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Skeletal Muscle Capillary Hemodynamics in Rats with Heart Failure with Preserved Ejection Fraction
Author(s) -
Hirai Daniel M.,
Tabuchi Ayaka,
Craig Jesse C.,
Colburn Trenton D.,
Caldwell Jacob T.,
Ade Carl J.,
Baumfalk Dryden R.,
Opoku-Acheampong Alex B.,
Behnke Brad J.,
Hageman K. Sue,
Musch Timothy I.,
Poole David C.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05827
Subject(s) - medicine , heart failure with preserved ejection fraction , preload , cardiology , heart failure , ejection fraction , hemodynamics , skeletal muscle
The cardinal symptom in heart failure with preserved ejection fraction (HFpEF) is severe exercise intolerance. Limited understanding of HFpEF pathophysiology has precluded the development of effective therapies. We examined the effects of HFpEF on nitric oxide (NO)‐mediated regulation of skeletal muscle capillary hemodynamics. The hypothesis was tested that HFpEF would reduce the proportion of capillaries supporting continuous red blood cell (RBC) flow and impair microvascular hemodynamics in perfused capillaries partly via deteriorations in NO‐mediated function. METHODS Intravital microscopy was used to evaluate the resting spinotrapezius muscle in old male Spontaneously Hypertensive Rats (SHR; n=7) and healthy normotensive Wistar‐Kyoto rats (WKY; n=5). Presence of HFpEF in SHR rats was determined using in vivo (echocardiography and micromanometer) and post‐mortem evaluation of cardiac structure and function. Capillary lumen diameter ( d cap ), %RBC‐perfused capillaries, and RBC flux ( f RBC ), velocity ( V RBC ) and hematocrit (Hct cap ) were assessed at physiological sarcomere lengths (2.8±0.1 μm) under control (CON) and non‐selective NO synthase blockade (L‐NAME; 1.5 mM) superfusion conditions. RESULTS Compared to WKY, SHR had elevated left ventricular end‐diastolic pressure (LVEDP; SHR: 11.3±1.3, WKY: 6.9±1.1 mmHg; P <0.05), preserved LV ejection fraction (EF; 76±3 and 81±4%; P >0.05) and fractional shortening (FS; 41±3 and 46±4%; P >0.05), and increased LV mass/body mass (2.54±0.09 and 2.01±0.04 mg/g; P <0.05). As expected, mean arterial pressure was higher in SHR compared to WKY under CON (139±14 and 93±5 mmHg, respectively; P <0.05) with no changes produced by L‐NAME ( P >0.05). There were no differences in the %RBC‐flowing capillaries between SHR and WKY under CON (88±2 and 92±2%; P >0.05) or L‐NAME ( P >0.05). In RBC‐flowing capillaries under CON, SHR had lower f RBC (10.9±1.3 and 13.7±1.4 cells/s) and V RBC (142±14 and 185±11 μm/s) than WKY ( P <0.05 for both). L‐NAME reduced f RBC in WKY (7.6±0.6; P <0.05) but not SHR (10.0±1.0 cells/s; P >0.05). Moreover, L‐NAME induced a greater magnitude of V RBC reduction in WKY (42±3%) than SHR (12±5%; P <0.05). No differences in Hct cap were observed between SHR and WKY under CON (0.25±0.01 and 0.23±0.02) or L‐NAME ( P >0.05 for all). Similarly, no differences in d cap were seen between SHR and WKY under CON (4.9±0.1 and 5.1±0.1 μm) or L‐NAME ( P >0.05 for all). CONCLUSIONS SHR displayed several cardiovascular alterations consistent with HFpEF, including elevated LVEDP, preserved EF and FS, and increased LV mass/body mass. Although not impacting d cap or Hct cap , SHR showed marked reductions in f RBC and V RBC resulting partly from impaired NO‐mediated function. These alterations in microvascular O 2 perfusion likely contribute to exercise intolerance in HFpEF. These data thus reveal important mechanistic clues into muscle dysfunction in this disease and identify the skeletal muscle capillary network as a potential therapeutic target in HFpEF. Support or Funding Information NIH HL‐2‐108328