Expanding the Evaluation and Treatment of Patients with Atrial Fibrillation to Minimize the Risk of Dementia

DOI: 10.19102/icrm.2012.030703

T. JARED BUNCH, MD, BRIAN G. CRANDALL, MD, J. PETER WEISS, MD, JEFFREY S. OSBORN, MD, DAVID L. JOHNSON, MPAS, PA-C and JOHN D. DAY, MD

Intermountain Heart Institute, Intermountain Medical Center, Murray, Utah

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KEYWORDS. atrial fibrillation, alzheimers disease.

The authors report no conflicts of interest for the published content.
Manuscript received May 2, 2012, final version accepted May 23, 2012.
Address correspondence to: T. Jared Bunch, MD, Intermountain Heart Rhythm Specialists, Intermountain Medical Center, Eccles Outpatient Care Center, 5169 Cottonwood St, Suite 510, Murray, Utah 84107. E-mail: Thomas.bunch@imail.org

Introduction

As clinicians we are facing an ever-increasing aging population. By the year 2030, one in five Americans will be 65 or older (an estimated 71.5 million).¹ Compounding age-based changes are that these patients are presenting with enhanced longevity with coexistent cardiovascular diseases.² Cardiovascular diseases impact multiple organ systems, and medications required to improve outcomes in one organ system may be detrimental to another. As such, a multisystem understanding and therapeutic approach to disease states will be essential to manage these patients.

Epidemiology of atrial fibrillation and dementia

Atrial fibrillation (AF) remains the most common cardiac arrhythmia in clinical practice. The incidence and prevalence of the arrhythmia is on the rise. Similar to many disease states, the prevalence of AF increases markedly with age. Approximately 5% of the population over the age of 65 years, and 10% of people aged over 80 years, will develop AF,^3–5 however, the prevalence of AF is increasing beyond what is explained by age alone. AF risk factors (Table 1) such as hypertension, congestive heart failure, left ventricular hypertrophy, coronary artery disease and diabetes mellitus, and obstructive sleep apnea are also on the rise.⁶ As such, the number of affected individuals with AF is expected to increase two to three times over the next three decades in Western populations.^2,7 Furthermore, the often multiple comorbid disease states that increase risk of AF produce challenges in therapy decisions and efficacy.

Dementia is a disorder that is a disease state characterized by impairment of memory and at least one additional cognitive domain.⁸ Dementia leads to a decline from previous levels of function and impacts quality of life and daily function.⁹ Similar to AF, age is a significant risk factor for dementia, in particular Alzheimer’s disease.¹⁰ For example, the estimated annual incidence of Alzheimer’s disease is 0.6–1.0% (65–74 years), 2.0–3.3% (75–84 years), and 8.4% (>85 years).¹⁰ Furthermore, dementia is estimated to be present in up to two-thirds of nursing home residents.¹¹ Risk factors (Table 2) for dementia include genetic factors such as apolipoprotein E, vascular disease states such as hypertension, diabetes, atherosclerosis, metabolic syndrome, chronic kidney disease, and lower function status across social, mental, and physical activity domains.^12–19

Atrial fibrillation and dementia disease associations

There have been many studies that have identified a potential association between AF and dementia (Table 2). The majority of these studies have shown a significant association when large populations are studied over time. In a large meta-analysis of 15 studies (14 used in pooled analysis), Kwok et al²⁰ examined whether the association of AF and dementia persisted across multiple study protocols and diverse populations. In 46,637 participants (mean age 71.7 years) they found that AF was associated with a significant increase in total or overall dementia (odds ratio (OR) 2.0, 95% CI 1.4–2.7, p<0.0001). The association of AF and dementia persisted in general populations and those that focused primarily on stroke patients (OR 2.4, 95% CI 1.7–3.5, p<0.001).

We examined the question regarding the association of AF and dementia and if there was an association across all potential dementia subtypes. We studied 37,025 patients with a mean age of 60.6±17.9 years who had a minimum of 5 years of follow-up. Within this population, 10,161 (27%) developed AF and 1,535 (4.1%) dementia. The dementia subtypes identified were vascular dementia (VD; n = 179), senile dementia (n = 321), Alzheimer’s dementia (n = 347), and non-specific dementia (n = 688). We found an increased incidence of dementia in general and all dementia subtypes in those patients with AF (non-specific, 1.3% (355) versus 3.3% (333), p<0.0001; Alzheimer’s, 0.7% (199) versus 1.5% (148); p<0.0001; senile, 0.6% (161) versus 1.6% (160), p<0.0001; and vascular, 0.3% (89) versus 0.9% (90), p<0.0001). In addition, in all types of dementia, the cognitive decline occurred earlier in patients with AF versus patients with no AF. Surprisingly, we found that the strongest association of AF and dementia was in the youngest cohort studied (patients ≤70 years). For example, for vascular dementia the OR was 2.20 (p = 0.004), for senile dementia the OR was 3.34 (p<0.0001), for Alzheimer’s dementia the OR was 2.3 (p = 0.001), and for non-specific dementia the OR was 2.87 (p<0.0001). The risk associations across all dementia subtypes declined with advancing age.²¹

Of the progressive dementias, Alzheimer’s disease is the most common. In addition to our data, other studies have found a risk trend or association between AF and Alzheimer’s disease. Piguet et al,²² in a study of 377 patients studied over 6 years, found that 13% of those with AF compared with 11% without AF developed Alzheimer’s dementia. In addition, Dublin et al,¹ in a study of 3,045 patients, studied for a mean of 6.8 years, found a significant risk for the development of Alzheimer’s disease in those with AF compared with those without (hazard ratio (HR) 1.50; 95% CI 1.16–1.94)).

Mechanisms underlying atrial fibrillation and dementia associations

For senile and Alzheimer’s dementia, the mechanisms underlying the association with AF are unknown. There are several biologic mechanisms that have been proposed. The most common proposed is the role of chronic system embolization (Figure 1). This hypothesis arises from the well-established role of left atrial appendage thrombus and systemic macroembolization and stroke (Figure 1a).^23–25 In patients with senile, vascular, or Alzheimer’s dementia, often there is diffuse cerebral atrophy and white matter changes.^26–28 In this regard, it is plausible that microemboli from the left atrial appendage results in chronic small ischemic insults, and once a critical mass of neuron loss has occurred clinical cognitive decline is manifest. In this sense, stroke and dementia are manifestations of the spectrum of left atrial appendage and left atrial mechanical dysfunction stemming from AF and subsequent blood stasis and embolization. This hypothesis is supported by the observation the cerebral microinfarcts are a predictor of clinical dementia.²⁹

Another potential aspect to consider in the association of dementia and AF is the treatment to prevent thromboembolism. Since age is a component of the CHADS2 score, many elderly patients with AF are treated with systemic anticoagulation with a vitamin K antagonist. Cerebral microbleeds can occur and tend to increase with age. Microbleeds have been shown to be associated with hippocampus atrophy.³⁰ Patients with cerebral microbleeds are also high risk of long-term cognitive decline.³¹ Hypertension is often seen in patients with microbleeds,³² which as discussed previously is also a common mechanism underlying both AF and dementia. Unfortunately, the risk factors for cerebral microbleeds with age have not been clearly defined. Although long-term anticoagulation and/or antiplatelet use are obvious targets of study, the role of these agents and the extent and presence of microbleeds with exposure has not been clearly defined.

Another possible mechanism is that AF unmasks dementia in patients with underlying cerebral microvascular dysfunction. In sinus rhythm, the vascular dynamics/pulse pressure is relatively uniform and consistent (Figure 2). With onset of AF, there can be broad fluctuations in peaks and valleys of pulse pressure. Abnormal pulse wave velocities are associated with subcortical cerebral lesions and dementia.³³ In general, the autoregulatory mechanisms result in microcirculation compensation in the setting of AF.³⁴ However, all organs have various sensitivities to vascular dysfunction, and in these organs long-term exposure to abnormal flow pulsatility may lead to organ dysfunction. The hippocampus is very sensitive to hypoxia and vascular disease.³⁵ This regional cerebral sensitivity may provide insight into the atrophy seen in this brain location in patients with AF and why AF patients are more likely to experience cognitive decline.³⁶

Another possibility is the long-term end-organ effects of system inflammation may result in microvascular cerebral injury and subsequent cognitive dysfunction. We have previously reported that AF independently increases systemic inflammation beyond other cardiac risk factors.³⁷ Risk of dementia increases in patients with elevated markers of systemic inflammation.³⁸ Adding to the intrigue of the role of system inflammation in patients with AF who develop dementia is that there is a significant association of elevated blood inflammatory markers and risk of cerebral microbleeds.³⁹

The many different mechanisms presented (Figure 3) may work in isolation or in combination, and likely evolve over time with disease state progression. There certainly will be new discoveries of risk factors and insights gleaned through genetic exploration. Finally, there is always the possibility that the association is an epiphenomenon, in that both diseases increase significantly with age and have similar risk factors (Table 1) and as such track together. We observed data contrary to this possibility: the highest risk of all types of dementia we observed was in the youngest cohort studied, opposite of what we initially predicted. Also, multiple studies with multivariate analysis methods and distinct comparative cohorts have noted the association (Table 2). Nonetheless, this possibility reinforces the need to elucidate the mechanisms underlying the association of AF and dementia to assure that the observational study data are correct.

Reducing risk of cognitive decline in patients with atrial fibrillation

Treatment of dementia typically involves a trial of a cholinesterase inhibitor for patients with mild to moderate dementia, vitamin E, and the addition of memantine to a cholinesterase inhibitor to those patients with more advanced disease. In addition, rehabilitation to maintain a high functional status can also provide benefit. Treatment of obstructive sleep apnea appears to slow cognitive decline and impact structural brain changes over time.^40–42 Although high blood pressure is a risk factor for dementia, antihypertensive agents have only a very modest impact in reducing the risk of cognitive decline.⁴³

In regards to this review, the more important question is what can be done to prevent onset of dementia all together. There are intriguing observational data regarding the role of vitamins, antioxidants, anti-inflammatory drugs, diet, and estrogen replacement therapies to suggest a potential role in dementia prevention.^44–49 Most data on therapies for preventing dementia come from observational studies. Unfortunately, for the most part, prospective randomized studies of these therapies have not substantiated the observational study results.

With the correlation observed of AF and dementia, arrhythmia treatment is an intriguing target to explore as a preventative strategy. We examined the question of whether the most aggressive rhythm control strategy, and all that goes along with it, would impact risk of dementia long term. We studied 4,212 consecutive patients who underwent AF ablation and compared them (1:4) with 16,848 age/gender-matched controls with AF (no ablation) and 16,848 age- and gender-matched controls without AF. Patients were enrolled if they had at least 3 years of follow-up. We found that patients who underwent an AF ablation had long-term rates of dementia (all types) similar to patients with no history of AF, and not surprisingly significantly lower rates than those with AF and no ablation. Specifically, Alzheimer’s dementia occurred in 0.2% of the AF ablation patients compared with 0.9% of the AF (no ablation) patients versus 0.5% of the no AF patients (p<0.0001). All other forms of dementia in a combined endpoint occurred in 0.4% of the AF ablation patients compared with 1.9% of the AF no ablation patients and 0.7% of the no AF patients (p<0.0001).⁵⁰

There are many potential explanations for the results we observed. First, we selected a healthier group of patients to undergo ablation. This is likely correct and explains the differences noted between the two AF groups (ablation versus no ablation). However, there was essentially normalization of dementia outcomes with patients who had no history of AF. Also, we included consecutive patients throughout the state of Utah with ablations performed by various operators, with the requisite of known long-term outcomes to minimize, but not completely eliminate, the inherent selection bias. Next, rhythm control with preserved vascular flow pulsatility improved outcomes in organs that are sensitive to the broad fluctuations which occur in AF. Next, these patients were carefully followed after their ablation with attention devoted to their blood pressure control, sleep apnea, and anticoagulation, and as such it was a multifactorial approach that influenced outcomes. Finally, perhaps the results reflect stopping system anticoagulation in a subset of patients where this is possible (CHADS2 ≤1), that minimized their risk to cerebral microbleeds over time. Regardless of the mechanism(s), the observational findings require confirmation in a large prospective randomized trial.

Antiarrhythmic drugs have not been shown to impact risk of dementia. Recent data involving dronedarone suggest that cerebral ischemic events can be favorably influenced. Dronedarone was studied in the ATHENA trial and reduced the primary endpoint of cardiovascular hospitalization or death by 24%, and the risk of first hospitalization due to cardiovascular events (primarily for AF) by 26%.⁵¹ In an interesting post hoc analysis of ATHENA a significant reduction in the risk of stroke was shown with dronedarone compared with placebo (HR 0.66 (95% CI 0.46–0.96, p = 0.027).⁵² Unfortunately, use of dronedarone for safety reasons is confined to those with paroxysmal AF and no significant heart failure or left ventricular dysfunction. Nonetheless, the data suggest that with safe antiarrhythmic drugs cerebral ischemic events can be influenced in a positive manner.

One disease that is correlated with the onset, progression, and adverse response to treatment strategies with both AF and dementia is the presence of obstructive sleep apnea. The question of whether continuous positive airway pressure can be used as a preventive strategy for the onset of dementia in those patients with AF requires further prospective study.

Examining the cognitive domain after catheter ablation

We have previously discussed the observational data regarding catheter ablation and long-term risk of dementia. However, periprocedural stroke is a known complication of catheter ablation estimated at 0.1–0.8%.^53,54 More importantly is the role of silent cerebral thromboembolism during and after ablation (Figure 4). Silent cerebral thromboembolism by nature is likely underappreciated and has not been an area of extensive investigation in prior studies. Of the available data, these cerebral ischemic episodes are device and technology dependent, with reported event rates between 8% and 18%.^55–57 In our practice we have not routinely screened for silent cerebral ischemia. In patients with neurologic symptoms, the magnetic resonance imaging studies that have been performed have typically been normal. The low incidence observed in our population may reflect that we do not cross the septum until the patient is fully anticoagulated; many of our operators do ablation procedures without interrupting warfarin anticoagulation and/or maintain the sheaths outside of the left atrium, and we truly have not looked at all patients to determine the actual incidence. At minimum, understanding the true incidence of silent cerebral thromboembolic events and the potential compounding of events with repeat ablations may help understand if there is a threshold in which ablation transitions from reducing cognitive dysfunction to increasing it.

Conclusion

Mounting evidence continues to support that AF is independently associated with dementia. This association extends across the dementia spectrum and includes Alzheimer’s dementia. The mechanisms underlying these associations are incompletely understood, but with discovery will provide insight into preventative and treatment strategies. These mechanisms underlying AF and dementia may also help in further understanding other disease progressions in patients with AF, such as chronic renal dysfunction. The observational findings with catheter ablation suggest the need to include long-term comprehensive neurocognitive assessment in future therapies, both pharmacologic and non-pharmacologic, to continue to examine the role of rhythm control strategies to prevent dementia.

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