Takahama, Hiroyuki

Background: In heart failure with preserved ejection fraction (HFpEF), left ventricular (LV) systolic elastance (Ees) increases in tandem with increases in arterial elastance (Ea), which maintains ejection fraction but limits systolic reserve and precipitates volume sensitivity. The left atrium (LA) lies in series with the LV and contributes to LV stroke volume. We hypothesized that HFpEF is associated with increased LA systolic elastance (E LA ) and deranged atrioventricular (AV) coupling which may additionally compromise cardiac performance. Methods: HFpEF was modeled by experimental hypertension (bilateral renal wrap + DOCA) in elderly dogs (n=9). LA and LV structure, function (echo, MRI) and invasively assessed pressure-volume relationships (PVR, open-chest; pericardiotomy; admittance catheter) were compared to sham-operated young dogs (control; n=13). Results: As compared to controls, HFpEF dogs displayed concentric remodeling, with increased diastolic stiffness, Ea and Ees (p<0.05 for all) and reduced Ea/Ees (p=0.03). LA maximum volume (28±3 vs 23±3mL, p=0.007), LA stroke volume (4±1 vs2±1mL, p=0.006), LA active emptying fraction (18±6 vs 12±2%, p=0.03) and LA ejection rate (51±14 vs 30±16mL/s) were higher in HFpEF versus controls, suggesting increased LA stroke work and inotropy. At matched heart rate and LA pressure, E LA was steeper in HFpEF than control (2.7±0.9 vs 1.5±0.6mmHg/mL, p=0.01) and positively correlated with Ees (r=0.6, p=0.005) and Ea (r=0.66, p=0.002). However AV mismatch occurred as increases in E LA were not proportionate to increases in Ees (Ees/E LA 1.3±0.4 HFpEF vs 0.8±0.4 control, p<0.05). On linear regression, worse AV coupling (i.e. higher Ees/E LA ) was associated with lower LV stroke volume ( Figure ). Conclusion: In experimental HFpEF, despite enhanced LA contractility, AV coupling was deranged. Worse AV coupling may further contribute to reserve dysfunction, LA pressure rise, and susceptibility to pulmonary edema in HFpEF.

Background: Reduced left atrial (LA) compliance (LAC) contributes to pulmonary venous hypertension in heart failure with preserved ejection fraction (HFpEF); however the underlying mechanisms are poorly defined. We hypothesized that microvascular inflammation with rarefaction and impaired nitric oxide (NO) signaling, LA titin hypophosphorylation and fibrosis may each contribute to reduced LAC in HFpEF. Methods: Invasive LA pressure-volume (PV) analyses (open-chest; pericardiotomy; admittance catheter) were performed in 9 aged dogs with experimental hypertension (bilateral renal wrap + DOCA; HFpEF) compared to 13 sham-operated young adult dogs (control). LAC was measured at end-LA reservoir during acute preload reduction (cava occlusion). LA tissue and LA microvascular function were analyzed. Results: Compared to controls, the curvilinear end-LA reservoir PV relationship ( Fig A ) was shifted upward/leftward in HFpEF (LA diastolic stiffness constant 0.08 vs 0.16 mmHg/mL in controls, p=0.005). LA microvascular density (MVD; CD31 stain) tended to be lower in HFpEF than controls (2154±578 vs 2650±523 vessels/mm 2 , p=0.07) and LA MVD negatively correlated with the LA diastolic stiffness constant (r=-0.66, p=0.006). LA microvessels from HFpEF dogs showed impaired endothelium-dependent shear stress-mediated dilation compared to controls, consistent with impaired NO signaling ( Fig B ). Titin isoform expression was similar between groups, but isoform N2B (stiffer) was (p=0.03) and N2BA (compliant) tended to be (p=0.09) hypophosphorylated in HFpEF LA appendage (LAA) tissue. Fibrosis (Picrosirius Red) was similar between groups in the LA free wall and LAA, but increased in areas adjacent to the pulmonary veins in HFpEF (27±12% vs controls 15±8%, p=0.01). Conclusion: In experimental HFpEF, LAC was reduced in association with evidence of LA microvascular rarefaction and impaired NO signaling, titin hypophosphorylation and regional increases in LA fibrosis.