Right ventricular myofilament functional differences in humans with systemic sclerosis-associated versus idiopathic pulmonary arterial hypertension

Steven Hsu, Kristen M. Kokkonen-Simon, Jonathan A. Kirk, Todd Matthew Kolb, Rachel L Damico, Stephen Mathai, Monica Mukherjee, Ami Shah, Fredrick Wigley, Kenneth B. Margulies, Paul M Hassoun, Marc K Halushka, Ryan J. Tedford, David A Kass

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function. METHODS: Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined. RESULTS: Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28% higher in IPAH but 37% lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2=0.46, P=0.002) and change in end-systolic elastance with exercise (R2=0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2=0.63, P<0.002), which also was a marker of depressed contractile reserve. CONCLUSIONS: A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.

Original languageEnglish (US)
Pages (from-to)2360-2370
Number of pages11
JournalCirculation
Volume137
Issue number22
DOIs
StatePublished - Jan 1 2018

Fingerprint

Myofibrils
Systemic Scleroderma
Pulmonary Hypertension
Muscle Cells
Calcium
Sarcomeres
Familial Primary Pulmonary Hypertension
Fibrosis
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Exercise
Biopsy
Right Ventricular Function
Cardiac Myocytes
Dyspnea

Keywords

  • Heart ventricles
  • Hypertension
  • Myofibrils
  • Protein kinases
  • Pulmonary
  • Scleroderma
  • Systemic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

@article{a2c28238f70540b5a5a423e756efded0,
title = "Right ventricular myofilament functional differences in humans with systemic sclerosis-associated versus idiopathic pulmonary arterial hypertension",
abstract = "BACKGROUND: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function. METHODS: Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined. RESULTS: Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28{\%} higher in IPAH but 37{\%} lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2=0.46, P=0.002) and change in end-systolic elastance with exercise (R2=0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2=0.63, P<0.002), which also was a marker of depressed contractile reserve. CONCLUSIONS: A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.",
keywords = "Heart ventricles, Hypertension, Myofibrils, Protein kinases, Pulmonary, Scleroderma, Systemic",
author = "Steven Hsu and Kokkonen-Simon, {Kristen M.} and Kirk, {Jonathan A.} and Kolb, {Todd Matthew} and Damico, {Rachel L} and Stephen Mathai and Monica Mukherjee and Ami Shah and Fredrick Wigley and Margulies, {Kenneth B.} and Hassoun, {Paul M} and Halushka, {Marc K} and Tedford, {Ryan J.} and Kass, {David A}",
year = "2018",
month = "1",
day = "1",
doi = "10.1161/CIRCULATIONAHA.117.033147",
language = "English (US)",
volume = "137",
pages = "2360--2370",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "22",

}

TY - JOUR

T1 - Right ventricular myofilament functional differences in humans with systemic sclerosis-associated versus idiopathic pulmonary arterial hypertension

AU - Hsu, Steven

AU - Kokkonen-Simon, Kristen M.

AU - Kirk, Jonathan A.

AU - Kolb, Todd Matthew

AU - Damico, Rachel L

AU - Mathai, Stephen

AU - Mukherjee, Monica

AU - Shah, Ami

AU - Wigley, Fredrick

AU - Margulies, Kenneth B.

AU - Hassoun, Paul M

AU - Halushka, Marc K

AU - Tedford, Ryan J.

AU - Kass, David A

PY - 2018/1/1

Y1 - 2018/1/1

N2 - BACKGROUND: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function. METHODS: Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined. RESULTS: Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28% higher in IPAH but 37% lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2=0.46, P=0.002) and change in end-systolic elastance with exercise (R2=0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2=0.63, P<0.002), which also was a marker of depressed contractile reserve. CONCLUSIONS: A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.

AB - BACKGROUND: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function. METHODS: Cardiac myocytes were isolated from RV septal endomyocardial biopsies from patients with SSc-PAH, IPAH, or SSc with exertional dyspnea but no resting PAH (SSc-d); control RV septal tissue was obtained from nondiseased donor hearts (6-7 per group). Isolated myocyte passive length-tension and developed tension-calcium relationships were determined and correlated with in vivo RV function and reserve. RV septal fibrosis was also examined. RESULTS: Myocyte passive stiffness from length-tension relations was similarly increased in IPAH and SSc-PAH compared with control, although SSc-PAH biopsies had more interstitial fibrosis. More striking disparities were found between active force-calcium relations. Compared with controls, maximal calcium-activated force (Fmax) was 28% higher in IPAH but 37% lower in SSc-PAH. Fmax in SSc-d was intermediate between control and SSc-PAH. The calcium concentration required for half-maximal force (EC50) was similar between control, IPAH, and SSc-d but lower in SSc-PAH. This disparity disappeared in myocytes incubated with the active catalytic subunit of protein kinase A. Myocyte Fmax directly correlated with in vivo RV contractility assessed by end-systolic elastance (R2=0.46, P=0.002) and change in end-systolic elastance with exercise (R2=0.49, P=0.008) and was inversely related with exercise-induced chamber dilation (R2=0.63, P<0.002), which also was a marker of depressed contractile reserve. CONCLUSIONS: A primary defect in human SSc-PAH resides in depressed sarcomere function, whereas this is enhanced in IPAH. These disparities correlate with in vivo RV contractility and contractile reserve and are consistent with worse clinical outcomes in SSc-PAH. The existence of sarcomere disease before the development of resting PAH in patients with SSc-d suggests that earlier identification and intervention may prove useful.

KW - Heart ventricles

KW - Hypertension

KW - Myofibrils

KW - Protein kinases

KW - Pulmonary

KW - Scleroderma

KW - Systemic

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UR - http://www.scopus.com/inward/citedby.url?scp=85049670026&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.117.033147

DO - 10.1161/CIRCULATIONAHA.117.033147

M3 - Article

VL - 137

SP - 2360

EP - 2370

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 22

ER -