The role of impaired myocardial energetics in the development and progression of heart failure (HF) seems to be central [1]. The energy-depletion theory of HF is not new and a multitude of recent studies have provided solid evidence that myocardial metabolism is strongly affected in humans as well as in many animal models of left ventricular hypertrophy and HF [1‐3]. Both systolic and diastolic functions seem to be intimately affected by impaired myocardial energetics [4‐8].

Alterations of myocardial metabolism caused by chronic valve disease such as aortic regurgitation (AR) are unclear and have not been studied like the ones caused by pressure overload or ischemia [9‐19]. Chronic AR is usually well tolerated for many years before HF occurs. AR patients develop severely dilated and hypertrophied hearts but remain in a clinical pre-HF state with a normal LV ejection fraction for long periods of time [20]. The reason why they suddenly progress towards symptoms and HF after this long stable period is not well understood. There is currently no treatment proven effective to decrease AR related morbidity-mortality or delay the evolution towards HF in humans [21]. The only solution available for now remains valve replacement surgery when the left ventricle becomes too dilated, systolic indices progressively decrease or when symptoms occur. Over the years, we have showed that treatment targeting the renin-angiotensin-aldosterone or the adrenergic systems can help reduce LH hypertrophy, maintain cardiac function and improve survival in a rat model of chronic AR [22‐25]. We did observe a similar effect by non-pharmaceutical strategy i.e. moderate endurance training [26].

We suggested that AR left ventricles with severe eccentric hypertrophy suffer from significant myocardial metabolic impairment even before systolic dysfunction becomes apparent and observed that as early as 8 weeks post-AR myocardial energy substrate preference was altered and a switch toward increased glucose utilization was observed [27].

Here, we studied the long-term alteration in LV energy metabolism associated with chronic volume overload caused by severe AR in Wistar rats. We show that treatments (training and beta-blockade) that reduce LV dilatation and help maintain function are also associated with a normalization of the energy metabolism.

All sham-operated animals were alive at the end of the protocol. After 3, 6 and 9 months, 14/15, 12/15 and 14/30 animals were still alive in the AR groups, respectively. As illustrated in Figure 1, no differences in body weight were observed between the sham and AR groups. Overall growth was similar between groups (similar tibial lengths, results not shown). LV wet tissue weights were significantly increased in the AR groups compared to controls and this increase was steady over the 9 month period.

Factors influencing the development and evolution of LV remodelling in AR are poorly understood. Here, we provide a longitudinal study focusing on myocardial energy metabolism in the LV of rats with chronic severe AR.

The heart is in a constant need of energy substrates since it does not maintain significant reserve [1]. The myocardial energetic machinery is complex and can be affected at many interacting levels including: substrate utilization/preference, oxidative energy production in the mitochondria, energy transport and consumption by the contractile myofibrils [35].

Our experimental model causes severe LV dilatation. Despite the presence of important hypertrophy in this rat model, HF remains a late occurring event as seen in humans [36]. As we have previously reported, the majority of AR rats have a systolic function within normal range (ejection fraction > 60%, normal dP/dt+) even after 9 months [26]. Diastolic abnormalities become clearly evident as soon as 2 or 3 months after AR induction [34, 37].

As reported by others in models of LV concentric hypertrophy and of HF, we too observed a shift in the ratio of the gene expression of myosin heavy chains α and β in AR rats. This also occurs but much less, with normal aging [38]. This shift can significantly affect the energetic efficiency of the heart and could point towards an imminent shift towards HF.

In this study, we showed in vivo using μPET that the LV myocardium of AR rats increased its glucose consumption. This increase seems to be more pronounced in the LV free wall mostly in the lateral and anterior portions. It could be suggested that dilation may not be homogeneous through the LV was and that the observed metabolic changes in the LV myocardium may reflect this. We already observed the opposite situation in the AR rat where fatty acid uptake was reduced in the same LV region where we now observe an increase in glucose uptake [25]. Concentric LV hypertrophy is associated with a shift in substrate preference from free fatty acids to glucose [35]. Our μPET results confirm this for our animals in vivo with eccentric VO LVH.

We also described the impact of normal aging on the levels of enzymatic activity related to myocardial metabolism. We detected a significant loss of myocardial activity for three central metabolic enzymes (HADH, CS and PFK) due to normal aging. The activity levels of these enzymes decreased by at least 25% in the last six months of the protocol. It is possible though that these changes reflect a progression from a stage of global body growth at a younger age to the more stable adult stage. Adding AR amplified this effect on HADH and CS activities. This suggests that fatty acid oxidation is further impaired in the late stage of AR and that the total mitochondrial oxidative capacity of the myocardium may then be less than normal [10]. On the other hand, PFK activity remained stable in the hearts of AR animals suggesting a shift towards glucose utilization as previously seen in concentric LV hypertrophy and HF [39]. μPET imaging also confirmed this hypothesis. Our data show a decrease in fatty acid transport-related Fat/CD36 in the animals with AR. Carnitine palmitoyl-transferase gene expression and enzymatic activity was also decreased. These observations are consistent with data published in other models of LVH [11, 40]. The mitochondrial energetic machinery also seems to be affected by the LV volume overload as shown not only by the decrease in CS activity but also by the strong decrease in the activity of the ETC. complex I in 9-month AR animals. These mitochondrial enzymatic abnormalities could result in myocardial energy starving either in the basal state or in response to an acute stress such as exercise or ischemia. It has been previously reported that VO could induce an inappropriate response to various stresses in two different animal models during the compensated phase of the disease [16, 19]. The down-regulation of ANT1 is another clue pointing towards an abnormal exportation of ATP from the mitochondrion [41] which seems to be seriously impaired in our AR animals after 9 months. The gene expression of PDH1α which is responsible for pyruvate entry into the mitochondria was reduced in AR animals after 9 months compared to normal age-matched controls. Myocardial energetic status at this late stage of the disease in our AR animals probably shares similarities to the one seen in established HF even if systolic function remains in the normal range in our animals.

This study also clearly shows that regular exercise has beneficial effects on the myocardial energetic machinery in this animal model of volume overload cardiomyopathy even before systolic heart failure occurs. These effects were detectable on enzymes and pathways related to fatty acid oxidation and glycolytic capacity as well as to mitochondrial efficiency. The benefits of exercise on LV remodeling, diastolic function and survival we have recently reported could therefore be in part related to improvement in myocardial energetics [26]. One possible mechanism may be via the activation of the IGF1/PI3K/Akt pathway by exercise which can activate survival pathways in cardiac myocytes [42, 43].

We also observed an improvement of myocardial energetics in AR animals treated with the beta-blocker, carvedilol. We had reported that beta-blockade using either metoprolol or carvedilol can reduce the extent of LV hypertrophy development in the rat AR model [23, 36]. The benefits in maintaining systolic function were similar to those observed in endurance-trained animals [26]. It is interesting to observe that although the effects of beta-blockade and exercise were similar at normalizing metabolic enzyme activities, carvedilol treatment also restored gene expression of a number of proteins implicated in the control of substrate uptake and metabolism. This suggests that similarities and differences exist between the mechanisms of action of exercise and beta-blockade. Another possibility is that by a better control of LVH development by carvedilol, many parameters may remain in the normal range.

Our results clearly show that the myocardium with chronic VO suffers from a significant metabolic stress and develops over time important metabolic abnormalities.

These findings provide for the first time new longitudinal data which may improve our view of the dilated hearts of patients with severe AR. Clinicians currently feel comfortable to follow those patients without any intervention for many years, simply waiting for the LV to become too dilated, for the occurrence of symptoms or until systolic function begins to fall. Based on our findings, we suggest that those volume overloaded hearts develop severe metabolic abnormalities even when systolic function seems preserved. Focusing on myocardial metabolism by various interventions such as targeted drugs, specific diets or exercise may help this metabolically stressed myocardium to improve energy production and maybe prolong the pre-heart failure state significantly. Further studies will be needed to confirm this hypothesis.