Natriuretic peptides and the genomics of left-ventricular hypertrophy

Abstract

Left-ventricular hypertrophy (LVH) is one of the strongest independent predictors of cardiovascular morbidity and mortality in the general population. Although hypertension and obesity are well-established, independent risk factors for the development of LVH, they explain less than 25% to 50% of the variance of left ventricular mass (LVM) in humans. A substantial body of evidence suggests that there is a genetic basis to the observed inter-individual variability in the susceptibility to the development of LVH. Given the continuous relationship between LVM and cardiovascular morbidity and mortality, elucidating the genetic determinants of inter-individual differences in the susceptibility to LVH is of considerable public health importance. It promises the opportunity to identify high-risk individuals for targeted intervention and may identify novel therapeutic targets for improved prevention and treatment strategies.

Figure 1

ProBNP is produced in cardiomyocytes where it is not stored but rapidly targeted for secretion after removal of the targeting sequence. Our current paradigm suggests that BNP 1-108 is released from ventricular cardiomyocytes and interacts with the extracellular protease fragment of membrane-bound corin, a type II transmembrane serine protease. This interaction cleaves corin in a sequence-dependent manner resulting in a 32 amino acid carboxyl fragment, termed BNP-32, and a 76 amino acid amino terminal fragment, termed NT-BNP.

Figure 2

The corin I555(P568) minor allele is comprised of two single nucleotide polymorphisms that are in complete linkage disequilibrium in African-Americans with an allelic prevalence of 6%. The SNPs result in a T555I and Q568P amino acid change within the second cysteine-rich, frizzled domain in corin. These amino acid changes are biochemically non-conservative and demonstrate strong conservation. Because of the linkage disequilibrium, the SNPs travel on the same parental chromosome are the two resulting amino acid changes will be transcribed into the same corin molecule in heterozygous carriers of the corin I555(P568) minor allele.

Figure 3

The relationship of left-ventricular mass indexed (LVMI) to either fat-free mass or body-surface area and systolic blood pressure as a function of corin I555(P568) carrier status was examined in untreated (no antihypertensive medication) African-Americans participating in the Dallas Heart Study. Participants heterozygous for the corin I555(P568) allele demonstrated increased LVMI as compared to wild-type corin carriers in the higher ranges of systolic blood pressure. († P < 0.1; * P<0.5 ).

Figure 4

An increase in the ratio of left ventricular mass (LVM) (grams) to left ventricular end diastolic volume (EDV) (cc) is a measure of concentric left ventricular hypertrophy. The untreated self-identified African-American Dallas Heart Study participants heterozygous for the corin I555(P568) allele as compared to wild-type participants demonstrated increasing degrees of concentric cardiac hypertrophy as systolic blood pressure increased.

Figure 5

The relationship of left-ventricular mass indexed (LVMI) to body-surface area and systolic blood pressure as a function of corin I555(P568) carrier status was examined in untreated (no antihypertensive medication) African-Americans participating in the Multi-Ethnic Study of Atherosclerosis (MESA). Similar to findings in the Dallas Heart Study, untreated African-American participants heterozygous for the corin I555(P568) allele demonstrated increased LVMI compared to corin wild-type participants in the higher ranges of systolic blood pressure. († P < 0.1; * P<0.5 ).

Figure 6A and B

In the Dallas Heart Study, the prevalence of LVH, defined by indexing left-ventricular mass to either fat-free mass (FFM) or body-surface area (BSA) was significantly greater in untreated hypertensive African-American participants that were heterozygous for the corin I555(P568) allele as compared to wild-type. In the Multi-Ethnic Study of Atherosclerosis, there was a trend for a higher prevalence of LVH, defined by indexing left-ventricular mass to body-surface area, in untreated African-American participants that were heterozygous for the corin I555(P568) allele as compared to wild-type