Canine Congestive Heart Failure Research Articles

Evaluating the diagnostic quality of exosomal versus free-circulating microRNAs as biomarkers of canine congestive heart failure

MicroRNAs (miRNA) show great potential as biomarkers, and eventually therapeutics in the form of mimics and inhibitors, in a diversity of diseases. MiRNA can be found freely-circulating in the bloodstream (FCmiRNA) or secreted from cells in exosomes as exosomal miRNA (exomiRNA). Exosomes are extracellular vesicles that carry cell-specific cargo to targeted cells elsewhere in the body, traveling through body fluids. ExomiRNA shows great potential to be more reliable than FCmiRNA as a biomarker of disease due to the added membrane, which preserves the miRNA cargo, and the theoretical increased likelihood of relevant miRNA to be present in exosomes. Multiple miRNAs have already been associated with the development of canine congestive heart failure (CHF) in dogs.In this study, we compared the expression of four miRNAs: miRNA 133, miRNA 1, miRNA29, and miRNA302 between healthy dogs and dogs with CHF, and compared the expression levels of these miRNAs as FCmiRNAs and exomiRNAs.Data from my previous study suggests that exomiRNA is better preserved in FCmiRNA from canine plasma samples. We predict that the results from this study will confirm association of the selected miRNAs and CHF status, meaning elevated levels of miRNA133 and miRNA1 correlate with presence of CHF, while decreased levels of miRNA29 and miRNA302 correlate with presence of CHF. We predict that exomiRNA expressions will be consistently higher than FCmiRNA expression among all four miRNAs, which suggests the exosomes protect the structural integrity of the miRNAs, and exomiRNA could be more reliable than FCmiRNA as a biomarker in diagnostic and prognostic clinical scenarios. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Breakthrough: a first-in-class virtual simulator for dose optimization of ACE inhibitors in translational cardiovascular medicine

The renin–angiotensin–aldosterone-systems (RAAS) play a central role in the pathophysiology of congestive heart failure (CHF), justifying the use of angiotensin converting enzyme inhibitors (ACEi) in dogs and humans with cardiac diseases. Seminal studies in canine CHF had suggested that the pharmacological action of benazepril was relatively independent of doses greater than 0.25 mg/kg P.O, thereby providing a rationale for the European labeled dose of benazepril in dogs with CHF. However, most of these earlier studies relied on measures of ACE activity, a sub-optimal endpoint to characterize the effect of ACEi on the RAAS. The objectives of this study were (i) to expand on previous mathematical modeling efforts of the dose-exposure–response relationship of benazepril on biomarkers of the RAAS which are relevant to CHF pathophysiology and disease prognosis; and (ii) to develop a software implementation capable of simulating clinical trials in benazepril in dogs bedside dose optimization. Our results suggest that 0.5 mg/kg PO q12h of benazepril produces the most robust reduction in angiotensin II and upregulation of RAAS alternative pathway biomarkers. This model will eventually be expanded to include relevant clinical endpoints, which will be evaluated in an upcoming prospective trial in canine patients with CHF.

Circulating MicroRNAs in Canine Congestive Heart Failure – Why Exosomes?

By influencing protein translation, microRNAs (miRNAs) have emerged as powerful regulators of a wide range of biological processes. miRNAs can be found freely circulating in blood as well as in circulating exosomes. It has been speculated that evaluating the quantity of miRNAs contained in exosomes may serve as a better diagnostic and prognostic tool than those found freely circulating.A good test case for this relationship is to look at miRNA dysregulation effecting Canine Congestive Heart Failure, resulting from Myxomatous Mitral Valve Disease (MMVD), in these two contexts. In order to do this, we are assessing levels of miR‐1, miR‐126, and miR‐133a, in nine small breed, older dogs with this disorder, compared to healthy dogs, using Realtime qPCR analysis.We hypothesize that our results will confirm the assertion that exosomes reveal a more reliable indication of MMVD than by quantifying freely circulating miRNAs.

The potential role of microRNA as bio markers in canine congestive heart failure

ObjectiveIn our focus regarding microRNA, single‐stranded, small non‐coding RNAs, we aim to understand miRNA's roll and functional importance concerning congestive heart failure (CHF) and myxomatous mitral valve degeneration (MMVD). Characterizing expression profiles of circulating microRNAs via genome‐wide sequencing for dogs with CHF secondary to MMVD.Animals8 healthy client‐owned dogs and 8 middle age‐matched client‐owned dogs with CHF secondary to MMVD.ProceduresBlood samples were collected before administering cardiac medications for the management of CHF. Quantitative reverse transcription PCR (qRT‐PCR) assays were used to validate expression profiles of differentially expressed circulating microRNAs identified from NGS analysis of dogs with CHF.Conclusion and Clinical RelevanceAwaiting data indicating the patterns of microRNA expression are distinctive and denote molecular biomarkers with CHF in dogs with MMV.

Inflammation and its association with oxidative stress in dogs with heart failure

BackgroundInflammation and oxidative stress can contribute to the development and progression of heart failure. This study aimed to investigate the association between inflammatory and oxidative stress markers in dogs with congestive heart failure (CHF). Associations between the disease severity marker N-terminal pro-B-type natriuretic peptide (NT-proBNP) and markers of inflammation and oxidative stress were also determined.ResultsThirty-seven dogs with cardiovascular diseases (dilated cardiomyopathy, DCM (16 dogs), myxomatous mitral valve disease, MMVD (21 dogs)) and ten healthy dogs were included in this prospective study. The patients were further divided into groups with (26) and without CHF (11). We found a significantly higher serum concentration of C-reactive protein (P = 0.012), white blood cell (P = 0.001), neutrophil (P = 0.001) and monocyte counts (P = 0.001) in patients with CHF compared to control dogs. The concentration of tumor necrosis factor-alpha (TNF-α) was significantly higher in patients with CHF compared to patients without CHF (P = 0.030). No significant difference was found in most of the measured parameters between MMVD and DCM patients, except for glutathione peroxidase (GPX) and NT-proBNP. In patients with CHF, TNF-α correlated positively with malondialdehyde (P = 0.014, r = 0.474) and negatively with GPX (P = 0.026, r = − 0.453), and interleukin-6 correlated negatively with GPX (P = 0.046, r = − 0.412). NT-proBNP correlated positively with malondialdehyde (P = 0.011, r = 0.493). In patients without CHF none of the inflammatory and oxidative stress markers correlated significantly. Furthermore, in the group of all cardiac patients, GPX activity significantly negatively correlated with NT-proBNP (P = 0.050, r = − 0.339) and several markers of inflammation, including TNF-α (P = 0.010, r = − 0.436), interleukin-6 (P = 0.026, r = − 0.382), white blood cell (P = 0.032, r = − 0.369), neutrophil (P = 0.027, r = − 0.379) and monocyte counts (P = 0.024, r = − 0.386).ConclusionInflammatory and oxidative stress markers are linked in canine CHF patients, but not in patients without CHF. These results suggest complex cross communication between the two biological pathways in advanced stages of CHF.

Glucocorticoid metabolism and the action of 11 beta-hydroxysteroid dehydrogenase 2 in canine congestive heart failure

The enzyme 11-beta-hydroxysteroid dehydrogenase isoenzyme 2 (11BHSD2) is responsible for converting the active glucocorticoid cortisol to inactive cortisone and in the renal medulla protects the mineralocorticoid receptor (MR) from activation by cortisol. Derangements in 11BHSD2 activity can result in reduced conversion of cortisol to cortisone, activation of the MR by cortisol and, consequently, sodium and water retention. The objective of this study was to examine glucocorticoid metabolism in canine congestive heart failure (CHF), specifically to evaluate whether renal 11BHSD2 activity and expression were altered. Dogs were prospectively recruited into one of two phases; the first phase (n=56) utilized gas chromatography-tandem mass spectrometry to examine steroid hormone metabolites normalised to creatinine in home-caught urine samples. Total serum cortisol was also evaluated. The second phase consisted of dogs (n=18) euthanased for refractory CHF or for behavioural reasons. Tissue was collected from the renal medulla for examination by quantitative reverse transcription polymerase chain reaction, immunohistochemistry and protein immune-blotting. Heart failure did not change urinary cortisol:cortisone ratio (P=0.388), or modify renal expression (P=0.303), translation (P=0.427) or distribution of 11BHSD2 (P=0.325). However, CHF did increase excretion of 5α-tetrahydrocortisone (P=0.004), α-cortol (P=0.002) and α-cortolone (P=0.009). Congestive heart failure modifies glucocorticoid metabolism in dogs by increasing 5α-reductase and 20α-hydroxysteroid dehydrogenase activity. Differences between groups in age, sex and underlying disease processes may have influenced these results. However, 11BHSD2 does not appear to be a potential therapeutic target in canine CHF.

MicroRNAs and Their Potential Role as Biomarkers in Canine COngestive Heart Failure

Myxomatous mitral valvular degeneration (MMVD) is the most common heart disease in dogs, accounting for more than 70% of canine heart disease cases. It primarily affects middle‐aged small dogs, though, any dog can develop MMVD. It can affect all heart valves but is usually detected in mitral valves. Degenerative processes cause mitral valves to thicken and retract, creating an unwanted hole which blood can flow through. Tearing of mitral valves can lead to blood overflow and later, CHF in the heart’s left‐side. Currently, there are no medications proven to prevent, slow, or reverse the development of MMVD. Because of limited knowledge on MMVD, heart murmurs and coughing are the earliest means of detection. A microRNA (miRNA) is a small non‐coding RNA molecule, about 22 nucleotides long. We would test miRNA‐21, miRNA‐29a‐3p, miRNA‐210, and miRNA‐133a. If said miRNA significantly upregulated in CHF‐positive dog plasma, then upregulation of those miRNA could indicate development of MMVD. Plasma would be collected from dogs at an animal shelter. Plasma RNA would be purified using QIAzol Lysis Reagent. RT‐PCR would be used to reverse transcribe RNA to cDNA. SYBR Green (fluorescent dye) would detect miRNA amplification. If we can determine which miRNAs have a significantly high concentration in CHF‐positive dog plasma, we would be able to detect MMVD in pre‐developmental stages. For example, if a dog’s blood screening results show abnormal upregulation of miRNA precursor to MMVD, inhibitors of said miRNA could administered as a preventative measure.

Blood variables associated with survival in canine congestive heart failure patients

Our study aimed to investigate the blood variables: coenzyme Q10, N-terminal pro-B-type natriuretic peptide (NT-proBNP), electrolytes, cholesterol, triglyceride, glutathione peroxidase, white blood cell, neutrophil, lymphocyte and monocyte counts and relative numbers of neutrophils, lymphocytes and monocytes that may be associated with survival of dogs in congestive heart failure (CHF). Twenty-one client-owned dogs in CHF were included in the study. Cox regression analysis showed significant association only between NT-proBNP blood concentration and survival.

Edoxaban suppresses the progression of atrial fibrosis and atrial fibrillation in a canine congestive heart failure model.

Coagulation factor Xa activates the protease-activated receptor 2 (PAR2) and causes tissue fibrosis; however, the effects of Xa inhibitor edoxaban on atrial fibrosis and atrial fibrillation (AF) have not been investigated. We examined the effect of edoxaban on the progression of atrial fibrosis in a canine congestive heart failure (CHF) model. Beagle dogs were assigned to sham, placebo, and edoxaban groups (n = 6/group). Dogs of the placebo or edoxaban groups received 19days of medication with daily oral placebo or edoxaban, respectively, followed by 14days of ventricular tachypacing. Dogs of the sham group had no medication or pacing. Ventricular tachypacing prolonged AF duration in dogs of the placebo group (159 ± 41s, p < 0.01 vs. sham); however, this effect was suppressed by edoxaban treatment. Compared with the sham group, tachypacing alone also significantly increased the atrial fibrotic area (2.9 ± 0.1% vs. 7.8 ± 0.4%, p < 0.01), PAR2 expression (1.0 ± 0.1 vs. 1.8 ± 0.3, p < 0.05), and atrial fibronectin expression (1.0 ± 0.2 vs. 2.0 ± 0.2, p < 0.01). These responses were suppressed by edoxaban treatment (area 5.9 ± 0.4%, p < 0.01; PAR2 1.1 ± 0.1, p < 0.05; fibronectin 1.2 ± 0.2, p < 0.05 vs. placebo). Edoxaban showed suppressive effects on atrial remodeling, AF progression, and excessive expressions of PAR2 and fibronectin in a canine CHF model. The suppression of the Xa/PAR2 pathway might be a potential pharmacological target of edoxaban.

Efficacy of pimobendan on survival and reoccurrence of pulmonary edema in canine congestive heart failure.

The aim of this study was to evaluate the efficacy of pimobendan with conventional therapies on survival and reocurrence of pulmonary edema in dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). Records of 197 client-owned dogs from 14 veterinary hospitals were included in this study. Dogs were administered conventional treatments with or without pimobendan. Sixty-four dogs received a standard dose of pimobendan (0.20–0.48 mg/kg every 12 hr (q12hr)), 49 dogs received a low dose of pimobendan (0.05–0.19 mg/kg q12hr), and 84 dogs received conventional therapy alone. Dogs in the standard-dose and low-dose pimobendan groups had significantly longer median survival times than dogs in the conventional group (334, 277 and 136 days, respectively; P<0.001). The reoccurrence rate of pulmonary edema in the standard-dose group was significantly lower than in the low-dose and conventional groups (43%, 59% and 62%, respectively; P<0.05). Combination of pimobendan with a conventional treatment regimen significantly prolonged survival time after an initial episode of pulmonary edema in dogs with CHF caused by MMVD. There was no difference in survival between dogs administered standard and low doses of pimobendan, but pimobendan did prevent the reoccurrence of pulmonary edema in a dose-dependent manner.

In this issue - September 2016: Portable negative pressure wound therapy for skin grafts in dogs · Wellness testing in small animals · Effects of pimobendan on myocardial perfusion and pulmonary transit time in dogs · Rispens CVI988 vaccine virus and Marek's disease virus in poultry · A field study of ovulation in oestrus mares · Post-weaning growth of beef

In this issue - September 2016: Portable negative pressure wound therapy for skin grafts in dogs · Wellness testing in small animals · Effects of pimobendan on myocardial perfusion and pulmonary transit time in dogs · Rispens CVI988 vaccine virus and Marek's disease virus in poultry · A field study of ovulation in oestrus mares · Post-weaning growth of beef

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs.

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

Chronobiology and Pharmacologic Modulation of the Renin-Angiotensin-Aldosterone System in Dogs: What Have We Learned?

Congestive heart failure (CHF) is a primary cause of morbidity and mortality with an increasing prevalence in human and canine populations. Recognition of the role of renin-angiotensin-aldosterone system (RAAS) overactivation in the pathophysiology of CHF has led to significant medical advances. By decreasing systemic vascular resistance and angiotensin II (AII) production, angiotensin-converting enzyme (ACE) inhibitors such as benazepril improve cardiac hemodynamics and reduce mortality in human and dog CHF patients. Although several experiments have pointed out that efficacy of ACE inhibitors depends on the time of administration, little attention is paid to the optimum time of dosing of these medications. A thorough characterization of the chronobiology of the renin cascade has the potential to streamline the therapeutic management of RAAS-related diseases and to help determining the optimal time of drug administration that maximizes efficacy of ACE inhibitors, while minimizing the occurrence of adverse effects. We have developed an integrated pharmacokinetic-pharmacodynamic model that adequately captures the disposition kinetics of the paradigm drug benazeprilat, as well as the time-varying changes of systemic renin-angiotensin-aldosterone biomarkers, without and with ACE inhibition therapy. Based on these chronobiological investigations, the optimal efficacy of ACE inhibitors is expected with bedtime dosing. The data further show that benazepril influences the dynamics of the renin-angiotensin-aldosterone cascade, resulting in a profound decrease in AII and aldosterone (ALD), while increasing renin activity for about 24h. From the results of recent investigations in human, it is hypothesized that reduction of AII and ALD is one of the drivers of increased survival and improved quality of life in dogs receiving ACE inhibitors. To support and consolidate this hypothesis, additional efforts should be directed toward the collection of circulating RAAS peptides in spontaneous cases of canine CHF. If such a link could be established, profiling of these biomarkers could support determination of the severity of heart failure, complement clinical and echocardiographic findings, and be used for therapeutic drug monitoring purposes.

Effect of amiodarone on dispersion of ventricular repolarization in a canine congestive heart failure model

The effects of amiodarone on ventricular electrophysiological parameters, especially the dispersion of ventricular repolarization, were investigated in a canine model of congestive heart failure (CHF). Dogs were randomized to either a control, amiodarone, CHF, or CHF+amiodarone group. Dogs in the CHF and CHF+amiodarone groups underwent 4-5weeks of rapid ventricular pacing; dogs in the control and amiodarone groups underwent sham operation only. Amiodarone (20 mg/kg per day) was administered orally, beginning on postoperative Day 1, in the treatment groups; ventricular electrophysiological variables were evaluated 4-5weeks after rapid pacing or sham operation. In CHF dogs, the transmural dispersion ventricular repolarization time (TDVRT) increased significantly. Amiodarone significantly decreased the TDVRT in CHF dogs. The ventricular fibrillation threshold (VFT) decreased in the CHF group. Amiodarone increased the VFT in CHF dogs. The TDVRT increased in CHF dogs, but amiodarone decreased TDVRT and increased VFT in these dogs. These results suggest a beneficial effect of amiodarone on malignant arrhythmias and may provide the basis for its use in CHF patients.

Associations between cardiac pathology and clinical, echocardiographic and electrocardiographic findings in dogs with chronic congestive heart failure

The objective of this study was to correlate defined pathological features with clinical findings in dogs with naturally occurring congestive heart failure (CHF). Fifty-eight dogs with CHF were examined clinically and using echocardiography and electrocardiography. Detailed cardiac post-mortem examination was used to assess intra-myocardial arterial narrowing, myocardial fibrosis and atrophy and myxomatous mitral valve degeneration (MMVD). Arterial narrowing significantly correlated with fibrosis (P<0.0001) and with fractional shortening, an indicator of systolic function (P=0.002). The grade of fibrosis was associated with shorter survival time (P=0.002), and the papillary muscle fibrosis score tended to correlate with proximal isovelocity surface area radius (P=0.03). Data from this study lend support to the hypothesis that naturally occurring canine CHF is affected by several factors such as MMVD, myocardial atrophy and fibrosis, and by arteriosclerosis. Further, more extensive research will be required to establish cause-effect relationships between these cardiac lesions and the pathophysiology of CHF in dogs.

Ventricular electrophysiology in congestive heart failure and its correlation with heart rate variability and baroreflex sensitivity: a canine model study

This study investigated ventricular electrophysiological characteristics and the correlation between these parameters and heart rate variability (HRV) and baroreflex sensitivity (BRS) in a canine congestive heart failure (CHF) model. Haemodynamics, HRV, BRS, and ventricular electrophysiological variables were measured 4-5 weeks after sham operation (control dogs) and pacemaker implantation, and rapid right ventricular pacing at 240 bpm (CHF group). In the CHF group, significant differences from the control group in ventricular effective refractory period (VERP), monophasic action potential (MAP) duration (MAPD(90)), ventricular late repolarization duration (VLRD), the ratio of VERP to MAPD(90), dispersion of ventricular recovery time (VRT-D), and ventricular fibrillation threshold (VFT) were noted. Both BRS and the time and power domain parameters of HRV were significantly decreased in the CHF group compared with the control group, and a significant, positive correlation between HRV and BRS was identified in the CHF group. Heart rate variability and BRS were negatively and significantly correlated with VLRD and VRT-D, and were positively correlated with VERP/MAPD(90) and VFT in the CHF group. These results suggest that ventricular electrophysiological characteristics correlated with abnormal autonomic nerve function may have important effects on sudden cardiac death. Further research is warranted.

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Pirfenidone Prevents the Development of a Vulnerable Substrate for Atrial Fibrillation in a Canine Model of Heart Failure

Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug's effects on multiple cytokines, including a reduction in transforming growth factor-beta1 expression. Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

Transmural expression of transient outward potassium current subunits in normal and failing canine and human hearts

The transient outward current (I(to)), an important contributor to transmural electrophysiological heterogeneity, is significantly remodelled in congestive heart failure (CHF). The molecular bases of transmural I(to) gradients and CHF-dependent ionic remodelling are incompletely understood. To elucidate these issues, we studied mRNA and protein expression of Kv4.3 and KChIP2, the principal alpha and beta subunits believed to form I(to), in epicardial and endocardial tissues and in isolated cardiomyocytes from control dogs and dogs with CHF induced by 240 beats min(-1) ventricular tachypacing. CHF decreased I(to) density in both epicardium and endocardium (by 73 and 55% at +60 mV, respectively), without a significant change in relative current density (endocardium/epicardium 0.11 control, 0.17 CHF). There were transmural gradients in mRNA expression of both Kv4.3 (endocardium/epicardium ratio 0.3 under control conditions) and KChIP2 (endocardium/epicardium ratio 0.2 control), which remained in the presence of CHF (Kv4.3 endocardium/epicardium ratio 0.4; KChIP2 0.4). There were qualitatively similar protein expression gradients in human and canine cardiac tissues and isolated canine cardiomyocytes; however, the KChIP2 gradient was only detectable with a highly selective monoclonal antibody and closely approximated the I(to) density gradient. Kv4.3 mRNA expression was reduced by CHF, but KChIP2 mRNA was not significantly changed. CHF decreased Kv4.3 protein expression in canine cardiac tissues and cardiomyocytes, as well as in terminally failing human heart tissue samples, but KChIP2 protein was not down-regulated in any of the corresponding sample sets. We conclude that both Kv4.3 and KChIP2 may contribute to epicardial-endocardial gradients in I(to), and that I(to) down-regulation in human and canine CHF appears due primarily to changes in Kv4.3.

High resolution mapping of the pulmonary vein and the vein of marshall during induced atrial fibrillation and atrial tachycardia in a canine model of pacing-induced congestive heart failure

ObjectivesThe study examined the activations in the pulmonary veins (PVs) and the vein of Marshall (VOM) during atrial fibrillation (AF) in dogs with congestive heart failure (CHF). BackgroundThe patterns of activation within the PVs and the VOM during AF in CHF are unclear. MethodsWe induced CHF in nine dogs by rapid ventricular pacing. The patterns of activation during induced AF were studied one week after ceasing ventricular pacing. ResultsThe duration of induced AF averaged 80.7 ± 177.3 s. The termination of low-amplitude fractionated activity in the PVs preceded the termination of AF in 25 of 29 episodes. High-density mapping (1-mm resolution) showed that the PV was activated by a focal wave front independent of left atrial (LA) activation in 22 AF episodes. Frequent intra-PV conduction blocks and multiple wave fronts in the PVs were recorded during 10 AF episodes. Focal activations were observed within the VOM in 4 of 12 episodes of AF. Three atrial tachycardia (AT) episodes originated from a focus within a PV. Histological studies showed extensive fibrosis in the PVs and in the atria. The PVs in five normal dogs did not have focal or fractionated activity during induced AF. ConclusionsAtrial fibrillation in canine CHF is associated with independent focal activations in the PVs and the VOM, and with complex wave fronts within the PVs. The PVs may also serve as the origin of AT. These findings suggest that electrical and anatomical remodeling of the PVs and the VOM are important in the maintenance of AF and AT in dogs with CHF.