HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation
State-of-the-Art Review
Central Illustration
Abstract
Both obesity and type 2 diabetes are important risk factors for the development of heart failure with a preserved ejection fraction (HFpEF), and both disorders increase the risk of systemic thromboembolic events. Traditionally, the risk of stroke has been explained by the strong association of these disorders with atrial fibrillation (AF). However, adiposity and diabetes are risk factors for systemic thromboembolism, even in the absence of AF, because both can lead to the development of an inflammatory and fibrotic atrial and ventricular myopathy, the 2 major elements of HFpEF. Atrial myopathy: 1) exacerbates pulmonary venous hypertension and exertional dyspnea; 2) leads to decreased flow, thrombogenesis, and systemic thromboembolization; and 3) often clinically manifests as AF; however, the relationship between AF and thromboembolism is unclear. Atrial fibrosis predisposes to thrombus formation, even in the absence of AF, and most thromboembolic events bear a poor temporal relationship to the occurrence of AF, whereas HFpEF (and the accompanying atrial disease) predicts stroke in patients with or without AF. Furthermore, rhythm control does not reduce the risk of stroke, although it reduces the burden of AF. These observations support the primacy of atrial myopathy as a critical component of HFpEF, rather than AF, as the mediator of systemic thromboembolism in obesity or diabetes. The well-established association between AF and stroke is likely explained by the fact that AF is a biomarker of more advanced inflammatory atrial disease but not necessarily a direct causal mechanism.
Highlights
| • | Obesity and type 2 diabetes are risk factors for heart failure with preserved ejection fraction and systemic thromboembolic events. | ||||
| • | The risk of stroke cannot be explained by atrial fibrillation but is related to heart failure with preserved ejection fraction. | ||||
| • | Atrial fibrillation is a marker for atrial myopathy, which contributes to heart failure and thromboembolism. | ||||
| • | Rhythm control of atrial fibrillation has not been shown to reduce the risk of stroke. | ||||
Introduction
Both obesity and type 2 diabetes can lead to the development of heart failure with a preserved ejection fraction (HFpEF) (1). Furthermore, both metabolic disorders increase the risk of arterial thromboembolic events, especially stroke (2,3). Are these 2 consequences of obesity and diabetes linked to each other? Does HFpEF itself contribute to the risk of systemic thromboembolism?
Traditionally, the association of obesity and diabetes with stroke has been explained by their strong association with atrial fibrillation (AF). Obesity represents the second highest population attributable risk for AF, and an increase in body mass contributes to AF in one-fifth of patients with arrhythmia (4). At the same time, diabetes also contributes significantly to the development of AF; the severity of hyperglycemia predicts the incidence of AF (5), and diabetes is an important element of risk models for AF that presage an increased risk of systemic thromboembolism (3). However, it is noteworthy that patients with abdominal adiposity and diabetes are at increased risk of thromboembolic stroke, even in the absence of AF (2,3,6,7).
This paper supports the premise that obesity and diabetes can trigger systemic thromboembolism by virtue of their ability to cause inflammatory left heart cardiomyopathy (i.e., HFpEF) (8). A critical component of HFpEF is the development of atrial myopathy, which not only contributes to elevated pulmonary venous pressures and exertional dyspnea but also to atrial thrombus formation and thromboembolic stroke independent of the presence or control of AF (9,10). An understanding of the relationship between HFpEF and stroke has important implications in the identification of patients at risk among those with obesity and type 2 diabetes.
Role of Obesity and Diabetes in the Genesis of Cardiac Inflammation and the Development of a Left-Sided Atrial and Ventricular Myopathy
Both obesity and diabetes promote a state of systemic inflammation, which can cause expansion of epicardial adipose tissue, thereby becoming a source of proinflammatory secretory products that cause structural and functional derangements in the underlying myocardium (11). If the abnormal epicardial fat adjoins the left ventricle (LV), the result is microcirculatory dysfunction and fibrosis, which impair the distensibility of the chamber and limit its ability to accommodate an increase in volume (12). Cardiac filling pressures rise, contributing to exertional dyspnea and the syndrome of HFpEF (13). Simultaneously, if the abnormalities of epicardial fat about the left atrium (LA), the resulting electroanatomic remodeling leads to atrial myopathy (14), which predisposes to blood stasis, spontaneous thrombus formation, and stroke (9). The most clinically evident biomarker of atrial myopathy is AF.
A common inflammatory process causes LA and LV myopathy in patients with obesity or type 2 diabetes
Viewed in this conceptual framework, the transduction and amplification of the systemic inflammatory process of obesity and diabetes onto both the LA and LV leads to the development of atrial and ventricular myopathy. Although clinicians often identify atrial myopathy as AF and refer to ventricular myopathy as HFpEF, they are both manifestations of the same inflammatory left-sided myocardial disorder that causes the syndrome of heart failure in patients whose LV ejection fraction is not meaningfully reduced (i.e., HFpEF) (Figure 1) (12).
Mechanisms by Which Obesity and Type 2 Diabetes Can Cause the Atrial and Ventricular Myopathy of HFpEF
Both obesity and type 2 diabetes can cause adipose tissue inflammation. The resulting systemic inflammatory state can lead to the expansion and proinflammatory transformation of epicardial adipose tissue. The transmission of proinflammatory mediators from the epicardium to the underlying myocardium can lead to cardiac inflammation, microcirculatory dysfunction, and cardiac fibrosis. The resulting combination of atrial and ventricular myopathy is the hallmark of heart failure with a preserved ejection fraction.
This paradigm is strongly supported by a broad range of clinical observations. AF and HFpEF are closely linked in epidemiological studies. AF is a powerful predictor of the development of HFpEF; the presence of AF increases the likelihood of subsequent HFpEF (by up to 4-fold) across diverse populations, and it precedes the diagnosis of HFpEF by 4 to 10 years (15,16). At the same time, most patients with HFpEF are destined to develop AF, if AF is not already evident. Among those in sinus rhythm, one-third with a diagnosis of HFpEF will develop AF during the following 3 to 5 years; eventually, two-thirds of patients with HFpEF will manifest clinically overt AF during the natural history of the disease (17,18).
These epidemiological studies underestimate the true convergence of AF and HFpEF. Asymptomatic paroxysms of AF occur for years before a formal diagnosis of AF; conversely, patients often experience exertional dyspnea for long periods before physicians identify the presence of heart failure. Accordingly, many patients who present with AF but without a confirmed diagnosis of HFpEF have increased LV filling pressures during invasive or noninvasive assessments, indicative of latent HFpEF. Approximately one-third of patients with AF have diastolic filling abnormalities on echocardiography whose severity is related to the degree of exercise intolerance (19). More directly, in patients with AF with a normal ejection fraction and no clinical evidence of heart failure, ≈40% have increased LA pressures at rest or during exercise (20). The proportion of patients with latent HFpEF is even higher among those with AF who have unexplained dyspnea; two-thirds have increased pulmonary wedge pressure on exercise (21). Therefore, patients with obesity or type 2 diabetes with AF often have underlying latent HFpEF, but the diagnosis is frequently missed because dyspnea is attributed to increased body mass or the arrhythmia.
Because AF and HFpEF appear to reflect a common inflammatory myopathy, it is not surprising that systemic inflammation precedes and predicts the development of both AF and HFpEF in the general community (22,23). Biomarkers of systemic inflammation (e.g., C-reactive protein and tumor necrosis factor-α) are elevated in patients with both AF and HFpEF, and the levels of proinflammatory biomarkers are strongly associated with exercise intolerance and the risk of major adverse outcomes (24,25). Furthermore, the volume of epicardial adipose tissue (the major amplifier of systemic inflammation) is increased in patients who have AF, particularly if they have evidence of obesity or diabetes or are at risk of thromboembolic events and other adverse outcomes (14,26,27). Epicardial fat mass predicts the incidence of AF in the general population (28), and it increases as AF progresses from a paroxysmal to a persistent arrhythmia (29). At the same time, epicardial adiposity is prominent in HFpEF, particularly with coexistent AF (30).
Interventions in obesity and diabetes can influence epicardial adipose tissue and the development of atrial myopathy and AF. Modest changes in weight have little effect on epicardial fat or on the risk of AF (31,32), but marked weight loss decreases epicardial fat volume, improves LA geometry, alleviates the burden of AF, and reduces the risk of stroke (33–36). Certain antihyperglycemic drugs (e.g., insulin) that promote epicardial adipogenesis increase the risk of atrial myopathy, AF, and thromboembolic events (8,37,38). In contrast, agents that ameliorate the inflammatory state of epicardial fat (e.g., statins and metformin) are accompanied by improvement in LA myopathy and a reduction in the incidence and prevalence of AF and the risk of systemic thromboembolism and stroke (39–45).
Left atrial myopathy is central to the pathogenesis of both AF and HFpEF
The development of LA myopathy is central to the pathogenesis of both AF and HFpEF. Although the LA in patients with heart failure with reduced ejection fraction is typically enlarged with increased distensibility (especially in those with secondary mitral regurgitation), LA reservoir function is diminished in patients with HFpEF (46). Accordingly, when compared with those with heart failure with a reduced ejection fraction, patients with HFpEF have greater LA stiffness leading to smaller (although still enlarged) LA volumes despite higher peak pressures (47,48). Yet, despite the lesser degree of LA dilatation, patients with HFpEF are more likely to have AF, suggesting that atrial fibrosis (not chamber distension) is a stronger determinant of AF. The powerful link between obesity and the risk of AF in epidemiological studies is entirely accounted for by the presence and severity of the underlying atrial myopathy (49).
Importantly, the increases in LA pressures that lead to exertional dyspnea in HFpEF are not entirely related to the retrograde transmission of LV end-diastolic pressures but instead may be caused by the atrial myopathy. In contrast to the expected relationship if LA hypertension were the result of LV myopathy, LA pressures are typically higher than LV end-diastolic pressures in patients with AF (50). Furthermore, measurements of LA strain are superior to ventricular diastolic filling dynamics in discriminating HFpEF from noncardiac causes of dyspnea (10,51) and in predicting pulmonary wedge pressures in HFpEF (52,53). The exaggerated LA pressures produced by a fibrotic LA explain why in HFpEF LA strain is more closely related to exercise capacity and outcomes than LV diastolic performance (10,54). Accordingly, the LA myopathy of HFpEF, independent of the LV myopathy, contributes to the symptoms of heart failure in patients with obesity and diabetes who have a preserved ejection fraction (Central Illustration).
Pathophysiological and Clinical Consequences of Atrial Myopathy in Patients With Obesity or Type 2 Diabetes
Both obesity and type 2 diabetes are commonly accompanied by atrial myopathy, which is characterized by 1) impaired left atrial systolic and diastolic function, leading to increased left atrial pressure and exertional dyspnea; 2) atrial fibrosis, stasis, and thrombogenesis, leading to left atrial thrombus formation and systemic thromboembolism; and 3) electroanatomic and electrophysiological remodeling, leading to atrial fibrillation. The contribution of atrial fibrillation to the occurrence of systemic thromboembolism, independent of atrial myopathy, has not been defined.
Does AF or Atrial Myopathy Lead to Thromboembolic Stroke?
Patients with HFpEF and AF are at markedly increased risk of thromboembolic events; the risk of stroke when both disorders are present is greater than with either alone (8,55,56). This synergism is present even when the diagnosis of HFpEF has not been made or if AF is a historical event (55) (i.e., patients with AF who have diastolic filling abnormalities on echocardiography are pre-disposed to LA thrombus formation [56,57] and thromboembolic events [58]).
Elusive role of AF as a proximate cause of thromboembolic stroke
Nevertheless, it is not clear if the enhanced risk of stroke is directly related to AF or is caused by the underlying LA myopathy. Physicians have long believed that the chaotic contraction seen in AF drives thrombus formation; however, it is the decrease in flow velocity in the LA (due to atrial myopathy) that pre-disposes to spontaneous echo contrast and thromboembolization (59). Indeed, mitral regurgitation protects against LA stasis even though it promotes chamber dilatation and increases the likelihood of AF (60). The fibrotic process in the LA is a primary determinant of the impairment of the chamber’s reservoir and conduit functions, even in the absence of AF (61); inflammation and fibrosis may also enhance the thrombogenic potential of the atrial endocardium (9). Accordingly, atrial fibrosis is independently associated with LA thrombus, and the extensive atrial fibrosis in patients with long-standing AF pre-disposes to the occurrence of stroke, independently of LA chamber size (Central Illustration) (62).
Additional doubts about the primacy of AF (rather than the underlying atrial myopathy) in causing stroke have been raised in studies of continuous electrocardiographic monitoring devices to detect AF in patients at risk for or with a history of stroke. In these studies, at-risk patients generally did not exhibit evidence of AF in the 30 days preceding the occurrence of stroke (63,64). Typically, patients who experienced a stroke manifested only very rare and transient episodes of AF and had no AF on >90% of days (65). Although intensive electrocardiographic monitoring increases the detection of AF, it identifies undiagnosed AF in only a small fraction of patients with cryptogenic stroke even after 3 years of continuous observation (66). One-third of patients with both AF and stroke exhibited AF only after the cerebrovascular event (67). Brief episodes of AF, even when frequent, do not increase the risk of stroke (68), and the use of intermittent anticoagulant agents guided by the presence or absence of AF in individual patients at risk does not effectively prevent thromboembolic events (69).
By contrast, a diagnosis of HFpEF increases the likelihood of a subclinical cerebral infarction in patients without a history of AF (70). Specifically, the severity of LA disease (as reflected by LA geometry or the degree of LA fibrosis) is a major determinant factor for stroke and vascular brain injury in patients with or without AF (71,72). In patients without risk factors that reflect the existence of atrial myopathy, the risk of stroke in patients with AF is similar to that in patients without AF (9,73). Additionally, current risk scores to guide the use of oral anticoagulant agents (which rely on the presence of heart failure and diabetes) predict the occurrence of stroke, even in patients without AF (3), and in patients with high risk scores, the magnitude of risk of thromboembolic events is not further increased by the presence of AF (74). Both obesity and diabetes presage a high risk of systemic thromboembolism (particularly in patients with heart failure) in the absence of or before the detection of AF (75,76). In contrast, systolic blood pressure—the most common risk factor for cerebrovascular disease—is not a determinant of stroke in patients with HFpEF (77).
Lack of benefit of rhythm control of AF in preventing thromboembolism
The premise that atrial myopathy, rather than AF, is the primary mechanism for thromboembolic events is further supported by a lack of benefit of rhythm control on the risk of thromboembolic events in patients with AF. If atrial myopathy, and not AF, is the primary driver of stroke risk, then the control of AF (which does not ameliorate the underlying myocardial disorder [78]) should not minimize thromboembolism. Although observational studies have suggested that rhythm control with catheter ablation reduces the risk of stroke (79), these reports relied on short-term follow-up and the analysis of a sparse number of events that were recorded in groups that were strikingly different from each other and could not be validly compared because of the presence of unmeasured confounders.
In contrast with these observational analyses, randomized controlled clinical trials that have compared rate control and rhythm control strategies in patients with established AF (with or without heart failure) demonstrated no reduction in the risk of systemic thromboembolism or stroke in patients assigned to rhythm control, even though these patients had a meaningfully reduced burden of AF; the lack of benefit was confirmed in a meta-analyses of 13 trials that enrolled > 8,000 patients (80). In fact, the rhythm control groups experienced an increased risk of thromboembolic events (81), possibly because oral anticoagulation was discontinued in some patients based on the belief that AF (rather than atrial myopathy) was the primary driver of stroke. Furthermore, abolition of AF by catheter ablation did not reduce the risk of stroke in a large-scale randomized controlled clinical trial; importantly, in this study, long-term oral anticoagulation therapy was maintained even if sinus rhythm was achieved (82).
Conclusions
The development of heart failure in patients with obesity and type 2 diabetes and a preserved ejection fraction is characterized by both an atrial and ventricular myopathy, which is likely related to inflammation and fibrosis of the LA and LV. The parallel evolution of these 2 disorders explains the strong association of AF and HFpEF in epidemiological studies and the clinical setting. The atrial myopathic component of HFpEF leads to mechanical LA dysfunction (thereby exacerbating the increase in pulmonary venous pressures), and the accompanying atrial fibrosis reduces blood velocity and promotes thrombogenesis. Although patients with an atrial myopathy often manifest AF, there is a poor temporal relationship between AF and stroke, and abnormalities of LA geometry and function as well as HFpEF are more important predictors of systemic thromboembolism than AF. Furthermore, rhythm control does not reduce the risk of stroke, although it alleviates the burden of AF. These observations support the primacy of atrial myopathy as a component of HFpEF, rather than AF, as the principal source of the systemic thromboembolism in patients with obesity and diabetes. In these patients, the well-established association between AF and stroke may be explained by the fact that AF is a biomarker of more advanced LA disease but not necessarily a direct mediator of thromboembolic events.
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Abbreviations and Acronyms
| AF | atrial fibrillation |
| HFpEF | heart failure with preserved ejection fraction |
| LA | left atrium |
| LV | left ventricle |
Footnotes
Dr. Packer has recently consulted for Abbvie, Actavis, Akcea, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Gilead, Johnson & Johnson, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics and Theravance; none of these relationships are relevant to the topic of this paper.
