP in the evaluation of patients with hypertrophic cardiomyopathy. Trial Registration ClinicalTrials.gov Identifier: NCT01915615

Cux1 is a homeobox gene involved in cell cycle regulation and kidney development. Cux1 is upregulated in the kidneys of both mice and humans with autosomal dominant polycystic kidney disease (ADPKD). However, Cux1 transgenic mice do not develop cystic kidneys, indicating that upregulation of Cux1 alone is insufficient to develop PKD. Mice carrying a deletion of the C‐terminus of Cux1 (Cux1 tm2Ejn‐/‐ ) express a truncated protein that does not localize to the nucleus, resulting in functional loss of Cux1 transcriptional activity. To test the hypothesis that Cux1 is required to develop PKD, we generated collecting duct specific Pkd1 mutant mice (Pkd1 CD ) that were also homozygous for the Cux1 mutation. When kidneys isolated from newborn Pkd1 CD /Cux1 tm2Ejn ‐/‐ mice were examined, we found a marked reduction in cystic dilations compared to the kidneys isolated from newborn Pkd1 CD mice. We confirmed the Cre activity by crossing the Pkd1 CD and Pkd1 CD / Cux1 tm2Ejn ‐/‐ mice to the membrane‐targeted Tomato/Green Fluorescent Protein (mT/mG) double fluorescent reporter mouse strain (Gt(ROSA)26Sor tm4(ACTB‐tdTomato,‐EGFP)Luo /J), which carries a loxP‐flanked Tomato cassette. Immunofluorescence of kidney sections indicated that collecting duct derived cysts were positive for the excision event in the Pkd1 CD mice. In contrast, although collecting ducts were positive for the excision event in Pkd1 CD / Cux1 tm2Ejn ‐/‐ mice, none of the positive tubules were cystic. Taken together, our results suggest that Cux1 gene dosage influences the progression of cystic disease in an ADPKD mouse model.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic hereditary disorders in humans characterized by fluid-filled cysts, primarily in the kidneys. Cux1, a cell cycle regulatory gene highly expressed during kidney development, is elevated in the cyst-lining cells of Pkd1 mutant mice, and in human ADPKD cells. However, forced expression of Cux1 is insufficient to induce cystic disease in transgenic mice or to induce rapid cyst formation after cilia disruption in the kidneys of adult mice. Here we report a double mutant mouse model that has a conditional deletion of the Pkd1 gene in the renal collecting ducts together with a targeted mutation in the Cux1 gene (Pkd1CD;Cux1tm2Ejn). While kidneys isolated from newborn Pkd1CDmice exhibit cortical and medullary cysts, kidneys isolated from newborn Pkd1CD;Cux1tm2Ejn−/−mice did not show any cysts. Because Cux1tm2Ejn−/−are perinatal lethal, we evaluated Pkd1CDmice that were heterozygote for the Cux1 mutation. Similar to the newborn Pkd1CD;Cux1tm2Ejn−/−mice, newborn Pkd1CD;Cux1tm2Ejn+/−mice did not show any cysts. Comparison of Pkd1CDand Pkd1CD;Cux1tm2Ejn+/−mice at later stages of development showed a reduction in the severity of PKD in the Pkd1CD;Cux1tm2Ejn+/−mice. Moreover, we observed an increase in expression of the cyclin kinase inhibitor p27, a target of Cux1 repression, in the rescued collecting ducts. Taken together, our results suggest that Cux1 expression in PKD is not directly involved in cystogenesis but promotes cell proliferation required for expansion of existing cysts, primarily by repression of p27.