Hypertension, stroke and the impact of atrial fibrillation

It is well-recognized that hypertension is associated with an increased risk for stroke, coronary heart disease and renal failure; importantly, blood pressure (BP) control markedly reduces major adverse cardiovascular events [1]. This result has been seen consistently with different drug regimens, with a reduction in the risk of nonfatal or fatal strokes of up to 30–40% with optimal BP control [2]. The improved clinical outcome relates more to systolic BP reduction than the reduction of diastolic BP per se[3]. Indeed, systolic BP levels are more predictive of cardiovascular mortality and morbidity in patients aged 60 years and over, when compared with diastolic BP levels [3].

The management of hypertension is very relevant to routine clinical practice with an increasingly elderly population. Indeed, aging is associated with systolic hypertension, which is a contributory factor for the increased risk of stroke in the elderly [4]. The benefits of treatment in such patients are illustrated by meta-analyses [5] and, more recently, in the Hypertension Control in Very Elderly study [6]. The latter trial is the latest placebo-controlled trial, and this clearly demonstrated the benefit of BP control, even in elderly patients, with a reduction in the risk of nonfatal or fatal strokes by 30%, as well as a 39% reduction in the risk of death from stroke.

Another common cardiovascular condition associated with aging is atrial fibrillation (AF). This is the most commonly occuring sustained cardiac arrhythmia, which is associated with a high mortality and morbidity rate from stroke, thromboembolism and heart failure. On a population basis, hypertension is the most common etiological factor associated with AF. Long-standing hypertension, especially if suboptimally controlled, leads to left ventricular hypertrophy (LVH), which is the most visible manifestation of hypertensive target organ damage. LVH is itself an independent predictor of adverse cardiac events. Due to the subsequently reduced left ventricular compliance, increased ventricular stiffness and changed left ventricular filling pressure, the presence of LVH leads to diastolic dysfunction and abnormal left atrial (LA) remodeling, dilatation and fibrosis. Such LA remodeling contributes to the pathogenesis of AF.

Nonetheless, few prospective population-based studies have used LVH, diastolic dysfunction and LA dilatation as surrogate markers to predict the risk of adverse cardiovascular events and AF. It is increasingly recognized that diastolic dysfunction is associated with an increased risk of AF [7]. In the Framingham Heart Study, the level of systolic BP and duration of hypertension was predictive of adverse LA remodeling [8]. In a study of 1655 older subjects from Olmsted County, Tsang et al. also demonstrated a 48% higher risk of AF in those with a 30% increase in LA volume, which was also an independent predictor of ischemic stroke [9].

Is stroke the end point of AF, hypertension or both in combination? As discussed previously, hypertension is a major contributor to stroke, but many studies also show that AF is an independent risk factor for stroke, with risk of stroke nearly fivefold higher in AF patients compared with controls in sinus rhythm [10]. The pathophysiology of AF is highly complex and multifactorial, but AF is associated with abnormal atrial stasis, structural heart disease and abnormal blood constituents, resulting in a prothrombotic or hypercoagulable state [11]. The risk of stroke is not homogeneous, and a recent analysis from the Stroke Risk in Atrial Fibrillation Working Group identified history of prior stroke or transient ischemic attack, advanced age (>75 years), hypertension and diabetes as independent risk factors for stroke in AF patients [12]. In this systematic review, no significant association was found with female gender, heart failure or coronary artery disease in the risk of stroke with AF. These conclusions are broadly consistent with the systematic review from the UK National Institute for Health and Clinical Excellence guidelines on stroke risk factors for AF [13], which identified previous history of stroke or transient ischemic attack, increasing age (>75 years), hypertension, structural heart disease (left ventricular dysfunction or hypertrophy) and previous myocardial infarction as strong predictors of stroke in AF patients, whereas diabetes mellitus and gender showed less consistent results.

What is the risk of stroke when hypertension is present with AF in the same patient? In the pooled data analysis of Atrial Fibrillation Investigators, the risk of stroke doubled (10.4%) in patients with AF associated with hypertension or diabetes or prior strokes compared with patients without those comorbidities (4.3%) [14]. In the Stroke Prevention in Atrial Fibrillation III trial, hypertensive patients had a higher risk of stroke with a relative risk of 3.3% irrespective of rhythm (that is, AF or not) [14]. In patients with AF and a history of hypertension, there was a threefold increase in the risk of stroke annually compared with those without any hypertension (3.6 vs 1.1%).

Thus, what would be the optimal target of BP levels for hypertension to be considered ‘optimally controlled’ in AF patients? In an analysis of pooled data from the Stroke Prevention using an Oral Thrombin Inhibitor in AF III and V trials, patients with a mean systolic pressure of over 140 mmHg were associated with increased risk of stroke and systemic embolic events [16]. The annual risk of stroke and systemic embolic events nearly doubled in patients with a mean pulse pressure of over 60 mmHg (2.4%) compared with pulse pressure higher than 40 mmHg (1.3%). This analysis also suggested that systolic BP was the major predictor of stroke rather than diastolic BP among these AF patients in a clinical trial setting.

Given that hypertension is associated with an increased risk of AF, and that the Stroke Prevention using an Oral Thrombin Inhibitor in AF analysis suggests that poor BP control contributes to increased risk of stroke and systemic embolism in AF, the primary goal should be optimizing BP control in AF patients. How low should we go, in terms of BP reduction? Is there a J-curve phenomenon, as seen in some BP-lowering studies? Clearly, more studies are required to answer these questions.

Of note, some common antihypertensive drug therapies have particular benefits in AF. In a combined analysis of recent angiotensin-converting enzyme inhibitors trials, there was a reduction in all cause mortality (7.8%), cardiovascular mortality (4.3%), nonfatal myocardial infarction (5.3%) and stroke (2.2%), independent of BP-lowering effects [17]. Meta-analysis of studies with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers showed a 28% reduction in the overall risk of developing AF [18], with the most impressive relative risk reduction in AF development seen among treated patients with heart failure (44–78%) and postmyocardial infarction (48%), but inconsistent results were seen in patients with hypertension.

Other studies of angiotensin II receptor blockers clearly show a regression of LVH, improved diastolic function and a reduction in LA size, which translate to less AF and better BP control [19]. In recent prospective, randomized control studies, such as the Losartan Intervention For End Point Reduction in Hypertension [19] and Valsartan Antihypertensive Long-term Use Evaluation trials [20], the inhibition of the renin–angiotensin–aldosterone system with angiotensin II receptor blockers reduced the incidence of AF by 33 and 16%, respectively, with significant reduction of strokes. Other prospective trials (e.g., the The GISSI Atrial Fibrillation trial, the Irbesartan for the Prevention of Atrial Arrhythmias and Cardiac Electrical Remodeling in Patients with Hypertension, Permanent Pacemakers or Defibrillator and Risk Factors for Developing Atrial Fibrillation trial, the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events I trial, and the Japanese Rhythm Management Trial for Atrial Fibrillation) in hypertensives will offer more information with regard to prevention of AF and reducing the risk of stroke and cardiovascular events with various angiotensin II receptor blockers.

In conclusion, the intimate link between hypertension and AF enforces the stroke risk associated with both conditions in combination. Therefore, the primary goal should be targeting BP and optimizing its control, thereby minimizing the risk of AF and complications, such as strokes and heart failure. The inhibition of the renin–angiotensin–aldosterone system with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers offers further hope in achieving both targets.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.