Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

Abstract

Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure. J Appl Physiol 111: 1778 -1788. First published September 1, 2011 doi:10.1152/japplphysiol.00691.2011.-Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4-or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to shortterm reversal (4-wk ACF ϩ 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered ␣/␤-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF ϩ 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.hemodynamics; cardiac remodeling/hypertrophy; collagen THE INCIDENCE OF HEART FAILURE (HF) is increasing due to an aging population and improved management of diseases that are precursors to ventricular dysfunction. The successes of therapeutic advances over the past decades have dramatically decreased mortality rates, such that the focus has now shifted towards reducing morbidities (12). As a result, cardiac remodeling has become a primary therapeutic target in patients with heart failure. Strategies to prevent or reverse adverse left ventricular (LV) remodeling include pharmacotherapy, surgical interventions, and device-based-therapies such as left ventricular assist devices (LVAD) and cardiac resynchro...

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

“…In that report, REV during pre-HF (i.e., 4 wk post-ACF) results in rapid structural recovery but delayed functional recovery (19). Although this mirrors human data where structure, but not function, returns postsurgically in 17% of patients with MR (27), the mechanism underlying the delayed functional recovery remains elusive.…”

“…At week 0, VO was induced under isoflurane anesthesia (2-2.5%) as described (17,19). Following abdominal incision, the abdominal aorta and caudal vena cava were exposed.…”

“…The aortocaval fistula (ACF) model of VO HF in the rodent mimics increased hemodynamic preload observed in human disease, irrespective of etiology. In this model, chronically increased LV preload leads to progressive LV pump failure, which is classified into three clinically relevant stages: 1) pre-HF [4-wk ACF; marked LV dilation, increased LV wall stress, mild LV dysfunction (ϳ10% decrease in % fractional shortening, %FS); no pulmonary congestion/edema], 2) established HF [8-wk ACF; severe LV dilation, significant LV systolic (25% decrease in %FS, ϳ50% decrease in end-systolic elastance, Ees, and preload-recruitable stroke work, PRSW) and diastolic dysfunction (10 -27% increase in and dP/dt min , respectively); no pulmonary congestion or edema], and 3) end-stage HF (15-21-wk ACF; LV pump failure with pulmonary congestion/edema) (17,19,34). This model is commonly used to identify molecular and cellular mechanisms driving disease progression and to test novel therapeutic approaches for improving LV structure and function (13,21,40).…”

“…We have previously characterized a technique to reverse (REV, close) the ACF (19). In that report, REV during pre-HF (i.e., 4 wk post-ACF) results in rapid structural recovery but delayed functional recovery (19).…”

Naringenin attenuates pressure overload-induced cardiac hypertrophy

“…The present results indicate that the mRNA expression levels of TGF-β1, CTGF, collagen Iα and collagen IIIα were increased following AB, and that naringenin evidently alleviated this upregulation. In addition, the results of the PSR staining suggested that naringenin attenuates the interstitial and perivascular fibrosis induced by pressure overload (25). Notably, naringenin has the pharmacological effect of normalizing the expression of pro-fibrotic genes, indicating that naringenin may be effective in attenuating extracellular remodeling following pressure overload.…”