Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

Abstract

Mechanical overload can be classified into pressure overload and volume overload, causing concentric and eccentric cardiac hypertrophy, respectively. Here, we aimed to differentiate the load-mediated signaling pathways involved in pressure versus volume overload cardiac hypertrophy. Pressure or volume overload was imposed on C57BL/6J mice by transverse aortic constriction (TAC) or aortic regurgitation (AR), respectively. After surgery (2 wk), left ventricular structure and function were evaluated by echocardiographic, hemodynamic, and histological analyses. Signaling pathways related to hypertrophy, fibrosis, angiogenesis, and apoptosis were studied by histological analysis, RT-PCR, and Western blot analysis. Although mean wall stress was similar in both TAC and AR mice, systolic wall stress was significantly increased in TAC and diastolic wall stress was mainly elevated in AR. TAC or AR induced concentric or eccentric compensated hypertrophy, respectively. TAC was associated with more significant fibrosis and apoptosis, whereas AR was associated with more significant angiogenesis. MAPK kinase family, β-arrestin-2, Akt, and Ca-related signaling pathways were markedly activated in TAC but mildly upregulated or unchanged in AR. Pressure overload and volume overload induce different phenotypic and molecular adaptations in cardiac hypertrophy. Most load-related signaling pathways assessed in this study predominate in pressure but not volume overload. The stimulus-specific heterogeneity in the signaling pathways requires distinct manipulations for further mechanistic and pharmacological studies. NEW & NOTEWORTHY Using the transverse aortic constriction mouse model and the newly developed aortic regurgitation mouse model, we delineated the prominent differences between concentric and eccentric cardiac hypertrophy on morphological, functional, and molecular levels. Our findings are important for the precise diagnosis and treatment of these two types of cardiac hypertrophy. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/chinese-english-language-podcast-on-differential-cardiac-remodeling-in-tac-vs-ar/ .

Implications of myocardial dysfunction before and after aortic valve intervention

“…Implications of myocardial dysfunction before and after aortic valve intervention 60 ᵃ Data is given as medians [IQR] or numbers (%). ᵇ = upper limit values for normal LV mass for females, ᶜ = upper limit values for normal LV mass for males, E/A = early diastolic filling velocity/late diastolic filling velocity, E/eʼ =early diastolic filling velocity/early diastolic myocardial velocity, ᵈ = reference value for E/eʼ indicating high filling pressure (Nagueh S F et 15 [11][12][13][14][15][16][17][18][19][20] 13 [8][9][10][11][12][13][14][15][16][17] 0.15…”

“…In eccentric hypertrophy, sarcomeres replicate in a serial pattern. Conversely, in aortic stenosis, the heart compensates with concentric hypertrophy, where sarcomeres replicated in a parallel pattern 18 .…”

Myotubularin-related protein 14 suppresses cardiac hypertrophy by inhibiting Akt

“…As a treatment option, inhibition of pathological CH has become a potential therapeutic target. Moreover, the signaling effectors underlying the pressure versus volume overload discrepancy remain to be clarified 6 .…”

Effect of atorvastatin on cardiomyocyte hypertrophy through suppressing MURC induced by volume overload and cyclic stretch

“…Pressure overload‐mediated concentric hypertrophy leads to a normal left ventricular volume and an increase in wall thickness . However, the eccentric hypertrophy induced by volume overload causes an increase in the left ventricular volume while not affecting the wall thickness . Recently, there has been a significant increase in the number of studies concerned with the molecular mechanism of hypertrophy, especially in concentric hypertrophy induced by pressure overload .…”

“…2 However, the eccentric hypertrophy induced by volume overload causes an increase in the left ventricular volume while not affecting the wall thickness. 3 Recently, there has been a significant increase in the number of studies concerned with the molecular mechanism of hypertrophy, especially in concentric hypertrophy induced by pressure overload. 4 However, the molecular regulation mechanism of eccentric hypertrophy caused by volume overload is still not fully understood.…”