Hypertension and Atrial Fibrillation: Epidemiological Data, Pathogenesis, and Therapeutic Implications

Atrial fibrillation (AF), the most prevalent chronic arrhythmia is closely associated with hypertension (HTN). Both conditions (AF and HTN) are associated with aging, and additionally, HTN is also associated with other cardiovascular comorbidities that seem to increase the risk for AF, including coronary artery disease, heart failure, metabolic syndrome, chronic kidney disease, and sleep apnea. In this issue of AJH, Chen et al. present their study investigating the association between blood pressure (BP) and AF in an elderly Chinese population. In the 6,966 participants, the prevalence of AF was 3.3%, and the prevalence of hypertension was 58.7%. In all participants, the association with prevalent AF appeared to be negative for systolic BP but positive for diastolic BP. In untreated participants, the association with prevalent AF was U-shaped for both systolic and diastolic BP. The investigators reached to the conclusion that in the elderly population, BP shows a complicated relationship with prevalent AF, with high-normal BP at the lowest risk and optimal systolic BP and stage 2 or 3 diastolic hypertension at increased risks.1 The findings by Chen et al. add valuable knowledge to the long-existing evidence on the association between hypertension and AF. In the Framingham study, hypertension portended an excess risk for AF by 50% in men and 40% in women, ranking fourth after heart failure, aging, and valvular heart disease.2 However, because of its higher prevalence in the population, hypertension accounts for more cases of AF than other risk factors.3,4 In the ARIC (Atherosclerosis Risk in Communities) study, hypertension appeared to be the main contributor to the burden of AF, explaining ≈20% of new cases.4 Despite the well-established epidemiological association between hypertension and AF, the possible underlying pathogenetic mechanisms, which could explain the higher propensity of hypertensive patients to develop AF are still incompletely known. A central role seems to be expressed by the so-called atrial cardiomyopathy, defined as a complex of structural, contractile, and electrophysiological alterations affecting the atria with the potential to produce clinically relevant manifestations, which may be induced by predominantly hemodynamic and nonhemodynamic mechanisms.5 The predominantly hemodynamic mechanisms include the increase in left ventricular wall thickness and stiffness, as well as the progressive impairment in left ventricular diastolic function associated with hypertension. These processes may result in a rise in left atrial stretch and pressure, with subsequent remodeling and dysfunction of the left atria, ultimately predisposing to AF. Several studies in animals and humans supported the role of histological changes in the atria as potential triggers of AF. The most important atrial changes include proliferation of fibroblasts, alterations of extracellular matrix, and myocyte hypertrophy. The resulting disorders of interconnections between muscle bundles may lead to shortening of left atrial refractoriness, unidirectional blocks, and reentry phenomena. These processes may initiate AF episodes eventually triggered by ectopic stimuli originating from pulmonary veins or other sites.6 The atria of hypertensive patients may even show subtle electrophysiological alterations predisposing to AF. In an electrophysiological study conducted in hypertensive patients and normotensive controls, the former group showed slowing of global and regional conduction, an increase in areas of low voltage, and, most importantly, an easier inducibility of sustained AF.7 Obstructive sleep apnea (OSA) is another condition potentially involved in the pathogenesis of AF in hypertensive patients. Clinical studies showed that OSA, which is present in ≈50% of patients with hypertension, is associated with left atrial dilatation and a higher risk of AF both in the presence and in the absence of left ventricular dysfunction. To date, there is growing evidence to suggest that OSA is an independent predictor for the development of hypertension and that it is associated with adverse cardiovascular outcomes. Furthermore, OSA and hypertension share a common pattern of risk factors, with obesity having a pivotal role in this setting. The pathophysiological mechanisms activated during obstructive apnea promote a variety of detrimental effects on both the vasculature and the heart, yielding early atherosclerosis and cardiac remodeling processes, respectively, beyond the effects that could be attributed to hypertension alone. Consequently, the coexistence of OSA and hypertension actually represents a “deadly duo.”8–13 The RAAS may also be involved in the pathogenesis of AF through proliferation of fibroblasts and extracellular matrix and hypertrophy of myocytes, with potentially detrimental electrophysiological changes.14 It should also be noted that myocardial fibrosis induced by RAAS seems to be BP independent. In an animal study by Sun et al., low doses of angiotensin II and aldosterone infused through a mini pump induced a marked increase of interstitial collagen after only 2–6 weeks of administration in the absence of any rise in BP.15 The majority of clinical studies show a direct and linear relation between BP levels and the risk of AF. However, the shape of this relation in the growing portion of high-risk vascular patients with coronary artery disease, cerebrovascular disease, peripheral artery disease, or diabetes mellitus remains unclear. This aspect was investigated in a post hoc analysis of the ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial)/TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease). The risk of AF appeared to increase significantly with systolic BP, pulse pressure, age, left ventricular hypertrophy, body mass index, serum creatinine and history of hypertension, and coronary and cerebrovascular disease. The impact of diastolic BP was not significant though.16 Chen et al., on the other hand, in this article, demonstrated that the lowest prevalence of AF was observed in high-normal BP and higher prevalence in optimal systolic BP and stage 2 or 3 diastolic hypertension. Indeed, the fully adjusted odd radios of AF for optimal relative to high-normal systolic BP were 2.75 in all participants and 3.11 in untreated participants. The corresponding odds ratios for stage 2 or 3 diastolic hypertension were 1.75 and 8.04, respectively.1 Of note, the nondipping pattern has also been associated with a 2-fold higher risk of developing AF when compared with those with a normal diurnal BP rhythm17 With increasing research efforts, the landscape of AF care will continue to evolve with growing understanding of AF pathogenesis to facilitate individualized therapeutic strategies. The rising burden of AF demands increasing attention on AF prevention and upstream therapy beyond improved phenotyping of AF patients, novel therapeutics, or ablative technologies. The current work by Chen et al.1 on the complex relationship between BP levels and AF contributes to the modern focus on personalized risk factor modification aiming to improve AF outcomes. It seems vital, though, that any risk factor management strategy addresses not only hypertension, but also all-known risk factors that are present in an AF individual to maximize the chance of reverse atrial remodeling and sinus rhythm maintenance. The authors declared no conflicts of interest.