Increased Stiffness Is the Major Early Abnormality in a Pig Model of Severe Aortic Stenosis and Predisposes to Congestive Heart Failure in the Absence of Systolic Dysfunction

Abstract

BackgroundIt remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis.Methods and ResultsYorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure–volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure–volume relationship β: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure–volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca2+) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis.ConclusionIncreased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…As shown by our lab17, 23 and others,30, 31, 32 aortic‐banded swine develop significant LV hypertrophy. Regarding our hypothesis, changes in cGMP levels and PDE5 activity following treatment with tadalafil or saxagliptin, respectively, did not limit LV hypertrophic remodeling in response to chronic pressure overload from a gross morphological perspective.…”

“…The HF‐TAD group presented features of the “systolic paradox” often found in HFpEF including normal ejection fraction, stroke volume, and increased LV contractility (ESPVR and PRSW; shown by our lab23 and others30 in aortic‐banded swine) in concert with reduced longitudinal, circumferential, and radial systolic mechanics. It is worthwhile to note that changes to systolic mechanics and cardiomyocyte function were greater than those observed in the HF group, implying systolic function may be more impaired in HF‐TAD animals.…”

Left atrial remodeling, hypertrophy, and fibrosis in mouse models of heart failure

“…In contrast to Doppler indices of diastolic function, which are sensitive to changes in preload and afterload (34), left atrial size may be a more stable indicator that reflects the duration and severity of diastolic dysfunction (35). Although, left atrial volume has been extensively used as a relevant functional endpoint in assessment of diastolic function in large animal models of cardiac injury (36), changes in atrial geometry and structure are seldom studied in mouse models of left ventricular disease. This is due in part to technical challenges in evaluation of the left atrium in mice, and in part to the absence of evidence characterizing the structural and geometric changes of the left atrium following murine cardiac injury.…”

Myocardial reverse remodeling: how far can we rewind?

“…Moderate TAC imposed at an early age triggers concentric LVH with compensated chamber performance, markedly with prominent diastolic filling abnormalities. For instance, Yorkshire pigs subjected to surgical banding of the ascending aorta for 5 mo exhibited LVH with increased stiffness and normal systolic function, compared with control pigs (108). However, in severe TAC and long-standing aortic constriction, the myocardial remodeling will, eventually, lead to LV dilation, impairment of systolic function, and progression of the abnormal filling (150).…”