Giulia Nardoianni (1), Maria Cotugno (2), Donatella Pietrangelo (2), Margherita Litterio (2), Caroline Lopa (2), Giuliano Tocci (1), Massimo Volpe (3), Emanuele Barbato (1), Speranza Rubattu (4), Giovanna Gallo (1)

(1) Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma, Unità di Cardiologia Azienda Ospedaliero Universitaria Sant'Andrea, Roma, Italia
(2) IRCCS Neuromed, Pozzilli (Is)
(3) Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma,IRCCS San Raffaele Roma
(4) Dipartimento di Medicina Clinica e Molecolare, Sapienza Università di Roma,IRCCS Neuromed, Pozzilli (Is)

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Background and aims: Previous experimental studies showed that dysfunctions of mitofusin 2 (Mfn2), a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial network regulation, are associated with the development of left ventricular hypertrophy (LVH). Mfn2 participates in various biological processes under physical and pathological conditions, including mitochondrial fusion, reticulum–mitochondria contacts, mitochondrial quality control, and apoptosis.

Methods and results: We examined the association of MFN2/rs2336384 and MNF2/rs2236057 polymorphic variants with the development of LVH in hypertensive patients. Three-hundred-fourty-five hypertensive subjects (199 male, 57.6%) with a mean age of 60±14 years were studied. One-hundred-thirteen individuals (33%) presented LVH. The association analysis for both SNPs showed that hypertensive patients carrying the GG genotype at the MFN2/rs2336384 had a significant increase of echocardiographically assessed septal thickness (p=0.001), posterior wall thickness (p=0.001), relative wall thickness (RWT) (p=0.003), LV mass/ body surface area (BSA) (p=0.001), LV mass/height2.(p=0.001), left atrium volume index (LAVi) (p=0.001) compared to subjects carrying either TT or TG genotypes. To better dissect the genetic effect, a covariate ANOVA was performed for each cardiac variable, considering age, gender, body mass index (BMI), office blood pressure (BP), antihypertensive treatment with a combination of 2 or more drugs and the number of BP-lowering agents as covariates. The adjustment for covariates revealed significant differences for septal thickness (p=0.039), posterior wall thickness (p=0.017), LV mass/BSA (p=0.036) and LAVi (p=0.002). With regard to MNF2/rs2236057, hypertensive subjects carrying the mutant A allele had a significant increase of septal thickness (p=0.001), posterior wall thickness (p=0.002), RWT (p=0.01), LV mass/BSA(p=0.001), LV mass/height2.7(p=0.002) and LAVi (p=0.001) compared to wild-type homozygotes (GG genotype) and heterozygotes (GA genotype). After adjustment for covariates, the results were significant for septal thickness (p=0.05), posterior wall thickness (p=0.038), LV mass/BSA (p=0.046) and LAVi(p=0.003).Multivariable logistic regression analysis, assuming the development of LVH as the dependent variable and both SNPs with the above-mentioned covariates as independent variables, demonstrated that the carrier status of both G allele at rs2336384 and AA genotype at s2236057was associated with an increased risk of LVH (OR=2.175 [95% confidence interval, 1.27–3.71]; P=0.004 and OR=1.617 [95% confidence interval, 1.13–2.31]; P=0.009, respectively).

Conclusions: Our results demonstrate a significant association of MFN2 variants with LVH in hypertensives and highlight a role of MFN2 dependent mitochondrial dysfunction on increased susceptibility to cardiac damage in human hypertension. This study paves the way of a new pathophysiological mechanism of LVH which may lead to new clinical strategies.