Why Valvular Cardiomyopathy May Persist after Surgery? A Joint Basic Science—Clinical Effort

Objectives: Aortic valve (AV) diseases leads to progressive pressure and/or volume overload of the left ventricle (LV) resulting into valvular cardiomyopathy, while progressive downregulation of β-adrenoceptors occurs. LV dysfunction may persist in one-fourth of patients after AV surgery, leading to terminal heart failure. We aimed to investigate whether differential remodeling in the protein kinase-A dependent inotropic response in myocytes and myocardial tissue is associated with the LV reremodeling after surgery.

Methods: A total of 124 consecutive patients undergoing elective AV surgery (2017–2019) were included in our study. LV biopsies were obtained intraoperatively from the LV outflow tract. In vitro force contractility testing was performed with myocardial tissue in an organ bath paced with 1 Hz at 37 °C. Simultaneously, freshly isolated cardiomyocytes were transduced with an adenovirus expressing a cytosolic Förster’s resonance energy transfer (FRET) based cAMP biosensor. FRET was used to measure cAMP in isolated human ventricular myocytes. In order to measure β-adrenergic sensitivity (expressed as, log EC50 [ISO]), isoprenaline ([ISO] 0.1 nM–30 μM) was used for β-adrenoceptor activation and forskolin (10 μM) to activate adenylyl cyclase directly. Maximum β-adrenoceptor mediated inotropic response was calculated by the ratio of ISO (30 μM) and forskolin (10 μM; Ratio ISO/FSK in %).

Results: Our study cohort (mean age 56.7 ± 15.8 years, 69% male) consisted of 72 AR patients and 52 AS patients. Overall, ejection fraction (EF; 55.3 ± 11.7%; range: 25–75%), levels of pro-BNP (range: 24–9,026 ng/L) and β-adrenergic sensitivity (–log EC50 [ISO]: − 6.75 ± 0.50; range: 5.87 to − 8.15) showed a large variability in patients with AV disease. Patients with increased levels of baseline pro-BNP (defined as >  200 ng/L) showed no differences in β-adrenergic sensitivity (p = 0.955) but a significant lower ratio ISO/FSK (£200: 82 ± 15.4% vs. > 200: 72.6 ± 15.04; p = 0.040), suggesting relevant β-adrenoceptor downregulation. A total of 33 patients (27%) showed a postoperative decline in EF >  10%. Those patients showed a trend towards decreased maximum response to ISO in myocardial tissue compared to the patients without decline in postoperative LVEF(1.1 ± 0.1 mN vs. 1.5 ± 0.2 mN; p = 0.157).

Conclusion: A wide spectrum of myocardial dysfunction is present in patients with AV disease. Patients with an increased pro-BNP might have a β-adrenoceptor dysfunction. Further follow-up is needed to test whether relevant β-adrenoceptor dysfunction relates to worse outcome with respect to the development of valvular cardiomyopathy in aortic valve disease.

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