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Background Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born Results Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p p = 3.44E−11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. Conclusions These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Diagnosis of heart failure with preserved ejection fraction (HFpEF) is becoming the prevalent form of disease type. Established treatments for heart failure with reduced ejection fraction (HFrEF) have proven minimally effective for HFpEF. This may reflect differences in underlying cardiomyocyte pathophysiology. In HFrEF cardiomyocyte phenotype is characterized by impaired contractile response and diminished systolic Ca 2+ levels. Studies of intact HFpEF-derived cardiomyocytes are lacking. Progress in understanding the etiology of HFpEF has been impeded by limited availability of appropriate pre-clinical models. Our goal was to validate and characterize a new rodent model of HFpEF, the ‘Hypertrophic Heart Rat’ (HHR), undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. The selectively inbred HHR strain exhibits adult cardiac enlargement (without hypertension) and premature mortality (40% at age 50 weeks) compared to the control ‘Normal Heart Rat’ (NHR). Echo analyses established that cardiac hypertrophy was characterized in vivo by maintained systolic parameters (i.e. ejection fraction at 85-90% control) with marked diastolic dysfunction (i.e. increased E/E’). Diastolic dysfunction was detectable in young adult HHR, as an early disease marker. Histological examination identified regions of focal reparative fibrosis in HHR hearts, most prominent in the transverse midwall area of the left ventricle adjacent to the interventricular septum. Evaluation of cardiomyocyte function using left ventricular myocytes isolated from hearts of 30 week (prefailing ) HHR revealed a hypercontractile phenotype with high Ca 2+ operational levels and arrhythmogenic vulnerability. HHR cardiomyocytes exhibited dramatically increased L-type Ca 2+ channel current density (almost 2-fold), and molecular analyses identified hyperphosphorylation of key sarcoplasmic reticulum Ca 2+ regulatory proteins, without change in total phospho-titin. These findings strongly support the contention that HFpEF and HFrEF can have different underlying cardiomyocyte phenotypes. New directions for HFpEF therapies are indicated, and the HHR provides a new model for preclinical HFpEF investigations.