ABSTRACT
Aging is a major risk factor for sinoatrial node (SAN) dysfunction, which can impair heart rate (HR) control and heart rate variability (HRV). HR and HRV are determined by intrinsic SAN function and its regulation by the autonomic nervous system (ANS). The purpose of this study was to use multi-scale multi-fractal detrended fluctuation analysis (MSMFDFA; a complexity-based approach to analyze multi-fractal dynamics) to longitudinally assess changes in multi-fractal HRV properties and SAN function in ECG time series recorded repeatedly across the full adult lifespan in mice. ECGs were recorded in anesthetized mice in baseline conditions and after autonomic nervous system blockade every three months beginning at 6 months of age until the end of life. MSMFDFA was used to assess HRV and SAN function every three months between 6 and 27 months of age. Intrinsic HR (i.e. HR during ANS blockade) remained relatively stable until 15 months of age, and then progressively declined until study endpoint at 27 months of age. MSMFDFA revealed sudden and rapid changes in multi-fractal properties of the ECG RR interval time series in aging mice. In particular, multi-fractal spectrum width (MFSW, a measure of multi-fractality) was relatively stable between 6 months and 15 months of age and then progressively increased at 27 months of age. These changes in MFSW were evident in baseline conditions and during ANS blockade. Thus, intrinsic SAN function declines progressively during aging and is manifested by age-associated changes in multi-fractal HRV across the lifespan in mice, which can be accurately quantified by MSMFDFA.
Subject(s)
Aging , Autonomic Nervous System , Electrocardiography , Heart Rate , Sinoatrial Node , Animals , Heart Rate/physiology , Sinoatrial Node/physiopathology , Sinoatrial Node/physiology , Aging/physiology , Autonomic Nervous System/physiopathology , Autonomic Nervous System/physiology , Mice , Male , Mice, Inbred C57BL , Longitudinal StudiesABSTRACT
Nonlinear analyses of heart rate variability (HRV) can be used to quantify the unpredictability, fractal properties and complexity of heart rate. Fractality and its analysis provides valuable information about cardiovascular health. Multi-Scale Multi-Fractal Detrended Fluctuation Analysis (MSMFDFA) is a complexity-based algorithm that can be used to quantify the multi-fractal dynamics of the HRV time series through investigating characteristic exponents at different time scales. This method is applicable to short time series and it is robust to noise and nonstationarity. We have used MSMFDFA, which enables assessment of HRV in the frequency ranges encompassing the very-low frequency and ultra-low frequency bands, to jointly assess multi-scale and multi-fractal dynamics of HRV signals obtained from telemetric ECG recordings in wildtype mice at baseline and after autonomic nervous system (ANS) blockade, from electrograms recorded from isolated atrial preparations and from spontaneous action potential recordings in isolated sinoatrial node myocytes. Data demonstrate that the fractal profile of the intrinsic heart rate is significantly different from the baseline heart rate in vivo, and it is also altered after ANS blockade at specific scales and fractal order domains. For beating rate in isolated atrial preparations and intrinsic heart rate in vivo, the average fractal structure of the HRV increased and multi-fractality strength decreased. These data demonstrate that fractal properties of the HRV depend on both ANS activity and intrinsic sinoatrial node function and that assessing multi-fractality at different time scales is an effective approach for HRV assessment.
ABSTRACT
Heart rate (HR) is controlled by the sinoatrial node (SAN). SAN dysfunction is highly prevalent in aging; however, not all individuals age at the same rate. Rather, health status during aging is affected by frailty. Natriuretic peptides regulate SAN function in part by activating natriuretic peptide receptor C (NPR-C). The impacts of NPR-C on HR and SAN function in aging and as a function of frailty are unknown. Frailty was measured in aging wild-type and NPR-C knockout (NPR-C-/-) mice using a mouse clinical frailty index (FI). HR and SAN structure and function were investigated using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology, and molecular biology. NPR-C-/- mice rapidly became frail leading to shortened life span. HR was reduced and SAN recovery time was increased in older versus younger mice, and these changes were exacerbated in NPR-C-/- mice; however, there was substantial variability among age groups and genotypes. HR and SAN recovery time were correlated with FI score and fell along a continuum regardless of age or genotype. Optical mapping demonstrates impairments in SAN function that were also correlated with FI score. SAN fibrosis was increased in aged and NPR-C-/- mice and was graded by FI score. Loss of NPR-C results in accelerated aging and rapid decline in health status in association with impairments in HR and SAN function. Frailty assessment was effective and better able to distinguish aging-dependent changes in SAN function in the setting of shortened life span due to loss of NPR-C.
Subject(s)
Frailty , Sinoatrial Node , Aged , Aging/physiology , Animals , Frail Elderly , Humans , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/pathology , Sinoatrial Node/physiologyABSTRACT
[Figure: see text].
Subject(s)
Aging/physiology , Atrial Fibrillation/blood , Heart Atria/physiopathology , Natriuretic Peptide, C-Type/blood , Animals , Atrial Fibrillation/physiopathology , Biomarkers/blood , Disease Models, Animal , Female , Male , MiceABSTRACT
BACKGROUND: Heart rate variability (HRV) is determined by intrinsic sinoatrial node (SAN) activity and the autonomic nervous system (ANS). HRV is reduced in aging; however, aging is heterogeneous. Frailty, which can be measured using a frailty index (FI), can quantify health status in aging separately from chronological age. OBJECTIVE: The purpose of this study was to investigate the impacts of age and frailty on HRV in mice. METHODS: Frailty was measured in aging mice between 10 and 130 weeks of age. HRV was assessed using time domain, frequency domain, and Poincaré plot analyses in anesthetized mice at baseline and after ANS blockade, as well as in isolated atrial preparations. RESULTS: HRV was reduced in aged mice (90-130 weeks and 50-80 weeks old) compared to younger mice (10-30 weeks old); however, there was substantial variability within age groups. In contrast, HRV was strongly correlated with FI score regardless of chronological age. ANS blockade resulted in reductions in heart rate that were largest in 90- to 130-week-old mice and were correlated with FI score. HRV after ANS blockade or in isolated atrial preparations was increased in aged mice but again showed high variability among age groups. HRV was correlated with FI score after ANS blockade and in isolated atrial preparations. CONCLUSION: HRV is reduced in aging mice in association with a shift in sympathovagal balance and increased intrinsic SAN beating variability; however, HRV is highly variable within age groups. HRV was strongly correlated with frailty, which was able to detect differences in HRV separately from chronological age.
Subject(s)
Aging/physiology , Autonomic Nervous System/physiopathology , Frailty/physiopathology , Heart Rate/physiology , Sinoatrial Node/physiopathology , Animals , Female , Male , Mice , Mice, Inbred C57BLABSTRACT
BACKGROUND: Atrial fibrillation (AF) is highly prevalent in diabetes mellitus (DM), yet the basis for this finding is poorly understood. Type 2 DM may be associated with unique patterns of atrial electrical and structural remodeling; however, this has not been investigated in detail. OBJECTIVE: The purpose of this study was to investigate AF susceptibility and atrial electrical and structural remodeling in type 2 diabetic db/db mice. METHODS: AF susceptibility and atrial function were assessed in male and female db/db mice and age-matched wildtype littermates. Electrophysiological studies were conducted in vivo using intracardiac electrophysiology and programmed stimulation. Atrial electrophysiology was also investigated in isolated atrial preparations using high-resolution optical mapping and in isolated atrial myocytes using patch-clamping. Molecular biology studies were performed using quantitative polymerase chain reaction and western blotting. Atrial fibrosis was assessed using histology. RESULTS: db/db mice were highly susceptible to AF in association with reduced atrial conduction velocity, action potential duration prolongation, and increased heterogeneity in repolarization in left and right atria. In db/db mice, atrial K+ currents, including the transient outward current (Ito) and the ultrarapid delayed rectifier current (IKur), were reduced. The reduction in Ito occurred in association with reductions in Kcnd2 mRNA expression and KV4.2 protein levels. The reduction in IKur was not related to gene or protein expression changes. Interstitial atrial fibrosis was increased in db/db mice. CONCLUSION: Our study demonstrates that increased susceptibility to AF in db/db mice occurs in association with impaired electrical conduction as well as electrical and structural remodeling of the atria.
Subject(s)
Atrial Fibrillation/physiopathology , Atrial Remodeling/physiology , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2/complications , Heart Atria/physiopathology , Myocytes, Cardiac/metabolism , Potassium Channels/metabolism , Action Potentials/physiology , Animals , Atrial Fibrillation/etiology , Atrial Fibrillation/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Female , Heart Atria/metabolism , Heart Atria/pathology , Male , Mice , Mice, Inbred Strains , Myocytes, Cardiac/pathology , Optical ImagingABSTRACT
BACKGROUND: Hypertensive heart disease is associated with sinoatrial node (SAN) dysfunction and reductions in heart rate variability (HRV). Alterations in HRV could occur in association with changes in autonomic nervous system (ANS) activity, changes in SAN function and responsiveness to ANS agonists, or both. These relationships are unclear. OBJECTIVE: The purpose of this study was to investigate the roles of ANS signaling, intrinsic SAN function, and changes in HRV in a mouse model of angiotensin II (AngII)-mediated hypertensive heart disease. METHODS: Mice were treated with saline or AngII (2.5 mg/(kgâ d)) for 3 weeks. ANS activity was assessed through HRV analysis of electrocardiograms collected in vivo by telemetry as well as direct recordings of vagal nerve activity and renal sympathetic nerve activity from anesthetized mice. The effects of the ANS agonists isoproterenol and carbachol on SAN function and beating interval variability were assessed from electrogram recordings in intact isolated atrial preparations and from spontaneous action potential recordings in isolated SAN myocytes. RESULTS: Time and frequency domain analysis demonstrates that mice infused with AngII had reduced HRV. AngII-infused mice had elevated renal sympathetic nerve activity while resting vagal nerve activity was unchanged. AngII caused an increase in SAN beating interval variability in isolated atrial preparations and isolated SAN myocytes. Furthermore, isolated atrial preparations and SAN myocytes from AngII-infused mice had impaired responses to both isoproterenol and carbachol. CONCLUSION: Reduced HRV in hypertension occurs in association with altered sympathovagal balance as well as intrinsic SAN dysfunction and reduced responsiveness of SAN myocytes to ANS agonists.
Subject(s)
Autonomic Nervous System/physiopathology , Electrocardiography , Heart Rate/physiology , Hypertension/complications , Sick Sinus Syndrome/physiopathology , Sinoatrial Node/physiopathology , Angiotensin II/toxicity , Animals , Disease Models, Animal , Heart Atria/physiopathology , Hypertension/chemically induced , Hypertension/physiopathology , Male , Mice , Mice, Inbred C57BL , Sick Sinus Syndrome/etiologyABSTRACT
Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.
Subject(s)
Atrial Fibrillation/metabolism , Atrial Remodeling/physiology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 1/complications , Insulin/metabolism , Action Potentials/drug effects , Action Potentials/physiology , Animals , Atrial Fibrillation/diagnosis , Atrial Fibrillation/etiology , Atrial Fibrillation/physiopathology , Atrial Remodeling/immunology , Cells, Cultured , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/metabolism , Disease Models, Animal , Echocardiography , Electrocardiography , Heart Atria/cytology , Heart Atria/metabolism , Heart Atria/pathology , Heart Atria/physiopathology , Humans , Insulin/administration & dosage , Insulin/genetics , Kv1.5 Potassium Channel/metabolism , Male , Mice , Mice, Transgenic , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Myocytes, Cardiac/physiology , NAV1.5 Voltage-Gated Sodium Channel/metabolism , Patch-Clamp Techniques , Potassium/metabolism , Primary Cell Culture , Sodium/metabolism , Streptozocin/toxicityABSTRACT
Cardiac looping is an essential and highly conserved morphogenetic process that places the different regions of the developing vertebrate heart tube into proximity of their final topographical positions. High-resolution 4D live imaging of mosaically labelled cardiomyocytes reveals distinct cardiomyocyte behaviors that contribute to the deformation of the entire heart tube. Cardiomyocytes acquire a conical cell shape, which is most pronounced at the superior wall of the atrioventricular canal and contributes to S-shaped bending. Torsional deformation close to the outflow tract contributes to a torque-like winding of the entire heart tube between its two poles. Anisotropic growth of cardiomyocytes based on their positions reinforces S-shaping of the heart. During cardiac looping, bone morphogenetic protein pathway signaling is strongest at the future superior wall of the atrioventricular canal. Upon pharmacological or genetic inhibition of bone morphogenetic protein signaling, myocardial cells at the superior wall of the atrioventricular canal maintain cuboidal cell shapes and S-shaped bending is impaired. This description of cellular rearrangements and cardiac looping regulation may also be relevant for understanding the etiology of human congenital heart defects.
Subject(s)
Bone Morphogenetic Proteins/metabolism , Gene Expression Regulation, Developmental , Heart/embryology , Myocytes, Cardiac/metabolism , Signal Transduction , Animals , Anisotropy , Embryo, Nonmammalian/metabolism , Embryonic Development , Green Fluorescent Proteins/metabolism , Microscopy, Confocal , Morphogenesis , Organogenesis , Torque , Transcription Factors/metabolism , Wnt Proteins/metabolism , Wnt Signaling Pathway , Zebrafish/embryology , Zebrafish Proteins/metabolismABSTRACT
BACKGROUND: Atrial fibrillation (AF) commonly occurs in hypertension and in association with elevated Ang II (angiotensin II) levels. The specific mechanisms underlying Ang II-mediated AF are unclear, and interventions to prevent the effects of Ang II are lacking. NPs (natriuretic peptides), which elicit their effects through specific NP receptors, including NPR-C (natriuretic peptide receptor-C), are cardioprotective hormones that affect cardiac structure and function. METHODS: This study used wild-type and NPR-C knockout (NPR-C-/-) mice to investigate the effects of Ang II (3 mg/kg per day for 3 weeks) on AF susceptibility and atrial function using in vivo electrophysiology, high-resolution optical mapping, patch clamping, and molecular biology. In some experiments, wild-type mice were cotreated with Ang II and the NPR-C agonist cANF (0.07-0.14 mg/kg per day) for 3 weeks. RESULTS: In wild-type mice, Ang II increased susceptibility to AF in association with a prolongation of P-wave duration, increased atrial refractory period, and slowed atrial conduction. These effects were exacerbated in Ang II-treated NPR-C-/- mice. Ang II prolonged action potential duration and reduced action potential upstroke velocity (Vmax). These effects were greater in left atrial myocytes from Ang II-treated NPR-C-/- mice. Ang II also increased fibrosis in both atria in wild-type mice, whereas Ang II-treated NPR-C-/- mice exhibited substantially higher fibrosis throughout the atria. Fibrotic responses were associated with changes in expression of profibrotic genes, including TGFß and TIMP1. Cotreating wild-type mice with Ang II and the NPR-C agonist cANF dose dependently reduced AF inducibility by preventing some of the Ang II-induced changes in atrial myocyte electrophysiology and preventing fibrosis throughout the atria. CONCLUSIONS: NPR-C may represent a new target for the prevention of Ang II-induced AF via protective effects on atrial electrical and structural remodeling.
Subject(s)
Angiotensin II , Atrial Fibrillation/metabolism , Atrial Remodeling , Heart Atria/metabolism , Myocytes, Cardiac/metabolism , Receptors, Atrial Natriuretic Factor/metabolism , Action Potentials , Animals , Atrial Fibrillation/chemically induced , Atrial Fibrillation/genetics , Atrial Fibrillation/physiopathology , Disease Models, Animal , Disease Progression , Fibrosis , Heart Atria/physiopathology , Heart Rate , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Male , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Cardiac/pathology , Receptors, Atrial Natriuretic Factor/deficiency , Receptors, Atrial Natriuretic Factor/genetics , Time FactorsABSTRACT
Atrial fibrillation (AF) is prevalent in hypertension and elevated angiotensin II (Ang II); however, the mechanisms by which Ang II leads to AF are poorly understood. Here, we investigated the basis for this in mice treated with Ang II or saline for 3â¯weeks. Ang II treatment increased susceptibility to AF compared to saline controls in association with increases in P wave duration and atrial effective refractory period, as well as reductions in right and left atrial conduction velocity. Patch-clamp studies demonstrate that action potential (AP) duration was prolonged in right atrial myocytes from Ang II treated mice in association with a reduction in repolarizing K+ currents. In contrast, APs in left atrial myocytes from Ang II treated mice showed reductions in upstroke velocity and overshoot, as well as greater prolongations in AP duration. Ang II reduced Na+ current (INa) in the left, but not the right atrium. This reduction in INa was reversible following inhibition of protein kinase C (PKC) and PKCα expression was increased selectively in the left atrium in Ang II treated mice. The transient outward K+ current (Ito) showed larger reductions in the left atrium in association with a shift in the voltage dependence of activation. Finally, Ang II caused fibrosis throughout the atria in association with changes in collagen expression and regulators of the extracellular matrix. This study demonstrates that hypertension and elevated Ang II cause distinct patterns of electrical and structural remodeling in the right and left atria that collectively create a substrate for AF.
Subject(s)
Action Potentials , Angiotensin II/metabolism , Atrial Fibrillation/diagnosis , Atrial Fibrillation/etiology , Atrial Remodeling , Angiotensin II/pharmacology , Animals , Biomarkers , Blood Pressure , Echocardiography , Electrocardiography , Immunohistochemistry , Male , Membrane Potentials/drug effects , Mice , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolismABSTRACT
Sinoatrial node (SAN) disease mechanisms are poorly understood, and therapeutic options are limited. Natriuretic peptide(s) (NP) are cardioprotective hormones whose effects can be mediated partly by the NP receptor C (NPR-C). We investigated the role of NPR-C in angiotensin II (Ang II)-mediated SAN disease in mice. Ang II caused SAN disease due to impaired electrical activity in SAN myocytes and increased SAN fibrosis. Strikingly, Ang II treatment in NPR-C-/- mice worsened SAN disease, whereas co-treatment of wild-type mice with Ang II and a selective NPR-C agonist (cANF) prevented SAN dysfunction. NPR-C may represent a new target to protect against the development of Ang II-induced SAN disease.
ABSTRACT
Natriuretic peptides (NPs) play essential roles in the regulation of cardiovascular function. NP effects are mediated by receptors known as NPR-A, NPR-B or NPR-C. NPs have potent effects on regulation of heart rate (HR) by the autonomic nervous system (ANS), but the role of NPR-C in these effects has not been investigated. Accordingly, we have used telemetric ECG recordings in awake, freely moving wildtype and NPR-C knockout (NPR-C-/-) mice and performed heart rate variability (HRV) analysis to assess alterations in sympatho-vagal balance on the heart following loss of NPR-C. Our novel data demonstrate that NPR-C-/- mice are characterized by elevations in HR, reductions in circadian changes in HR and enhanced occurrence of sinus pauses, indicating increased arrhythmogenesis and a loss of HRV. Time domain and frequency domain analyses further demonstrate that HRV is reduced in NPR-C-/- mice in association with a reduction in parasympathetic activity. Importantly, the low frequency to high frequency ratio was increased in NPR-C-/- mice indicating that sympathetic activity is also enhanced. These changes in autonomic regulation were confirmed using atropine and propranolol to antagonize the ANS. These findings illustrate that loss of NPR-C reduces HRV due to perturbations in the regulation of the heart by the ANS.
Subject(s)
Autonomic Nervous System/physiology , Heart Rate , Receptors, Atrial Natriuretic Factor/deficiency , Animals , Arrhythmias, Cardiac/genetics , Arrhythmias, Cardiac/physiopathology , Autonomic Nervous System/physiopathology , Gene Knockout Techniques , Mice , Receptors, Atrial Natriuretic Factor/geneticsABSTRACT
Atrial fibrillation (AF) is prevalent in aging populations; however not all individuals age at the same rate. Instead, individuals of the same chronological age can vary in health status from fit to frail. Our objective was to determine the impacts of age and frailty on atrial function and arrhythmogenesis in mice using a frailty index (FI). Aged mice were more frail and demonstrated longer lasting AF compared to young mice. Consistent with this, aged mice showed longer P wave duration and PR intervals; however, both parameters showed substantial variability suggesting differences in health status among mice of similar chronological age. In agreement with this, P wave duration and PR interval were highly correlated with FI score. High resolution optical mapping of the atria demonstrated reduced conduction velocity and action potential duration in aged hearts that were also graded by FI score. Furthermore, aged mice had increased interstitial fibrosis along with changes in regulators of extracellular matrix remodelling, which also correlated with frailty. These experiments demonstrate that aging results in changes in atrial structure and function that create a substrate for atrial arrhythmias. Importantly, these changes were heterogeneous due to differences in health status, which could be identified using an FI.
Subject(s)
Aging/genetics , Atrial Fibrillation/genetics , Frailty/genetics , Heart Atria/metabolism , Myocytes, Cardiac/metabolism , Action Potentials/physiology , Animals , Atrial Fibrillation/diagnostic imaging , Atrial Fibrillation/metabolism , Atrial Fibrillation/pathology , Biomarkers/metabolism , Collagen Type I/genetics , Collagen Type I/metabolism , Collagen Type I, alpha 1 Chain , Collagen Type III/genetics , Collagen Type III/metabolism , Extracellular Matrix/chemistry , Extracellular Matrix/metabolism , Fibrosis , Frailty/diagnostic imaging , Frailty/metabolism , Frailty/pathology , Gene Expression , Heart Atria/diagnostic imaging , Heart Atria/pathology , Heart Function Tests , Isoenzymes/genetics , Isoenzymes/metabolism , Male , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/pathology , Severity of Illness Index , Tissue Inhibitor of Metalloproteinase-1/genetics , Tissue Inhibitor of Metalloproteinase-1/metabolism , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/metabolism , Voltage-Sensitive Dye ImagingABSTRACT
KEY POINTS: Sinoatrial node (SAN) function declines with age; however, not all individuals age at the same rate and health status can vary from fit to frail. Frailty was quantified in young and aged mice using a non-invasive frailty index so that the impacts of age and frailty on heart rate and SAN function could be assessed. SAN function was impaired in aged mice due to alterations in electrical conduction, changes in SAN action potential morphology and fibrosis in the SAN. Changes in SAN function, electrical conduction, action potential morphology and fibrosis were correlated with, and graded by, frailty. This study shows that mice of the same chronological age have quantifiable differences in health status that impact heart rate and SAN function and that these differences in health status can be identified using our frailty index. ABSTRACT: Sinoatrial node (SAN) dysfunction increases with age, although not all older adults are affected in the same way. This is because people age at different rates and individuals of the same chronological age vary in health status from very fit to very frail. Our objective was to determine the impacts of age and frailty on heart rate (HR) and SAN function using a new model of frailty in ageing mice. Frailty, which was quantified in young and aged mice using a frailty index (FI), was greater in aged vs. young mice. Intracardiac electrophysiology demonstrated that HR was reduced whereas SAN recovery time (SNRT) was prolonged in aged mice; however, both parameters showed heteroscedasticity suggesting differences in health status among mice of similar chronological age. Consistent with this, HR and corrected SNRT were correlated with, and graded by, FI score. Optical mapping of the SAN demonstrated that conduction velocity (CV) was reduced in aged hearts in association with reductions in diastolic depolarization (DD) slope and action potential (AP) duration. In agreement with in vivo results, SAN CV, DD slope and AP durations all correlated with FI score. Finally, SAN dysfunction in aged mice was associated with increased interstitial fibrosis and alterations in expression of matrix metalloproteinases, which also correlated with frailty. These findings demonstrate that age-related SAN dysfunction occurs in association with electrical and structural remodelling and that frailty is a critical determinant of health status of similarly aged animals that correlates with changes in HR and SAN function.
Subject(s)
Aging/physiology , Sinoatrial Node/physiology , Action Potentials , Animals , Fibrosis , Heart Rate , Male , Mice, Inbred C57BL , Sinoatrial Node/pathologyABSTRACT
Natriuretic peptides (NPs) are a family of cardioprotective hormones with numerous beneficial effects in cardiovascular system. The NP family includes several peptides including atrial NP (ANP), B-type NP (BNP), C-type NP (CNP) and Dendroaspis NP (DNP). These peptides elicit their effects by binding to three distinct cell surface receptors called natriuretic peptide receptors A, B and C (NPR-A, NPR-B and NPR-C). NPR-A (which binds ANP, BNP and DNP) and NPR-B (which is selective for CNP) are particulate guanylyl cyclase (GC)-linked receptors that mediate increases in cGMP upon activation. cGMP can then target several downstream signaling molecules including protein kinase G (PKG), phosphodiesterase 2 (PDE2) and phosphodiesterase 3 (PDE3). NPR-C, which is able to bind all NPs with comparable affinity, is coupled to the activation of inhibitory G-proteins (Gi) that inhibit adenylyl cyclase (AC) activity and reduce cAMP levels. NPs are best known for their ability to regulate blood volume and fluid homeostasis. More recently, however, it has become apparent that NPs are essential regulators of cardiac electrophysiology and arrhythmogenesis. Evidence for this comes from numerous studies of the effects of NPs on cardiac electrophysiology and ion channel function in different regions and cell types within the heart, as well as the identification of mutations in the NP system that cause atrial fibrillation in humans. Despite the strong evidence that NPs regulate cardiac electrophysiology different studies have reported varying effects of NPs. The reasons for disparate observations are not fully understood, but likely occur as a result of several factors, including the fact that NP signaling can be highly complex and involve multiple receptors and/or downstream signaling molecules which may be differentially activated in different conditions. The goal of this review is to provide a comprehensive summary of the different effects of NPs on cardiac electrophysiology that have been described and to provide rationale and explanation for why different results may be obtained in different studies.
Subject(s)
Electrophysiological Phenomena , Heart/physiology , Myocardium/metabolism , Natriuretic Peptides/metabolism , Receptors, Atrial Natriuretic Factor/metabolism , Amino Acid Sequence , Animals , Heart Diseases/metabolism , Heart Diseases/physiopathology , Heart Diseases/therapy , Humans , Natriuretic Peptides/chemistryABSTRACT
BACKGROUND: Atrial natriuretic peptide (ANP) is a hormone with numerous beneficial cardiovascular effects. Recently, a mutation in the ANP gene, which results in the generation of a mutant form of ANP (mANP), was identified and shown to cause atrial fibrillation in people. The mechanism(s) through which mANP causes atrial fibrillation is unknown. Our objective was to compare the effects of wild-type ANP and mANP on atrial electrophysiology in mice and humans. METHODS AND RESULTS: Action potentials (APs), L-type Ca(2+) currents (ICa,L), and Na(+) current were recorded in atrial myocytes from wild-type or natriuretic peptide receptor C knockout (NPR-C(-/-)) mice. In mice, ANP and mANP (10-100 nmol/L) had opposing effects on atrial myocyte AP morphology and ICa,L. ANP increased AP upstroke velocity (Vmax), AP duration, and ICa,L similarly in wild-type and NPR-C(-/-) myocytes. In contrast, mANP decreased Vmax, AP duration, and ICa,L, and these effects were completely absent in NPR-C(-/-) myocytes. ANP and mANP also had opposing effects on ICa,L in human atrial myocytes. In contrast, neither ANP nor mANP had any effect on Na(+) current in mouse atrial myocytes. Optical mapping studies in mice demonstrate that ANP sped electric conduction in the atria, whereas mANP did the opposite and slowed atrial conduction. Atrial pacing in the presence of mANP induced arrhythmias in 62.5% of hearts, whereas treatment with ANP completely prevented the occurrence of arrhythmias. CONCLUSIONS: These findings provide mechanistic insight into how mANP causes atrial fibrillation and demonstrate that wild-type ANP is antiarrhythmic.
Subject(s)
Action Potentials/drug effects , Atrial Fibrillation/drug therapy , Atrial Fibrillation/physiopathology , Atrial Natriuretic Factor/pharmacology , Electrophysiological Phenomena/drug effects , Heart Atria/drug effects , Myocytes, Cardiac/drug effects , Action Potentials/physiology , Animals , Cardiac Pacing, Artificial , Heart Atria/physiopathology , Humans , Mice , Mice, KnockoutABSTRACT
Cardiovascular autonomic neuropathy (CAN) is a serious complication of diabetes mellitus that impairs autonomic regulation of heart rate (HR). This has been attributed to damage to the nerves that modulate spontaneous pacemaker activity in the sinoatrial node (SAN). Our objective was to test the hypothesis that impaired parasympathetic regulation of HR in diabetes is due to reduced responsiveness of the SAN to parasympathetic agonists. We used the Akita mouse model of type 1 diabetes to study the effects of the parasympathetic agonist carbachol (CCh) on SAN function using intracardiac programmed stimulation, high resolution optical mapping and patch-clamping of SAN myocytes. CCh decreased HR by 30% and increased corrected SAN recovery time (cSNRT) by 123% in wildtype mice. In contrast, CCh only decreased HR by 12%, and only increased cSNRT by 37% in Akita mice. These alterations were due to smaller effects of CCh on SAN electrical conduction and spontaneous action potential firing in isolated SAN myocytes. Voltage clamp experiments demonstrate that the acetylcholine-activated K(+) current (IKACh) is reduced in Akita SAN myocytes due to enhanced desensitization and faster deactivation kinetics. These IKACh alterations were normalized by treating Akita SAN myocytes with PI(3,4,5)P3 or an inhibitor of regulator of G-protein signaling 4 (RGS4). There was no difference in the effects of CCh on the hyperpolarization-activated current (If) between wildtype and Akita mice. Our study demonstrates that Akita diabetic mice demonstrate impaired parasympathetic regulation of HR and SAN function due to reduced responses of the SAN to parasympathetic agonists. Our experiments demonstrate a key role for insulin-dependent phosphoinositide 3-kinase (PI3K) signaling in the parasympathetic dysfunction seen in the SAN in diabetes.
Subject(s)
Parasympathetic Nervous System/physiopathology , Sinoatrial Node/innervation , Acetylcholine/pharmacology , Action Potentials/drug effects , Animals , Carbachol/pharmacology , Cardiotonic Agents/pharmacology , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/physiopathology , Disease Models, Animal , Heart/drug effects , Heart/physiopathology , Insulin/administration & dosage , Insulin/pharmacology , Mice , Myocardium/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , RGS Proteins/antagonists & inhibitors , RGS Proteins/metabolism , Sinoatrial Node/drug effectsABSTRACT
Natriuretic peptides (NPs) are critical regulators of the cardiovascular system that are currently viewed as possible therapeutic targets for the treatment of heart disease. Recent work demonstrates potent NP effects on cardiac electrophysiology, including in the sinoatrial node (SAN) and atria. NPs elicit their effects via three NP receptors (NPR-A, NPR-B and NPR-C). Among these receptors, NPR-C is poorly understood. Accordingly, the goal of this study was to determine the effects of NPR-C ablation on cardiac structure and arrhythmogenesis. Cardiac structure and function were assessed in wild-type (NPR-C(+/+)) and NPR-C knockout (NPR-C(-/-)) mice using echocardiography, intracardiac programmed stimulation, patch clamping, high-resolution optical mapping, quantitative polymerase chain reaction and histology. These studies demonstrate that NPR-C(-/-) mice display SAN dysfunction, as indicated by a prolongation (30%) of corrected SAN recovery time, as well as an increased susceptibility to atrial fibrillation (6% in NPR-C(+/+) vs. 47% in NPR-C(-/-)). There were no differences in SAN or atrial action potential morphology in NPR-C(-/-) mice; however, increased atrial arrhythmogenesis in NPR-C(-/-) mice was associated with reductions in SAN (20%) and atrial (15%) conduction velocity, as well as increases in expression and deposition of collagen in the atrial myocardium. No differences were seen in ventricular arrhythmogenesis or fibrosis in NPR-C(-/-) mice. This study demonstrates that loss of NPR-C results in SAN dysfunction and increased susceptibility to atrial arrhythmias in association with structural remodelling and fibrosis in the atrial myocardium. These findings indicate a critical protective role for NPR-C in the heart.
Subject(s)
Atrial Fibrillation/genetics , Atrial Fibrillation/metabolism , Receptors, Atrial Natriuretic Factor/genetics , Sinoatrial Node/metabolism , Action Potentials , Animals , Cells, Cultured , Collagen/metabolism , Male , Mice , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/physiology , Receptors, Atrial Natriuretic Factor/metabolism , Sinoatrial Node/physiopathologyABSTRACT
Early detection of squamous dysplasia and esophageal squamous cell carcinoma is of great importance. Adopting computer aided algorithms in predicting cancer risk using its risk factors can serve in limiting the clinical screenings to people with higher risks. In the present study, we show that the application of an advanced classification method, the Minimum Classification Error, could considerably enhance the classification performance in comparison to the logistic regression model and the variable structure fuzzy neural network, as the latest successful methods. The results yield the accuracy of 89.65% for esophageal squamous cell carcinoma, and 88.42% for squamous dysplasia risk prediction.