Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis

Authors, Journal, Affiliations, Type, DOI

• Hagit Baris Feldman, Chofit Chai Gadot, David Zahler, Adi Mory, Galit Aviram, Emil Elhanan, Gabi Shefer, Ilana Goldiner, Yam Amir, Alina Kurolap, Jacob N. Ablin
• N Engl J Med 2023;389:1685-92
• Tel Aviv Sourasky Medical Center / Tel Aviv University, Israel
• Brief Report (original article — case series of two siblings + functional experiments)
• DOI: 10.1056/NEJMoa2301908

Overview

Two Filipino siblings with a homozygous loss-of-function frameshift in CORIN (c.684dupG; p.Met229Aspfs*16) each presented with a distinctive syndrome: isolated left atrial cardiomyopathy (LA fibrosis + LA hypertrophic remodelling), resistant hypertension, and refractory atrial arrhythmia (AF). Functional experiments confirmed complete absence of plasma corin and NT-proANP, establishing that CORIN is the enzyme solely responsible for proANP → ANP conversion in the left atrium. BNP rose compensatorily but could not fully substitute: β-ENaC remained upregulated (sodium retention), PICP was elevated (ongoing collagen turnover), and hypertension persisted despite antihypertensive therapy. This is the first human demonstration that complete corin deficiency causes a primary isolated left atrial cardiomyopathy, and provides a mechanistic explanation for why ANP — not BNP — is essential for left atrial homeostasis.

Keywords

Corin, atrial natriuretic peptide, ANP, proANP, NT-proANP, BNP, ENaC, left atrial cardiomyopathy, atrial fibrosis, hypertension, atrial fibrillation, CORIN frameshift variant

Key Takeaways

Clinical Presentation

• Two Filipino siblings (Patient 1: female; Patient 2: male) presented separately with cardiac arrhythmia; Patient 1 additionally had haemodynamic instability and multiorgan failure
• Both had a history of resistant hypertension and refractory atrial arrhythmia requiring repeat cardioversions and regular antiarrhythmic medications
• Mild hypertension persisted throughout hospitalisation despite antihypertensive treatment in both patients
• Patient 1 underwent pulmonary vein isolation for AF — initial success, but recurred to AF (ventricular rate 100–113 bpm) at 1-year follow-up; Patient 2 lost to follow-up
• Cardiac imaging (CT + CMR) in both siblings: isolated structural left atrial abnormalities — LA fibrosis and left atrial hypertrophic cardiomyopathy; no ventricular or right heart structural involvement documented
• Family history: early-onset hypertension in 8 family members; a niece confirmed hypertensive at age 35 (up to 163/113 mmHg on treatment); heterozygous CORIN carrier status identified in family — no confirmed cosegregation with hypertension

Genetic Findings

• Exome sequencing identified a homozygous frameshift in CORIN (NM_006587.4): c.684dupG; p.Met229Aspfs*16 — shared by both siblings; classified pathogenic by ACMG criteria (PVS1 + PS3 + PM2 + PP1 + PP4)
• Variant is extremely rare globally: MAF 0.009204%; 0.1304% in East Asians (gnomAD); all 26 gnomAD carriers are East Asian, suggesting enrichment in Southeast Asian populations
• Three other shared cardiovascular variants (SCN5A, CACNA1C, PRDM16) classified as benign or likely benign in ClinVar — not disease-driving
• Patient 1 (but not Patient 2) also carries a heterozygous PKP2 c.1711T→A; p.Ser571Thr — uncertain pathogenicity; no ARVC features; may have contributed to more severe acute presentation but unconfirmed

Corin and the ANP Pathway

• CORIN is a transmembrane serine protease on left atrial cardiomyocytes that cleaves proANP → active ANP + NT-proANP; the active ANP then drives cGMP-dependent natriuresis, diuresis, and vasodilation, and inhibits cardiac fibrosis
• Patient 1: plasma corin undetectable (ELISA); NT-proANP negligible — confirming complete failure of proANP processing
• BNP moderately elevated — compensatory upregulation activating the shared NPR-A receptor; explains the relatively mild (not severe) hypertension despite complete ANP absence
• Intracellular cGMP (HEK293 cells + patient plasma): similar to healthy controls (BNP compensating), lower than hypertensive controls — partial downstream signalling preserved
• β-ENaC protein (HEK293 cells): highest with patient plasma and AF-control plasma; α-ENaC unchanged across groups — consistent with impaired ANP-mediated ENaC inhibition → sodium retention → hypertension
• Urinary electrolytes and creatinine mildly reduced — consistent with some sodium/water retention despite elevated BNP
• Plasma renin activity and aldosterone: within normal range — primary RAAS not deranged

Atrial Fibrosis

• Both siblings had imaging-confirmed LA fibrosis; ANP normally inhibits fibroblast infiltration into cardiac tissue — its absence promotes atrial fibro-inflammatory remodelling → AF substrate
• PICP (C-terminal propeptide of type I procollagen): elevated in Patient 1 vs. healthy controls — active collagen turnover consistent with ongoing fibrosis
• TIMP-1 (tissue inhibitor of metalloproteinases 1, prognostic marker in HF): normal in Patient 1 — similar to healthy controls, lower than hypertensive or AF controls; potentially a favourable prognostic signal for heart failure severity

Mouse vs. Human Phenotype Discrepancy

• Corin⁻/⁻ mice: hypertension + cardiac hypertrophy, elevated cardiomyocyte proANP, undetectable blood ANP — but no atrial fibrosis in cardiac biopsy specimens
• Human CORIN LOF: atrial fibrosis is a prominent feature — the human left atrium appears uniquely dependent on ANP-mediated anti-fibrotic signalling beyond what murine models capture

Broader Corin Landscape and Therapeutic Implications

• Heterozygous CORIN missense variants previously linked to hypertension, arrhythmia, and preeclampsia
• NPPA (ANP precursor) frameshift mutation → familial AF (NEJM 2008) — supports the CORIN/ANP axis as a monogenic AF pathway
• Plasma corin: decreased in HF, increased in AF — bidirectional dysregulation; soluble corin may serve as a biomarker
• Soluble corin infusion in Corin⁻/⁻ mice transiently restored proANP cleavage → elevated blood ANP and cGMP — proof-of-concept for corin replacement as a therapeutic target
• Amiloride (ENaC blocker): targets the downstream sodium retention mechanism; a candidate therapy for CORIN LOF and refractory hypertension more broadly

Limitations of the Document

• n=2 (two siblings from a single family with the identical variant); all functional experiments derived from Patient 1 alone (Patient 2 declined further participation)
• Case report design: cannot establish clinical spectrum, prevalence, or penetrance of CORIN LOF
• Plasma ANP not directly measured (lack of assay with acceptable specificity); inferred from absent NT-proANP
• cGMP and ENaC experiments performed in HEK293 cells (non-cardiac, non-primary cells); extrapolation to in vivo renal tubular physiology is indirect
• Mouse model lacks atrial fibrosis — mechanistic gap between rodent and human phenotype unresolved
• Heterozygous carrier hypertension risk: not confirmed by cosegregation; hypothesis requires population-level validation
• PKP2 variant of uncertain significance in Patient 1: cannot exclude contribution to more severe presentation

Key Concepts Mentioned

• concepts/Atrial-Cardiomyopathy — CORIN LOF is the first monogenic cause of primary isolated left atrial cardiomyopathy
• entities/Atrial-Fibrillation — AF as a sequela of atrial fibrosis in CORIN LOF

Key Entities Mentioned

• entities/CORIN — homozygous LOF variant; ANP-converting enzyme; cardiac natriuretic peptide system
• entities/Hypertension — primary presentation; ENaC-mediated sodium retention mechanism
• entities/PKP2 — heterozygous variant of uncertain significance in Patient 1

Wiki Pages Updated

• Created wiki/sources/corin-acmp-nejm-2023.md
• Created wiki/entities/CORIN.md
• Updated wiki/concepts/Atrial-Cardiomyopathy.md
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md