The present study demonstrates that LV longitudinal function has been already impaired in a group of patients with AVS and that IR is a powerful independent predictor of subclinical abnormalities of LV longitudinal function in patients with AVS. This negative contribution of IR to LV function remained significant even after adjustment for demographic variables, LV mass index, and visceral adiposity on multiple linear regression analysis.
Impairment of global LV function in AVS
This study demonstrates subclinical abnormalities of global LV systolic and diastolic function, as reflected by reduced LV longitudinal, not circumferential, strain and SRs, which are more sensitive indices of LV contractility than LV ejection fraction, in patients with AVS. Recent cross-sectional sub-studies of the ASTRONOMER trial have pointed out the impact of metabolic syndrome not only on progression of aortic stenosis, but also on progression of LV hypertrophy and reduced myocardial velocities in patients with mild and moderate aortic stenosis[7, 18]. Furthermore, the metabolic abnormalities linked to IR, metabolic syndrome, and diabetes mellitus have an additive adverse effect on the prevalence and progression of LV hypertrophy and reduced global LV longitudinal function in patients with aortic stenosis beyond known factors of pressure overload[6, 11]. The association between valve disease and myocardial abnormality in those studies[6, 18], however, are rarely investigated in patients with AVS, which is considered as an early, asymptomatic stage of calcific aortic valve disease. Ng et al. reported on impairment of global longitudinal strain and SRs in patients with type 2 diabetes mellitus, suggesting that the injured myocardial fibers are located predominantly in the epicardium/endocardium. However, these results could have been influenced by potential confounding comorbidities, such as unregulated hypertension, chronic kidney disease, coronary artery disease, and concomitant LV hypertrophy, because AVS has been associated with cardiovascular risk factors and coronary atherosclerosis[2, 3]. In this study, we therefore excluded patients with several of these comorbidities, including coronary artery disease (exclusion based on coronary computed tomography angiography).
In the Cardiovascular Health Study, AVS has increased the risk of developing congestive heart failure even in the absence of hemodynamically significant obstruction of LV outflow. However, the mechanism by which AVS influences LV function has not been sufficiently elucidated. In contrast, our results suggest that subclinical LV dysfunction and subsequent overt heart failure is partly due to adverse effects of IR in patients with AVS. In addition, these results may have important clinical implications with regard to life style modification in this setting.
IR and AVS progression
Our results also suggest that IR is an important mediator of the association between AVS and subclinical LV dysfunction. IR, a central feature of metabolic syndrome and diabetes mellitus, has been a causative or contributing factor in the pathogenesis of AVS. Several prospective studies have shown that metabolic syndrome is associated with increased prevalence and incidence of AVS. Also in the present study, we demonstrated that the AVS+IR group had a higher aortic valve calcium score along with a larger VAT area. Moreover, recent studies have implicated the renin-angiotensin system, which is upregulated in metabolic syndrome, in aortic valve disease pathogenesis. Currently, no medical interventions are capable of delaying or halting AVS progression. Whether the treatment of IR targeted to patients with AVS leads to both preventing subclinical LV dysfunction and slowing the progression of calcific aortic valve disease is need to be clarified in future prospective studies.
Pathogenesis of adverse effects of IR on LV function and remodeling
Previous studies have indicated the close relationship between impaired LV longitudinal function and dysmetabolic state, such as diabetes mellitus, normal-weight obesity (visceral obesity), and nonalcoholic steatohepatitis. Our study provides novel information suggesting the role of IR on an early impairment of the longitudinal function, independently of concomitant visceral obesity and LV hypertrophy. These data may fit with recent evidence showing a strong link between IR and reduced LV contractile reserve, leading to non-ischemic heart failure. The concept of a specific insulin-resistant cardiomyopathy is now emerging. Diffuse interstitial fibrosis throughout the myocardium of diabetic patients suggests widespread cardiomyocyte damage and the influence of cytokine activity. Domenighetti et al. demonstrated that cardiac IR is characterized by reduced availability of sarcolemmal Glut-4 transporters and consequent lower glucose uptake. A shift away from glycolysis towards fatty acid oxidation for ATP supply is associated with myocardial oxidative stress and induces profound alterations in cardiomyocyte Ca2+ homeostasis. Recent studies have shown that LV hypertrophy and interstitial fibrosis can also be triggered by activation of several insulin-related signaling pathways, altered adipokine levels (including leptin and adiponectin), or the activity of peroxisome proliferator-activated receptors, all indicating that metabolic disorders may play a role in the pathophysiology of LV dysfunction. Also in this study, higher plasma level of leptin and lower levels of total and high-molecular-weight adiponectin were shown in the AVS+IR group. Mellor et al. suggested that significant cardiomyocyte loss in the insulin-resistant heart is driven by a non-apoptotic type of programmed cell death: autophagy. The insulin resistant myocardium exhibits various pro-autophagic characteristics, including suppression of the PI3K(I)-Akt signaling pathway and metabolic dysregulation, making the affected heart prone to autophagic demise.
Regional LV function and spherical alteration in AVS
The present study also provides the interesting finding that LV longitudinal strain alteration shows mid-apical predominance. Possible mechanisms include the distribution of insulin receptor, the change in regional stress–strain relationship due to apical thin wall, and LV remodeling. In this study, the shape of the LV was more spherical in patients with a high HOMA index than in those with a low HOMA index. However, whether LV spherical alteration in AVS translates to regional longitudinal dysfunction remains to be addressed in larger-scale studies.
First, although our data support the notion that IR is an important factor in the pathogenesis of LV dysfunction in patients with AVS, causality cannot be fully established because this is a cross-sectional study. Furthermore, larger prospective and larger-population studies are needed to clarify whether IR per se could be held responsible to the subclinical LV dysfunction independently of the metabolic syndrome with all its risk factors. However, we could reach the statistical significance in the multiple linear regression models including visceral obesity (i.e., key component of the metabolic syndrome). Second, in this study, the serum level of high-sensitivity C-reactive protein was not associated with IR and impairment of LV function. However, a previous article demonstrates that other inflammatory markers, such as tumor necrosis factor-α and IL-6, are the mediators of the hyperinsulinemic state specifically related to excess adiposity. Third, we defined IR in terms of the median HOMA index value of 1.8. In general, a HOMA index < 2 is believed to be normal in Caucasian. Because the insulin secretion capacity in Japanese is lower than that in Caucasian, the lower threshold of HOMA index would be reasonable. Thus, larger observational studies including other ethnic group will be required to confirm our findings.
Finally, current two-dimensional speckle-tracking analysis is affected by cardiac motion; namely, through-plane motion. In particular, the values of radial strain and SR are likely to be susceptible to this effect. Thus, we omitted data in the radial direction. However, the easy availability and non-invasiveness of two-dimensional speckle-tracking echocardiography may allow assessment of patients with AVS and concomitant insulin-resistant cardiomyopathy and observation of disease progression.