Energy substrate metabolism and contractile function are tightly coupled in the heart. Within this framework, heart failure may be viewed as a state of impaired energy transfer. The metabolic changes ...in the failing heart are linked to functional and structural changes. A worthwhile goal is to measure metabolic flux and its regulation quantitatively, and to do this in a manner that leads to targeted interventions. For several good reasons, this goal has been elusive until now. The development of new analytical and imaging techniques offers the potential of exploring the landscape of metabolic changes across the different stages of heart failure. In this Review Topic of the Month, the authors focus on concepts and brevity to provide a strategic overview of cardiac metabolism in the diagnosis, prevention, and treatment of nonischemic heart failure.
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•Metabolic remodeling precedes, triggers, and sustains functional and structural remodeling of the heart.•Understanding cardiac metabolism offers a spectrum of opportunities to diagnose, prevent, and treat the failing heart.•Flux-based analysis unveils the hallmarks of metabolic alterations across heart failure stages.•A main challenge remains to identify new perspectives of strategic value.
Disruption of the physiologic sleep-wake cycle and low melatonin levels frequently accompany cardiac disease, yet the underlying mechanism has remained enigmatic. Immunostaining of sympathetic axons ...in optically cleared pineal glands from humans and mice with cardiac disease revealed their substantial denervation compared with controls. Spatial, single-cell, nuclear, and bulk RNA sequencing traced this defect back to the superior cervical ganglia (SCG), which responded to cardiac disease with accumulation of inflammatory macrophages, fibrosis, and the selective loss of pineal gland-innervating neurons. Depletion of macrophages in the SCG prevented disease-associated denervation of the pineal gland and restored physiological melatonin secretion. Our data identify the mechanism by which diurnal rhythmicity in cardiac disease is disturbed and suggest a target for therapeutic intervention.
Up next: The dawn of systems biology in HFpEF research Bode, David; Sotomayor-Flores, Cristian; Schiattarella, Gabriele G.
Journal of molecular and cellular cardiology,
July 2022, 2022-Jul, 2022-07-00, 20220701, Letnik:
168
Journal Article
Recenzirano
Odprti dostop
•A systems biology approach will greatly help to better understand the complexity of HFpEF•Increase availability of human tissue samples from in-depth phenotyped HFpEF patients is critically needed ...in the field•Large scale -omics data from HFpEF tissue samples will accelerate translational research studies in HFpEF
Can HFpEF and HFrEF Coexist? Schiattarella, Gabriele G; Tong, Dan; Hill, Joseph A
Circulation (New York, N.Y.),
2020-March-03, Letnik:
141, Številka:
9
Journal Article
Background To date, assessment of right ventricular (RV) function in mice has relied extensively on invasive measurements. Echocardiographic advances have allowed adaptation of measures used in ...humans for serial, noninvasive RV functional assessment in mice. We evaluated the diagnostic performance of tricuspid annular plane systolic excursion (TAPSE), RV peak systolic myocardial velocity (s'), RV myocardial performance index (MPI), and RV fractional area change (FAC) in a mouse model of pulmonary hypertension. Methods and Results Echocardiography was performed on mice at baseline and 3 weeks after induction of pulmonary hypertension using inhaled bleomycin or saline, including adapted measures of TAPSE, s', MPI, and FAC. RV systolic pressure was measured by invasive catheterization, and RV contractility was measured as the peak slope of the RV systolic pressure recording (maximum change pressure/change time). Postmortem morphological assessment of RV hypertrophy was performed. RV systolic pressure was elevated and maximum change pressure/change time was reduced in bleomycin versus control (n=8;
=0.002). Compared with controls, bleomycin mice had reduced TAPSE (0.79±0.05 versus 1.06±0.04 mm;
=0.003), s' (21.3±1.2 versus 29.2±1.3 mm/s;
<0.001), and FAC (20.3±0.7% versus 31.0±1.3%;
<0.001), whereas MPI was increased (0.51±0.03 versus 0.37±0.01;
=0.006). All measures correlated with RV systolic pressure and maximum change pressure/change time. Intraobserver and interobserver variability were minimal. Receiver operating characteristic curves demonstrated that TAPSE (<0.84 mm), s'(<23.3 mm/s), MPI (0.42), and FAC (<23.3%) identified maximum change pressure/change time ≤2100 mm Hg/s with high accuracy. Conclusions TAPSE, s', MPI, and FAC are measurable consistently using high-resolution echocardiography in mice, and are sensitive and specific measures of pulmonary pressure and RV function. This validation opens the opportunity for serial noninvasive measures in mouse models of pulmonary hypertension, enhancing the statistical power of preclinical studies of novel therapeutics.
Calcium (Ca
) dysregulation is a hallmark of heart failure and is characterized by impaired Ca
sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca
-ATPase (SERCA). We recently discovered ...a micropeptide named DWORF (
arf
pen
eading
rame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mouse model of dilated cardiomyopathy (DCM) due to genetic deletion of the muscle-specific LIM domain protein (MLP), we show that DWORF overexpression restores cardiac function and prevents the pathological remodeling and Ca
dysregulation classically exhibited by MLP knockout mice. Our results establish DWORF as a potent activator of SERCA within the heart and as an attractive candidate for a heart failure therapeutic.
Forkhead box O (FoxO) proteins and thyroid hormone (TH) have well established roles in cardiovascular morphogenesis and remodeling. However, specific role(s) of individual FoxO family members in ...stress-induced growth and remodeling of cardiomyocytes remains unknown. Here, we report that FoxO1, but not FoxO3, activity is essential for reciprocal regulation of types II and III iodothyronine deiodinases (Dio2 and Dio3, respectively), key enzymes involved in intracellular TH metabolism. We further show that Dio2 is a direct transcriptional target of FoxO1, and the FoxO1-Dio2 axis governs TH-induced hypertrophic growth of neonatal cardiomyocytes in vitro and in vivo. Utilizing transverse aortic constriction as a model of hemodynamic stress in wild-type and cardiomyocyte-restricted FoxO1 knockout mice, we unveil an essential role for the FoxO1-Dio2 axis in afterload-induced pathological cardiac remodeling and activation of TRα1. These findings demonstrate a previously unrecognized FoxO1-Dio2 signaling axis in stress-induced cardiomyocyte growth and remodeling and intracellular TH homeostasis.
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