Electrophysiological Atrial Remodeling and Sustained Obesity
Electrophysiological Atrial Remodeling and Sustained Obesity
This study presents new information on the global endocardial electrophysiological, electroanatomic remodeling, and fatty infiltration of the atria as a result of sustained obesity. Animals gained weight over 36 weeks to achieve stable obesity and maintained this for another 36 weeks to replicate a state more comparable with chronic obesity in humans. The obese group accumulated 5-fold greater total body fat (34.5 kg), as compared with controls (8.7 kg). The obese sheep model is unique, because it does not experience OSA, because of the typical habitus and sleeping posture, thereby excluding the confounding effects of OSA. It demonstrates the following.
Structural and hemodynamic changes
Electrophysiological remodeling
As a result of these hemodynamic, structural, and electrophysiological changes, obese animals were more vulnerable to AF. Importantly, this study provides causative evidence that links obesity directly with the development of the AF substrate.
Over the last decade, several studies have presented evaluations of the atrial substrate in conditions known to result in AF. Li et al. were the first to distinguish these abnormalities forming the "second factor" from the electrical remodeling associated with AF. They highlighted the importance of conduction abnormalities and structural changes, particularly diffuse atrial fibrosis in an experimental heart failure model. These findings were subsequently confirmed to be the unifying feature of structural remodeling in other conditions, in both pre-clinical studies and clinical studies.
Although an epidemiological link has been established between obesity and AF, the underlying electrophysiological changes and mechanism still remain to be defined. OSA is closely associated with obesity in humans and predisposes to AF by causing hypertension, diastolic dysfunction, LA stretch, and autonomic imbalance during sleep. Iwasaki et al. demonstrated that obesity facilitates AF inducibility in the presence of acute OSA. However, despite the structural remodeling, AF inducibility was not enhanced in obese rats in the absence of obstruction. The ovine model allows evaluation of obesity in the absence of OSA and, in this study, demonstrated diffuse conduction abnormalities and interstitial fibrosis with chronic obesity alone. The Central Illustration summarizes the structural changes that result in electrical remodeling and promote AF in obesity.
(Enlarge Image)
Central Illustration.
Obesity and the Substrate for AF
Progressive weight gain has been demonstrated to result in atrial stretch and leads to the development of high-frequency triggers and the substrate for AF. With chronic obesity, there is greater epicardial adipose tissue, activation of the cytokines, and the development of fibrosis. In addition, there is infiltration of the contiguous atrial myocardium by fat cells. All of these result in the milieu of slowed and inhomogeneous conduction that forms the substrate for AF. AF = atrial fibrillation; LA = left atrial; TGF = transforming growth factor.
Global endocardial biatrial conduction slowing and increased fractionation were demonstrated in chronically obese animals. However, the degree of slowing varied in different regions, resulting in increased conduction heterogeneity. This is consistent with the finding with limited epicardial mapping with short-term weight gain in an ovine model. Munger et al. have also reported slowed longitudinal conduction velocities from the LA to the pulmonary veins in obese patients with AF. However, this human study did not observe any change in conduction velocity along the coronary sinus. The more pronounced findings in our animal model may result from extreme obesity and more detailed mapping. The obese animals did not demonstrate electrical scars or alterations in global voltage; however, there was reduction in posterior LA voltage with increased voltage heterogeneity. Contiguous epicardial fat was observed to infiltrate the region demonstrating the voltage reduction. Thus, we hypothesize that fatty infiltration of the posterior LA by epicardial fat could potentially represent a unique substrate that could predispose to AF in obesity. As with other studies evaluating clinical substrate for AF, endocardial atrial refractoriness was not altered with sustained obesity. This finding differs from that of Munger et al., who reported shortened atrial refractoriness in obese patients undergoing ablation for AF. However, they acknowledged that AF induced during ERP testing could potentially affect atrial refractoriness. In addition, a marked increase in complex fractionated signals was observed with sustained obesity in our study. This could be a result of conduction slowing secondary to interstitial fibrosis or fat infiltration.
Sustained obesity was associated with diffuse atrial interstitial fibrosis. This is consistent with changes observed with heart failure and chronic hypertension. Spach et al. have demonstrated elegantly that fibrosis can produce conduction abnormalities promoting re-entry and AF. The fibrosis observed in their study was only interstitial in nature, without the areas of replacement fibrosis usually seen with infarction. Moreover, there was only a 50% increase in interstitial fibrous tissue, in comparison to the 16-fold increase observed with heart failure, suggesting a more subtle insult with obesity.
TGF-β1 has been shown to be a crucial cytokine in the signal transduction pathways responsible for fibrosis. It occupies a central position, downstream of angiotensin and upstream of endothelin pathways, and acts in a paracrine–autocrine fashion. Verheule et al. have shown that overexpression of constitutional TGF-β1 in transgenic mice led to selective atrial fibrosis, conduction heterogeneity, and AF. In our study, TGF-β1 expression was increased 5-fold with sustained obesity and could explain the increase in interstitial fibrosis. We have previously reported increased endothelin receptor expression with short-term weight gain. There are similar reports of TGF-β superfamily and endothelin signaling pathway overexpression in humans.
There is emerging evidence that localized epicardial fat depots may have a significant and independent role in development of AF. The development of the obese state has been shown to be associated with hypoxia of the expanding adipose tissue, resulting in adipose tissue fibrosis and production of a myriad of adipocytokines, including those in the TGF-β superfamily. The absence of fascial barriers between epicardial fat and the contiguous atrial musculature, and the common vascular supply may facilitate paracrine action. Venteclef et al. elegantly demonstrated paracrine action in an organ-culture model. They incubated rat atrial tissue in a secretome derived from human epicardial fat and demonstrated atrial fibrosis mediated by members of the TGF-β superfamily. We demonstrated several-fold increased expression of TGF-β1 in atrial tissue; however, the source was not evaluated. In addition, a new finding was observed with epicardial fat infiltrating the underlying myocardium. Epicardial fat is predominantly deposited on the posterior LA. The reduction in posterior LA voltage noted on endocardial mapping was consistent with this finding. We hypothesize that fat infiltration separates myocytes and could result in conduction abnormalities in a fashion similar to microfibrosis. Considering the infiltration was observed only adjacent to epicardial fat deposits, the distribution of epicardial fat could contribute to conduction heterogeneity.
Although the observed electrical and structural abnormalities predispose to AF, the development of clinical AF is a complex process, with other factors, such as triggers and perpetuators, not addressed in the current study. This study has shown that epicardial fat cells infiltrate the posterior LA. However, a causal relationship between fatty infiltration and AF vulnerability could only be studied to a limited extent in this model. Furthermore, the profibrotic signal transducing pathways responsible for AF in obesity were not fully elucidated.
Discussion
Major Findings
This study presents new information on the global endocardial electrophysiological, electroanatomic remodeling, and fatty infiltration of the atria as a result of sustained obesity. Animals gained weight over 36 weeks to achieve stable obesity and maintained this for another 36 weeks to replicate a state more comparable with chronic obesity in humans. The obese group accumulated 5-fold greater total body fat (34.5 kg), as compared with controls (8.7 kg). The obese sheep model is unique, because it does not experience OSA, because of the typical habitus and sleeping posture, thereby excluding the confounding effects of OSA. It demonstrates the following.
Structural and hemodynamic changes
Biatrial enlargement with diastolic dysfunction, reflected by elevated LA pressure in the presence of normal ventricular function
Elevated right heart pressures and systemic BP
Increased expression of profibrotic TGF-β1 and increased interstitial fibrosis
Fat infiltration of the atrial myocardium
Electrophysiological remodeling
Slowed and heterogeneous conduction
Increased complex fractionated electrograms
Increased voltage heterogeneity without significant change in mean voltage or appearance of scar/low voltage
No change in ERP and ERP heterogeneity
As a result of these hemodynamic, structural, and electrophysiological changes, obese animals were more vulnerable to AF. Importantly, this study provides causative evidence that links obesity directly with the development of the AF substrate.
Atrial Substrate Pre-disposing to AF
Over the last decade, several studies have presented evaluations of the atrial substrate in conditions known to result in AF. Li et al. were the first to distinguish these abnormalities forming the "second factor" from the electrical remodeling associated with AF. They highlighted the importance of conduction abnormalities and structural changes, particularly diffuse atrial fibrosis in an experimental heart failure model. These findings were subsequently confirmed to be the unifying feature of structural remodeling in other conditions, in both pre-clinical studies and clinical studies.
AF substrate in obesity
Although an epidemiological link has been established between obesity and AF, the underlying electrophysiological changes and mechanism still remain to be defined. OSA is closely associated with obesity in humans and predisposes to AF by causing hypertension, diastolic dysfunction, LA stretch, and autonomic imbalance during sleep. Iwasaki et al. demonstrated that obesity facilitates AF inducibility in the presence of acute OSA. However, despite the structural remodeling, AF inducibility was not enhanced in obese rats in the absence of obstruction. The ovine model allows evaluation of obesity in the absence of OSA and, in this study, demonstrated diffuse conduction abnormalities and interstitial fibrosis with chronic obesity alone. The Central Illustration summarizes the structural changes that result in electrical remodeling and promote AF in obesity.
(Enlarge Image)
Central Illustration.
Obesity and the Substrate for AF
Progressive weight gain has been demonstrated to result in atrial stretch and leads to the development of high-frequency triggers and the substrate for AF. With chronic obesity, there is greater epicardial adipose tissue, activation of the cytokines, and the development of fibrosis. In addition, there is infiltration of the contiguous atrial myocardium by fat cells. All of these result in the milieu of slowed and inhomogeneous conduction that forms the substrate for AF. AF = atrial fibrillation; LA = left atrial; TGF = transforming growth factor.
Global endocardial biatrial conduction slowing and increased fractionation were demonstrated in chronically obese animals. However, the degree of slowing varied in different regions, resulting in increased conduction heterogeneity. This is consistent with the finding with limited epicardial mapping with short-term weight gain in an ovine model. Munger et al. have also reported slowed longitudinal conduction velocities from the LA to the pulmonary veins in obese patients with AF. However, this human study did not observe any change in conduction velocity along the coronary sinus. The more pronounced findings in our animal model may result from extreme obesity and more detailed mapping. The obese animals did not demonstrate electrical scars or alterations in global voltage; however, there was reduction in posterior LA voltage with increased voltage heterogeneity. Contiguous epicardial fat was observed to infiltrate the region demonstrating the voltage reduction. Thus, we hypothesize that fatty infiltration of the posterior LA by epicardial fat could potentially represent a unique substrate that could predispose to AF in obesity. As with other studies evaluating clinical substrate for AF, endocardial atrial refractoriness was not altered with sustained obesity. This finding differs from that of Munger et al., who reported shortened atrial refractoriness in obese patients undergoing ablation for AF. However, they acknowledged that AF induced during ERP testing could potentially affect atrial refractoriness. In addition, a marked increase in complex fractionated signals was observed with sustained obesity in our study. This could be a result of conduction slowing secondary to interstitial fibrosis or fat infiltration.
Sustained obesity was associated with diffuse atrial interstitial fibrosis. This is consistent with changes observed with heart failure and chronic hypertension. Spach et al. have demonstrated elegantly that fibrosis can produce conduction abnormalities promoting re-entry and AF. The fibrosis observed in their study was only interstitial in nature, without the areas of replacement fibrosis usually seen with infarction. Moreover, there was only a 50% increase in interstitial fibrous tissue, in comparison to the 16-fold increase observed with heart failure, suggesting a more subtle insult with obesity.
TGF-β1 has been shown to be a crucial cytokine in the signal transduction pathways responsible for fibrosis. It occupies a central position, downstream of angiotensin and upstream of endothelin pathways, and acts in a paracrine–autocrine fashion. Verheule et al. have shown that overexpression of constitutional TGF-β1 in transgenic mice led to selective atrial fibrosis, conduction heterogeneity, and AF. In our study, TGF-β1 expression was increased 5-fold with sustained obesity and could explain the increase in interstitial fibrosis. We have previously reported increased endothelin receptor expression with short-term weight gain. There are similar reports of TGF-β superfamily and endothelin signaling pathway overexpression in humans.
Epicardial Fat and AF
There is emerging evidence that localized epicardial fat depots may have a significant and independent role in development of AF. The development of the obese state has been shown to be associated with hypoxia of the expanding adipose tissue, resulting in adipose tissue fibrosis and production of a myriad of adipocytokines, including those in the TGF-β superfamily. The absence of fascial barriers between epicardial fat and the contiguous atrial musculature, and the common vascular supply may facilitate paracrine action. Venteclef et al. elegantly demonstrated paracrine action in an organ-culture model. They incubated rat atrial tissue in a secretome derived from human epicardial fat and demonstrated atrial fibrosis mediated by members of the TGF-β superfamily. We demonstrated several-fold increased expression of TGF-β1 in atrial tissue; however, the source was not evaluated. In addition, a new finding was observed with epicardial fat infiltrating the underlying myocardium. Epicardial fat is predominantly deposited on the posterior LA. The reduction in posterior LA voltage noted on endocardial mapping was consistent with this finding. We hypothesize that fat infiltration separates myocytes and could result in conduction abnormalities in a fashion similar to microfibrosis. Considering the infiltration was observed only adjacent to epicardial fat deposits, the distribution of epicardial fat could contribute to conduction heterogeneity.
Study Limitations
Although the observed electrical and structural abnormalities predispose to AF, the development of clinical AF is a complex process, with other factors, such as triggers and perpetuators, not addressed in the current study. This study has shown that epicardial fat cells infiltrate the posterior LA. However, a causal relationship between fatty infiltration and AF vulnerability could only be studied to a limited extent in this model. Furthermore, the profibrotic signal transducing pathways responsible for AF in obesity were not fully elucidated.