Abstract
Mechanism-based therapy centred on the molecular understanding of disease-causing pathways in a given patient is still the exception rather than the rule in medicine, even in cardiology. ...However, recent successful drug developments centred around the second messenger cyclic guanosine-3′-5′-monophosphate (cGMP), which is regulating a number of cardiovascular disease modulating pathways, are about to provide novel targets for such a personalized cardiovascular therapy. Whether cGMP breakdown is inhibited or cGMP synthesis is stimulated via guanylyl cyclases or their upstream regulators in different cardiovascular disease phenotypes, the outcomes seem to be so far uniformly protective. Thus, a network of cGMP-modulating drugs has evolved that act in a mechanism-based, possibly causal manner in a number of cardiac conditions. What remains a challenge is the detection of cGMPopathy endotypes amongst cardiovascular disease phenotypes. Here, we review the growing clinical relevance of cGMP and provide a glimpse into the future on how drugs interfering with this pathway may change how we treat and diagnose cardiovascular diseases altogether.
Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes ...and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.
Cardiac Magnetic Resonance Assessment of Dyssynchrony and Myocardial Scar Predicts Function Class Improvement Following Cardiac Resynchronization Therapy Kenneth C. Bilchick, Veronica Dimaano, ...Katherine C. Wu, Robert H. Helm, Robert G. Weiss, Joao A. Lima, Ronald D. Berger, Gordon F. Tomaselli, David A. Bluemke, Henry R. Halperin, Theodore Abraham, David A. Kass, Albert C. Lardo There remains a significant nonresponse rate to cardiac resynchronization therapy (CRT), with recent data also questioning the reproducibility of standard echocardiography-based dyssynchrony metrics. A circumferential mechanical dyssynchrony index (circumferential uniformity ratio estimate CURE) derived from cardiac magnetic resonance (CMR) myocardial tagging was tested for predicting clinical function class improvement following CRT. The CURE index predicted improved functional class in CRT patients with 90% accuracy (positive predictive value: 87%; negative predictive value: 100%). Adding late gadolinium-enhanced data improved accuracy further. Combined CMR tagging and late enhancement data offers promise in the prediction of functional improvement after CRT. As pointed out by Dr. Gorcsan in the accompanying editorial, further studies in larger prospective cohorts will be useful to confirm these findings.
Cardiac myocyte targeted MerCreMer transgenic mice expressing tamoxifen-inducible Cre driven by the alpha-myosin heavy chain promoter are increasingly used to control gene expression in the adult ...heart. Here, we show tamoxifen-mediated MerCreMer (MCM) nuclear translocation can induce severe transient dilated cardiomyopathy in mice with or without loxP transgenes. The cardiomyopathy is accompanied by marked reduction of energy/metabolism and calcium-handling gene expression (eg, PGC1-alpha, peroxisome proliferator-activated alpha, SERCA2A), all fully normalized with recovery. MCM-negative/flox-positive controls display no dysfunction with tamoxifen. Nuclear Cre translocation and equally effective gene knockdown without cardiomyopathy is achievable with raloxifene, suggesting toxicity is not simply from Cre. Careful attention to controls, reduced tamoxifen dosing and/or use of raloxifene is advised with this model.
Impact of Arterial Load and Loading Sequence on Left Ventricular Tissue Velocities in Humans Barry A. Borlaug, Vojtech Melenovsky, Margaret M. Redfield, Kristy Kessler, Hyuk-Jae Chang, Theodore P. ...Abraham, David A. Kass The relationship between individual components of left ventricular afterload and tissue Doppler echocardiography (TDE) velocities was examined in humans. Early-diastolic velocity (E′) varied inversely with total, nonpulsatile, and early arterial afterload, but the relationship was strongest for components of pulsatile load, particularly late-systolic load, which is affected predominantly by vascular stiffening and wave reflection. Peak systolic TDE velocities (S′) were found to vary inversely with afterload, suggesting that they may not be optimal measures of contractility. The association of increased late-systolic load with impaired E′ velocity suggests that reduction of afterload and vascular stiffening may enhance diastolic function.
The regulation of myocardial function by constitutive nitric oxide synthases (NOS) is important for the maintenance of myocardial Ca(2+) homeostasis, relaxation and distensibility, and protection ...from arrhythmia and abnormal stress stimuli. However, sustained insults such as diabetes, hypertension, hemodynamic overload, and atrial fibrillation lead to dysfunctional NOS activity with superoxide produced instead of NO and worse pathophysiology.
Major strides in understanding the role of normal and abnormal constitutive NOS in the heart have revealed molecular targets by which NO modulates myocyte function and morphology, the role and nature of post-translational modifications of NOS, and factors controlling nitroso-redox balance. Localized and differential signaling from NOS1 (neuronal) versus NOS3 (endothelial) isoforms are being identified, as are methods to restore NOS function in heart disease.
Abnormal NOS signaling plays a key role in many cardiac disorders, while targeted modulation may potentially reverse this pathogenic source of oxidative stress.
Improvements in the clinical translation of potent modulators of NOS function/dysfunction may ultimately provide a powerful new treatment for many hearts diseases that are fueled by nitroso-redox imbalance.
Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in ...this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain- or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC ₅₀, 3–21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells as well as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.
The human heart primarily metabolizes fatty acids, and this decreases as alternative fuel use rises in heart failure with reduced ejection fraction (HFrEF). Patients with severe obesity and diabetes ...are thought to have increased myocardial fatty acid metabolism, but whether this is found in those who also have heart failure with preserved ejection fraction (HFpEF) is unknown.
Plasma and endomyocardial biopsies were obtained from HFpEF (n=38), HFrEF (n=30), and nonfailing donor controls (n=20). Quantitative targeted metabolomics measured organic acids, amino acids, and acylcarnitines in myocardium (72 metabolites) and plasma (69 metabolites). The results were integrated with reported RNA sequencing data. Metabolomics were analyzed using agnostic clustering tools, Kruskal-Wallis test with Dunn test, and machine learning.
Agnostic clustering of myocardial but not plasma metabolites separated disease groups. Despite more obesity and diabetes in HFpEF versus HFrEF (body mass index, 39.8 kg/m
versus 26.1 kg/m
; diabetes, 70% versus 30%; both
<0.0001), medium- and long-chain acylcarnitines (mostly metabolites of fatty acid oxidation) were markedly lower in myocardium from both heart failure groups versus control. In contrast, plasma levels were no different or higher than control. Gene expression linked to fatty acid metabolism was generally lower in HFpEF versus control. Myocardial pyruvate was higher in HFpEF whereas the tricarboxylic acid cycle intermediates succinate and fumarate were lower, as were several genes controlling glucose metabolism. Non-branched-chain and branched-chain amino acids (BCAA) were highest in HFpEF myocardium, yet downstream BCAA metabolites and genes controlling BCAA metabolism were lower. Ketone levels were higher in myocardium and plasma of patients with HFrEF but not HFpEF. HFpEF metabolomic-derived subgroups were differentiated by only a few differences in BCAA metabolites.
Despite marked obesity and diabetes, HFpEF myocardium exhibited lower fatty acid metabolites compared with HFrEF. Ketones and metabolites of the tricarboxylic acid cycle and BCAA were also lower in HFpEF, suggesting insufficient use of alternative fuels. These differences were not detectable in plasma and challenge conventional views of myocardial fuel use in HFpEF with marked diabetes and obesity and suggest substantial fuel inflexibility in this syndrome.
Significance BDNF plays a key role in neuron development, survival, and function, with actions occurring through the stimulation of the tropomyosin-related kinase receptor B (TrkB) receptor. Whether ...BDNF/TrkB signaling has any physiologic role in governing myocardial function is unknown. Here we report that intact BDNF/TrkB signaling is required for the heart to fully contract and relax. These actions occur independently from and in addition to β-adrenergic influence. BDNF-induced enhancement of myocardial performance occurs via direct modulation of Ca ²⁺ cycling in a calmodulin-dependent protein kinase II-dependent manner. Thus, BDNF/TrkB signaling represents a previously unidentified way by which the peripheral nervous system controls cardiac muscle physiology. Our study suggests that loss or alterations in BDNF/TrkB stimulation may contribute to the pathogenesis of myocardial dysfunction in acute or chronic disease conditions.
BDNF and its associated tropomyosin-related kinase receptor B (TrkB) nurture vessels and nerves serving the heart. However, the direct effect of BDNF/TrkB signaling on the myocardium is poorly understood. Here we report that cardiac-specific TrkB knockout mice (TrkB ⁻/⁻) display impaired cardiac contraction and relaxation, showing that BDNF/TrkB signaling acts constitutively to sustain in vivo myocardial performance. BDNF enhances normal cardiomyocyte Ca ²⁺ cycling, contractility, and relaxation via Ca ²⁺/calmodulin-dependent protein kinase II (CaMKII). Conversely, failing myocytes, which have increased truncated TrkB lacking tyrosine kinase activity and chronically activated CaMKII, are insensitive to BDNF. Thus, BDNF/TrkB signaling represents a previously unidentified pathway by which the peripheral nervous system directly and tonically influences myocardial function in parallel with β-adrenergic control. Deficits in this system are likely additional contributors to acute and chronic cardiac dysfunction.
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