Aldosterone, through novel signaling proteins, is a fundamental molecular bridge between the genetic defect and the cardiac phenotype of hypertrophic cardiomyopathy.
BACKGROUND
Human hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in the young, is characterized by cardiac hypertrophy, myocyte disarray, and interstitial fibrosis. The genetic basis of HCM is largely known; however, the molecular mediators of cardiac phenotypes are unknown.


RESULTS
We show myocardial aldosterone and aldosterone synthase mRNA levels were elevated by 4- to 6-fold in humans with HCM, whereas cAMP levels were normal. Aldosterone provoked expression of hypertrophic markers (NPPA, NPPB, and ACTA1) in rat cardiac myocytes by phosphorylation of protein kinase D (PKD) and expression of collagens (COL1A1, COL1A2, and COL3A1) and transforming growth factor-beta1 in rat cardiac fibroblasts by upregulation of phosphoinositide 3-kinase (PI3K)-p100delta. Inhibition of PKD and PI3K-p110delta abrogated the hypertrophic and profibrotic effects, respectively, as did the mineralocorticoid receptor (MR) antagonist spironolactone. Spironolactone reversed interstitial fibrosis, attenuated myocyte disarray by 50%, and improved diastolic function in the cardiac troponin T (cTnT)-Q92 transgenic mouse model of human HCM. Myocyte disarray was associated with increased levels of phosphorylated beta-catenin (serine 38) and reduced beta-catenin-N-cadherin complexing in the heart of cTnT-Q92 mice. Concordantly, distribution of N-cadherin, predominantly localized to cell membrane in normal myocardium, was diffuse in disarrayed myocardium. Spironolactone restored beta-catenin-N-cadherin complexing and cellular distribution of N-cadherin and reduced myocyte disarray in 2 independent randomized studies.


CONCLUSIONS
The results implicate aldosterone as a major link between sarcomeric mutations and cardiac phenotype in HCM and, if confirmed in additional models, signal the need for clinical studies to determine the potential beneficial effects of MR blockade in human HCM.
Section of Cardiology, Department of Medicine, Baylor College of Medicine and The Methodist Hospital, Houston, Tex 77030, USA.
Natalia
N
Tsybouleva
Lianfeng
L
Zhang
Suetnee
S
Chen
Rajnikant
R
Patel
Silvia
S
Lutucuta
Shintaro
S
Nemoto
Gilberto
G
DeFreitas
Mark
M
Entman
Blase A
BA
Carabello
Robert
R
Roberts
A J
AJ
Marian
D000368:Aged; D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D015415:Biomarkers; D015820:Cadherins / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis; D000242:Cyclic AMP / Q000032:analysis; D019405:Cytochrome P-450 CYP11B2 / Q000096:biosynthesis / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D006801:Humans; D006984:Hypertrophy; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000378:metabolism; D020107:Troponin T / Q000235:genetics; D051176:beta Catenin
D015415:Biomarkers; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D020107:Troponin T; D051176:beta Catenin; D013148:Spironolactone; D000450:Aldosterone; D003094:Collagen; D000242:Cyclic AMP; D019405:Cytochrome P-450 CYP11B2; D019869:Phosphatidylinositol 3-Kinases