Heart Failure With Preserved Ejection Fraction Is Characterized by Dynamic Impairment of Active Relaxation and Contraction of the Left Ventricle on Exercise and Associated With Myocardial Energy Deficiency

Phan, Thanh; Abozguia, Khalid; Shivu, Ganesh Nallur; Gnanadevan, Mahadevan; Ahmed, Ibrar; Williams, Lynne; Dwivedi, Girish; Patel, Kiran; Steendijk, Paul; Ashrafian, Houman; Henning, A; Frenneaux, Michael

doi:10.1016/j.jacc.2009.05.012

Cited by 281 publications

(244 citation statements)

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“…However, cTnI phosphorylation has been shown to be necessary for clinically relevant modulatory effects (37,40,53), emphasizing the importance of understanding its molecular regulation. In addition, thin filament dysfunction was associated with increased PKC␤ expression in failing human myocardium and reduced after left ventricular assist device support (54).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Cardiac Troponin I at Protein Kinase C Site Threonine 144 Depresses Cooperative Activation of Thin Filaments

Hinken

Patrick

et al. 2010

Journal of Biological Chemistry

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There is evidence for PKC-dependent multisite phosphorylation of cardiac troponin I (cTnI) at Ser-23 and Ser-24 (also PKA sites) in the cardiac-specific N-terminal extension and at Thr-144, a unique residue in the inhibitory region. The functional effect of these phosphorylations in combination is of interest in view of data indicating intramolecular interaction between the N-terminal extension and the inhibitory region of cTnI. To determine the role of PKC-dependent phosphorylation of cTnI on sarcomeric function, we measured contractile regulation at multiple levels of complexity. Ca 2؉ binding to thin filaments reconstituted with either cTnI(wild-type) or pseudo-phosphorylated cTnI(S23D/S24D), cTnI(T144E), and cTnI(S23D/S24D/ T144E) was determined. Compared with controls regulated by cTnI(wild-type), thin filaments with cTnI(S23D/S24D) and cTnI(S23D/S24D/T144E) exhibited decreased Ca 2؉ sensitivity. In contrast, there was no significant difference between Ca 2؉ binding to thin filaments with cTnI(wild-type) and with cTnI(T144E). Studies of the pCa-force relations in skinned papillary fibers regulated by these forms of cTnI yielded similar results. However, in both the Ca 2؉ binding measurements and the skinned fiber tension measurements, the presence of cTnI(S23D/S24D/T144E) induced a much lower Hill coefficient than either wild type, S23D/S24D, or T144E. These data highlight the importance of thin filament-based cooperative mechanisms in cardiac regulation, with implications for mechanisms of control of function in normal and pathological hearts.In experiments reported here, we have investigated functional effects of multisite phosphorylation in cardiac troponin I (cTnI).3 cTnI is an inhibitory subunit of the cardiac troponin (cTn) complex, which consists also of troponin C (TnC), a Ca 2ϩ binding component and troponin T (TnT), a tropomyosin (Tm) binding component. cTnI functions as a key protein in the cardiac muscle contraction-relaxation cycle by relieving or restoring its inhibitory influence that is regulated by Ca 2ϩ association to or dissociation from the regulatory Ca 2ϩ binding site of TnC (1-4). It is now well recognized that cTnI has multiple sites, which are substrates for a variety of kinases, especially PKA and PKD (Ser-23 and Ser-24), and PKC . These phosphorylations have been demonstrated to occur in various signaling pathways that control cardiac dynamics and growth (for review, see Ref. 5). There is reasonable agreement that phosphorylation of Ser-23/Ser-24 located in the unique N terminus of cTnI enhances the "off" rate for Ca 2ϩ dissociation from cTnC and is important in the abbreviated cycle time associated with ␤-adrenergic stimulation of the heart. However, the functional significance of the PKC sites remains unclear and controversial.Previous work has focused on PKC-dependent phosphorylation of cTnI at Ser-43/Ser-45, which decreases maximum Ca 2ϩ -activated force, ATPase activity, and sliding velocity, and desensitizes myofilaments to [Ca 2ϩ ] by stabilizing the off-state of the thin...

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Cardiac Troponin I at Protein Kinase C Site Threonine 144 Depresses Cooperative Activation of Thin Filaments

Hinken

Patrick

et al. 2010

Journal of Biological Chemistry

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“…Other factors -both cardiac and extracardiac -including increased arterial stiffness, altered ventricular-arterial coupling [42,43], endothelial dysfunction, reduced vasodilator reserve [44,45] and chronotropic incompetence [46,47] have been recently implicated in the pathophysiology of this complex syndrome. Furthermore, coexisting abnormalities in LV regional systolic function assessed by various parameters have been documented in HFpEF [13,15,17,18,[48][49][50].…”

Section: Pathophysiologymentioning

confidence: 99%

Heart Failure with Preserved Ejection Fraction

Čulić

2017

N Engl J Med

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Heart failure with preserved ejection fraction (HFpEF) has recently emerged as a major cause of cardiovascular morbidity and mortality. Contrary to initial beliefs, HFpEF is now known to be as common as heart failure with reduced ejection fraction (HFrEF) and carries an unacceptably high mortality rate. With a prevalence that has been steadily rising over the past two decades, it is very likely that HFpEF will represent the dominant heart failure phenotype over the coming few years. The scarcity of trials in this semi-discrete form of heart failure and lack of unified enrolment criteria in the studies conducted to date might have contributed to the current absence of specific therapies. Understanding the epidemiological, pathophysiological and molecular differences (and similarities) between these two forms of heart failure is cornerstone to the development of targeted therapies. Carefully designed studies that adhere to unified diagnostic criteria with the recruitment of appropriate controls and adoption of practical end-points are urgently needed to help identify effective treatment strategies.

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“…This reflects rapid ventricular ejection and surge in left ventricular pressure, and is associated with efficient ventricular relaxation 26. However, patients with obstructive coronary stenoses likely have a reduced ventricular energetic reserve,35 which when combined with significant resistance vessel vasoconstriction predisposes the efficiency of ventricular ejection and relaxation to be compromised in the face of acutely increased afterload 31. In addition, downregulation of ß‐adrenoceptors following chronic sympathetic stimulation36 in patients with obstructive stenoses may also dampen the inotropic and chronotropic response to cold air.…”

Section: Discussionmentioning

confidence: 99%

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

Williams

Asrress

Lumley

et al. 2018

JAHA

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BackgroundCold air inhalation during exercise increases cardiac mortality, but the pathophysiology is unclear. During cold and exercise, dual‐sensor intracoronary wires measured coronary microvascular resistance (MVR) and blood flow velocity (CBF), and cardiac magnetic resonance measured subendocardial perfusion.Methods and ResultsForty‐two patients (62±9 years) undergoing cardiac catheterization, 32 with obstructive coronary stenoses and 10 without, performed either (1) 5 minutes of cold air inhalation (5°F) or (2) two 5‐minute supine‐cycling periods: 1 at room temperature and 1 during cold air inhalation (5°F) (randomized order). We compared rest and peak stress MVR, CBF, and subendocardial perfusion measurements. In patients with unobstructed coronary arteries (n=10), cold air inhalation at rest decreased MVR by 6% (P=0.41), increasing CBF by 20% (P<0.01). However, in patients with obstructive stenoses (n=10), cold air inhalation at rest increased MVR by 17% (P<0.01), reducing CBF by 3% (P=0.85). Consequently, in patients with obstructive stenoses undergoing the cardiac magnetic resonance protocol (n=10), cold air inhalation reduced subendocardial perfusion (P<0.05). Only patients with obstructive stenoses performed this protocol (n=12). Cycling at room temperature decreased MVR by 29% (P<0.001) and increased CBF by 61% (P<0.001). However, cold air inhalation during cycling blunted these adaptations in MVR (P=0.12) and CBF (P<0.05), an effect attributable to defective early diastolic CBF acceleration (P<0.05) and associated with greater ST‐segment depression (P<0.05).ConclusionsIn patients with obstructive coronary stenoses, cold air inhalation causes deleterious changes in MVR and CBF. These diminish or abolish the normal adaptations during exertion that ordinarily match myocardial blood supply to demand.

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Heart Failure With Preserved Ejection Fraction Is Characterized by Dynamic Impairment of Active Relaxation and Contraction of the Left Ventricle on Exercise and Associated With Myocardial Energy Deficiency

Abstract: Patients with HFpEF have reduced cardiac energetic reserve that may underlie marked dynamic slowing of LV active relaxation and abnormal VVC during exercise.

Cited by 281 publications

References 49 publications

Phosphorylation of Cardiac Troponin I at Protein Kinase C Site Threonine 144 Depresses Cooperative Activation of Thin Filaments

Phosphorylation of Cardiac Troponin I at Protein Kinase C Site Threonine 144 Depresses Cooperative Activation of Thin Filaments

Heart Failure with Preserved Ejection Fraction

Deleterious Effects of Cold Air Inhalation on Coronary Physiological Indices in Patients With Obstructive Coronary Artery Disease

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