Peter H Backx

• dvm phd
• professor at York University

BACKGROUND Protein-truncating mutations in the titin gene are associated with increased risk of atrial fibrillation. However, little is known about the underlying pathophysiology. METHODS We identified a heterozygous titin truncating variant (TTNtv) in a patient with unexplained early onset atrial fibrillation and normal ventricular function. We g...

Cardiac fibrosis during Duchenne muscular dystrophy (DMD) arises from cellular damage and inflammation and is associated with myofibre hypertrophy and metabolic dysfunction. However, the extent to which these relationships develop across all 4 cardiac chambers, particularly during early-stage disease, remains unknown. Here, we discovered that very...

Mitochondrial creatine kinase (mtCK) regulates the “fast” export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such “creatine-dependent” phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 w...

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Mitochondria exhibit high levels of adaptability to various stimuli such as chronic muscle use (i.e. exercise) or disuse, such as immobilization or denervation. These changes in the mitochondrial network ultimately affect the health and functioning of skeletal muscle, which contributes to whole-body metabolism, locomotion, and postural stability. I...

Mitochondrial creatine kinase (mtCK) regulates the fast export of phosphocreatine to support cytoplasmic phosphorylation of ADP to ATP which is more rapid than direct ATP export. Such creatine-dependent phosphate shuttling is attenuated in several muscles, including the heart, of the D2.mdx mouse model of Duchenne muscular dystrophy at only 4 weeks...

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia that is strongly associated with cardiovascular (CV) disease and sedentary lifestyles. Despite the benefits of exercise on overall health, AF incidence in high‐level endurance athletes rivals that of CV disease patients, suggesting a J‐shaped relationship with AF. To investigate the dep...

Background: While the protective effects of n-3 polyunsaturated fatty acids (PUFAs) on cardiac ischemia-reperfusion (IR) injury have been previously reported, limited data are available regarding how these fatty acids affect membrane receptors and their downstream signaling following IR injury. We aimed to identify potential receptors activated by...

Aims Endurance exercise is associated with an increased risk of atrial fibrillation (AF). We previously established that adverse atrial remodelling and AF susceptibility induced by intense exercise in mice require the mechanosensitive and pro-inflammatory cytokine tumour necrosis factor (TNF). The cellular and mechanistic basis for these TNF-mediat...

Heart failure remains a highly prevalent condition with diverse etiology, yet the underlying signaling mechanisms are not fully understood. Despite the profound effects of post-translational protein modifications on downstream signaling, limited studies have investigated the cardiac phosphoproteome in human heart failure. We hypothesized that a com...

A comprehensive view of the role of NLRP3/caspase-1/GSDMD–mediated pyroptosis in pressure overload cardiac hypertrophy is presented in this study. Furthermore, mitigation of NLRP3 deficiency-induced pyroptosis confers cardioprotection against pressure overload through activation of TAK1, whereas this salutary effect is abolished by inhibition of TA...

To better understand sodium channel (SCN5A)-related cardiomyopathies, we generated ventricular cardiomyocytes from induced pluripotent stem cells obtained from a dilated cardiomyopathy patient harbouring the R222Q mutation, which is only expressed in adult SCN5A isoforms. Because the adult SCN5A isoform was poorly expressed, without functional diff...

The prognosis and treatment outcomes of heart failure (HF) patients rely heavily on disease etiology, yet the majority of underlying signaling mechanisms are complex and not fully elucidated. Phosphorylation is a major point of protein regulation with rapid and profound effects on the function and activity of protein networks. Currently, there is a...

Introduction: Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide. Most conditions linked to AF, such as cardiovascular (CVD) and valvular disease, are linked to elevated atrial pressures and atrial cardiomyocyte (CM) stretch, which are powerful stimuli for atrial remodeling. We have shown that the proinflamm...

The intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. He...

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, current iPSC- CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targ...

The intercalated disc (ICD) is unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin 43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Her...

Background The murine transverse aortic constriction (TAC) model is frequently used to investigate molecular mechanisms underlying heart failure. However, limited data is available regarding the expression of mRNAs and circRNAs in murine heart failure progression induced by pressure overload. Methods Transverse aortic constriction was used to indu...

Previous studies have established that fast transmural gradients of transient outward K+ current (Ito,f) correlate with regional differences in action potential (AP) profile and excitation-contraction coupling (ECC) with high Ito,f expression in the epimyocardium (EPI) being associated with short APs and low contractility and vice versa. Herein, we...

Background: Pressure overload can result in dilated cardiomyopathy. The beneficial effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) on heart disorders have been widely recognized. However, the molecular mechanisms underlying their protective effects against cardiomyopathy remain unclear. Methods: Pressure overload in mice induced by 8 weeks o...

Heart rate (HR) and blood pressure as well as adverse cardiovascular events show clear circadian patterns, which are linked to interdependent daily variations in physical activity and cardiac autonomic nerve system (ANS) activity. We set out to assess the relative contributions of the ANS (alone) and physical activity to circadian HR fluctuations....

Aged nonhuman primate (NHP) models are of great value for studying the pathology of metabolic heart diseases and developing therapeutic strategies. In this study, aged male cynomolgus monkeys were fed a regular diet or a high-fat/high-sugar diet (HFSD) for 8 months. Metabolic disorders were diagnosed by ¹H-NMR and serum biochemistry, and cardiac fu...

BACKGROUND Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis,...

Heart failure is induced by multiple pathological mechanisms, and current therapies are ineffective against heart failure with preserved ejection fraction (HFpEF). As there are limited animal models of HFpEF, its underlying mechanisms have not yet been elucidated. Here, we employed the descending aortic constriction (DAC) technique to induce chroni...

Acute exhaustive endurance exercise can differentially impact the right ventricle (RV) versus the left (LV). However, the hemodynamic basis for these differences and its impact on post-exercise recovery remains unclear. Therefore, we assessed cardiac structure and function along with hemodynamic properties of mice subjected to single bouts (216±8mi...

Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, inten...

Previous studies have shown an association between elevated atrial NADPH-dependent oxidative stress and decreased plasma apelin in patients with atrial fibrillation (AF), though the basis for this relationship is unclear. In the current study, RT-PCR and immunofluorescence studies of human right atrial appendages (RAAs) showed expression of the ape...

Background: Variability in the anatomy and orientation of the triangle of Koch (TK) complicates ablation procedures involving the atrioventricular (AV) node. We used CT angiography (CTA) to assess the anatomical TK orientation, the CS ostium direction, and the relationship between the two, and we validated an individualized CS-guided projection du...

Background The secreted glycoprotein Slit2, previously known as an axon guidance cue, has recently been found to protect tissues in pathological conditions; however, it is unknown whether Slit2 functions in cardiac ischemia–reperfusion (IR) injury. Methods Langendorff-perfused isolated hearts from Slit2-overexpressing (Slit2-Tg) mice and C57BL/6J...

Background: Although aortic regurgitation (AR) is a clinically important condition that is becoming increasingly common, few relevant murine models and mechanistic studies exist for this condition. In this study, we attempted to delineate the pathological and molecular changes and address the roles of some potentially relevant molecules in an anim...

Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino aci...

Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR co...

Myocardial fibrosis is a severe global health problem due to its prevalence in all forms of cardiac diseases and direct role in causing heart failure. The discovery of efficient antifibrotic compounds has been hampered due to the lack of a physiologically relevant disease model. Herein, we present a disease model of human myocardial fibrosis and us...

Organ-on-a-chip systems have the potential to revolutionize drug screening and disease modeling through the use of human stem cell-derived cardiomyocytes. The predictive power of these tissue models critically depends on the functional assembly and maturation of human cells that are used as building blocks for organ-on-a-chip systems. To resemble a...

Phosphodiesterase type 3 (PDE3) inhibitors block the cAMP hydrolyzing activity of both PDE3 isoforms, PDE3A and PDE3B, which have distinct roles in the heart. Although PDE3 inhibitors improve cardiac function in heart disease patients, they also increase mortality. Nevertheless, PDE3 inhibitors can provide benefit to non-ischemic heart disease pati...

Key points Ninety‐eight per cent of patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy, with 40% developing heart failure. While increased propensity for mitochondrial induction of cell death has been observed in left ventricle, it remains unknown whether this is linked to impaired mitochondrial respiratory control and elevated...

Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing un...

Intense endurance exercise is linked to atrial fibrillation (AF). We established previously that interventions that simultaneously interfere with TNFα signaling, mediated via both the enzymatically liberated soluble and membrane-bound forms of TNFα, prevent atrial remodeling and AF vulnerability in exercised mice. To investigate which signaling mod...

RATIONALE Duchenne Muscular Dystrophy is a progressive muscle wasting disease in males resulting from mutations in the X‐linked gene dystrophin. The loss of dystrophin in the dystroglycan complex causes severe muscle pathology including cardiomyopathy which can lead to early death. While the cardiac dysfunction in mouse models of this disease has b...

Most exercise studies in mice have relied on forced training which can introduce psychological stress. Consequently, the utility of mouse models for understanding exercise-mediated effects in humans, particularly autonomic nervous system (ANS) remodeling, have been challenged. We compared the effects of voluntary free-wheel running vs. non-voluntar...

Moderate physical activity levels are associated with increased longevity and lower risk of atrial fibrillation (AF). However, the relative risk of lone AF is 3–5-fold higher in intensive endurance-trained athletes compared with healthy adults. There is growing concern that “excessive” endurance exercise may promote cardiac remodelling, leading to...

Background The SCN5A mutation, P1332L, is linked to a malignant form of congenital long QT syndrome, type 3 (LQT3), and affected patients are highly responsive to the Na⁺ channel blocking drug, mexiletine. In contrast, A647D is an atypical SCN5A mutation causing Brugada syndrome. An asymptomatic male with both P1332L and A647D presented with varyin...

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity. There is considerable inter-patient variability in the pathologic processes that promote AF, and this variability likely has a significant genetic basis. Clinically this is reflected by the observation that anti-arrhythmic drugs (AADs) and i...

Background: Heart failure (HF) is associated with reduced expression of plasma membrane Ca2+-ATPase 4 (PMCA4). Cardiac-specific overexpression of human PMCA4b in mice inhibited nNOS activity and reduced cardiac hypertrophy by inhibiting calcineurin. Here we examine temporally-regulated cardiac-specific over-expression of hPMCA4b in mouse models of...

Since current experimental models of Atrial Fibrillation (AF) have significant limitations, we used human embryonic stem cells (hESCs) to generate an atrial-specific tissue model of AF for pharmacologic testing. We generated atrial-like cardiomyocytes (CMs) from hESCs which preferentially expressed atrial-specific genes, and had shorter action pote...

As central nodes in cardiomyocyte signaling, nuclear AKT appears to play a cardio-protective role in cardiovascular disease. Here we describe a circular RNA, circ-Amotl1 that is highly expressed in neonatal human cardiac tissue, and potentiates AKT-enhanced cardiomyocyte survival. We hypothesize that circ-Amotl1 binds to PDK1 and AKT1, leading to A...

Supplementary figures and tables.

The ability to direct the differentiation of human pluripotent stem cells (hPSCs) to the different cardiomyocyte subtypes is a prerequisite for modeling specific forms of cardiovascular disease in vitro and for developing novel therapies to treat them. Here we have investigated the development of the human atrial and ventricular lineages from hPSCs...

Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however little is known about their function in regulating homeostasis and proliferation in terminally differentiated ce...

Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1L613V/+ knock-in mice. Here, using inducible Raf1L613V expres...

Supplementary Figures and Supplementary Tables.

In mice, myocardial hypertrophic preconditioning (HP), which is produced by the removal of short-term transverse aortic constriction (TAC), was recently reported to render the heart resistant to hypertrophic responses induced by subsequent re-constriction (Re-TAC). However, there is no efficient non-invasive method for ensuring that the repeated ao...

Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, the induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively expresse...

Noonan syndrome (NS) is caused by mutations in RAS/ERK pathway genes, and is characterized by craniofacial, growth, cognitive and cardiac defects. NS patients with kinase-activating RAF1 alleles typically develop pathological left ventricular hypertrophy (LVH), which is reproduced in Raf1L613V/+ knock-in mice. Here, using inducible Raf1L613V expres...

The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating...

The generation of human cardiomyocytes (CMs) from human pluripotent stem cells (hPSCs) has become an important resource for modeling human cardiac disease, and for drug screening and also holds significant potential for cardiac regeneration. Many challenges remain to be overcome however, before innovation in this field can translate into a change i...

The fast transient outward potassium current (Ito,f) plays a critical role in the electrical and contractile properties of the myocardium. Ito,f channels are formed by the co-assembly of the pore-forming α-subunits, Kv4.2 and Kv4.3, together with the accessory β-subunit KChIP2. Reductions of Ito,f are common in the diseased heart, which is also ass...

The Ca(2+)-independent transient outward K(+ )current (Ito) plays a critical role in underlying phase 1 of repolarization of the cardiac action potential and, as a result, is central to modulating excitation-contraction coupling and propensity for arrhythmia. Additionally, Ito and its molecular constituents are consistently reduced in cardiac hyper...

Gradients of the fast transient outward K+ current (Ito,f) contribute to heterogeneity of ventricular repolarization in a number of species. Cardiac Ito,f levels and gradients change notably with heart disease. Human cardiac Ito,f appears to be encoded by the Kv4.3 pore-forming alpha-subunit plus the auxiliary KChIP2 beta-subunit while mouse cardia...

Cardiomyocyte (CM) hypertrophy and increased heart mass in response to pressure overload is associated with hyper-activation of the myocyte enhancer factor-2 (MEF2) family of transcriptional regulators, and concomitant initiation of the fetal gene program. Adiponectin, an adipokine that is reduced in individuals with obesity and diabetes, has been...

Objectives This study sought to determine the characteristics of human LDVF, particularly as it contrasts with short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance. Background The electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been studied in the human heart. Methods VF w...

Although inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3) has been reported to protect rodent heart against ischemia/ reperfusion (I/R) injury, neither the specific PDE3 isoform involved nor the underlying mechanisms have been identified. Targeted disruption of PDE3 subfamily B (PDE3B), but not of PDE3 subfamily A (PDE3A), protected...

Unlike ventricular myocytes, atrial myocytes have a much less well-developed T-tubular network, especially in rodents. In this study, we carried out computer simulations to investigate the consequences of a T tubular network on the development of spatially discordant Ca alternans in atrial myocytes. Our study was motivated by experimental observati...

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, in...

Purpose of review: Endurance exercise, despite a plethora of proven health benefits, is increasingly recognized as a potential cause of lone atrial fibrillation. Moderate exercise reduces all-cause mortality and protects against developing atrial fibrillation. However, more intense exercise regimes confer modest incremental health benefits, induce...

Background Endoplasmic reticulum (ER) resident protein 44 (ERp44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca2+ homeostasis. However, the role of ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac dev...

Background: J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG. Methods and r...

ESC-derived cardiomyocytes are excitable cells that express many of the ion channels also found in adult cardiomyocytes. The patch-clamp technique is a powerful technique to characterize both the electrophysiological properties of excitable cells as well as the underlying ion channel currents responsible for these electrophysiological properties. T...

Cardiac sarcolemmal syntaxin (Syn)-1A interacts with sulfonylurea receptor (SUR) 2A to inhibit ATP-sensitive potassium (KATP) channels. Phosphatidylinositol 4,5-bisphosphate (PIP2), a ubiquitous endogenous inositol phospholipid, known to bind Kir6.2 subunit to open KATP channels, has recently been shown to directly bind Syn-1A in plasma membrane to...

We have previously shown that ischemic preconditioning (IPC) protection against necrosis in whole hearts and both fresh and cultured cardiomyocytes, as well as improved regulatory volume decrease (RVD) to hypo-osmotic swelling in cardiomyocytes, are abrogated through Cl- channel blockade, pointing to a role for enhanced cell volume regulation in IP...

Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek (BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to no...

Heart failure can be a consequence of insufficient palliation of structural malformations in patients with congenital heart disease (CHD) or genetic perturbations resulting in cardiomyopathies. Although CHD is traditionally considered a pediatric clinical problem, there is a rapidly increasing population of patients surviving into adulthood with CH...

Structural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role.To define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics.High throughput real-time RT-PCR was use...

Resistant ventricular fibrillation, re-fibrillation and diminished myocardial contractility are important factors leading to poor survival following cardiac arrest. We hypothesized dantrolene improves survival following VF by rectifying calcium dysregulation caused by VF. VF was induced in 26 Yorkshire pigs for 4 min. CPR was then commenced for 3 m...