Hypertension and cardiac arrhythmias: executive summary of a consensus document from the European Heart Rhythm Association (EHRA) and ESC Council on Hypertension, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE)

Abstract

Hypertension (HTN) is a common cardiovascular risk factor leading to heart failure (HF), coronary artery disease (CAD), stroke, peripheral artery disease and chronic renal failure. Hypertensive heart disease can manifest as many types of cardiac arrhythmias, most commonly being atrial fibrillation (AF). Both supraventricular and ventricular arrhythmias may occur in HTN patients, especially in those with left ventricular hypertrophy (LVH), CAD, or HF. In addition, high doses of thiazide diuretics commonly used to treat HTN, may result in electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia), contributing further to arrhythmias, while effective blood pressure control may prevent the development of the arrhythmias such as AF. In recognizing this close relationship between HTN and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology (ESC) Council on Hypertension convened a Task Force, with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE), with the remit of comprehensively reviewing the available evidence and publishing a joint consensus document on HTN and cardiac arrhythmias, and providing up-to-date consensus recommendations for use in clinical practice. The ultimate judgment on the care of a specific patient must be made by the healthcare provider and the patient in light of all individual factors presented. This is an executive summary of the full document co-published by EHRA in EP-Europace.

Preamble

Hypertension (HTN) is a common cardiovascular risk factor (CVRF) and underlies many cardiovascular (CV) conditions, including heart failure (HF), coronary artery disease (CAD), stroke, and chronic renal failure (CRF). Hypertensive heart disease may manifest as various cardiac arrhythmias, most commonly atrial fibrillation (AF). Both AF and HTN individually contribute to an increased stroke risk, which is further accentuated when both are present in combination. Both supraventricular arrhythmias and ventricular arrhythmias may occur in the HT patients, especially when associated with left ventricular hypertrophy (LVH) or HF. In addition, some of the antihypertensive drugs commonly used to reduce blood pressure (BP), such as thiazide diuretics, may result in electrolyte abnormalities (e.g. hypokalaemia, hypomagnesemia), further contributing to arrhythmias, whereas effective control of BP may prevent the development of the arrhythmias such as AF.

In recognizing this close relationship between HTN and arrhythmias, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology (ESC) Council on Hypertension convened a Task Force, with representation from the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE), with the remit of comprehensively reviewing the available evidence and publishing a joint consensus document on HTN and cardiac arrhythmias, and providing up-to-date consensus recommendations for use in clinical practice. The ultimate judgment on the care of a specific patient must be made by the healthcare provider and the patient in light of all individual factors presented. This is an executive summary of the full document co-published by EHRA in EP-Europace.

Evidence review

This document was prepared by the Task Force with representation from EHRA, HRS, APHRS, and SOLAECE and peer-reviewed by official external reviewers representing EHRA, HRS, APHRS, and SOLAECE. Their members made a detailed literature review, weighing the strength of evidence for or against a specific treatment or procedure, and including estimates of expected health outcomes where data exist. In controversial areas, or with respect to issues without evidence other than usual clinical practice, a consensus was achieved by agreement of the expert panel after thorough deliberation

In contrast to guidelines, we opted for an easier and user-friendly system of ranking using ‘coloured hearts’ that should allow physicians to easily assess the current status of the evidence and consequent guidance (Table  1). This EHRA grading of consensus statements does not have separate definitions of the level of evidence. This categorization, used for consensus statements, must not be considered as directly similar to that used for official society guideline recommendations, which apply a classification (Class I–III) and level of evidence (A, B, and C) to recommendations used in official guidelines.

Table 1.

Scientific rationale of recommendations^a

Definitions where related to a treatment or procedure	Consensus statement instruction	Symbol
Scientific evidence that a treatment or procedure is beneficial and effective. Requires at least one randomized trial, or is supported by strong observational evidence and authors’ consensus (as indicated by an asterisk)	‘Should do this’
General agreement and/or scientific evidence favour the usefulness/efficacy of a treatment or procedure. May be supported by randomized trials based on a small number of patients or which is not widely applicable	‘May do this’
Scientific evidence or general agreement not to use or recommend a treatment or procedure	‘Do not do this’

^aThis categorization for our consensus document should not be considered as being directly similar to that used for official society guideline recommendations which apply a classification (I-III) and level of evidence (A, B and C) to recommendations.

Thus, a green heart indicates a ‘should do this’ consensus statement or indicated treatment or procedure that is based on at least one randomized trial, or is supported by strong observational evidence that it is beneficial and effective. A yellow heart indicates general agreement and/or scientific evidence favouring a ‘may do this’ statement or the usefulness/efficacy of a treatment or procedure. A ‘yellow heart’ symbol may be supported by randomized trials based on a small number of patients or which is not widely applicable. Treatment strategies for which there is scientific evidence of potential harm and should not be used (‘do not do this’) are indicated by a red heart

Pathogenesis of arrhythmias in hypertension—a brief overview

Haemodynamic changes, neuroendocrine factors, atrial and ventricular structural remodelling (i.e. myocardial fibrosis), and a proarrhythmogenic electrophysiologic phenotype of a hypertrophied left ventricle, and prolonged QTc interval all contribute to the complex pathophysiology of arrhythmogenesis in HTN.¹

Atrial fibrillation is the most frequent arrhythmia in hypertensive patients and HTN is the most prevalent co-morbidity in patients with AF. Poor BP control seems to worsen outcomes in AF via left ventricular diastolic dysfunction [where associated HF is present, this is referred to as ‘HF with preserved ejection fraction (HFpEF’], left atrial overload and remodelling. Atrial fibrillation is also related to the circadian rhythm of BP whereby a blunted nocturnal fall increases the occurrence of AF, perhaps due to the sustainability of high BP and the resultant hemodynamic burden on the left atrium.²

Myocardial changes induced by HT have been described in detail.³ Mechanical overload due to high BP may induce an abnormal expression of ion channels and/or junctional complexes, such as connexin 40 and connexin 43, which can enhance myocardium vulnerability by triggering focal ectopic and re-entry activity.⁴ Activation of the renin-angiotensin-aldosterone system (RAAS) is strongly implicated in the development of AF. AF may also induce microvascular dysfunction in the ventricles.⁵ Angiotensin II promotes fibrosis via AT1 receptors by increasing the synthesis of TGF-beta1 in the atria and ventricles, as well as the release of growth factors and inflammation mediators such as IL-6.⁶ Structural remodelling results in disruption of the myocardial cell bundles and heterogeneity in intra-atrial conduction creates a substrate for multiple re-entrant circuits which helps perpetuate the triggered AF. Aldosterone-induced oxidative stress and inflammation is an ‘add on’ effect of RAAS favouring atrial structural and electrical remodelling. Moreover, atrial fibrosis has been shown to create a thrombogenic milieu which may underlie thromboembolic events even in the absence of AF.^7,8

Left ventricular hypertrophy is also the major determinant of the development of ventricular arrhythmias and sudden cardiac death (SCD) in hypertensive patients. Activation of the sympathetic nervous system and RAAS are important components of the pathophysiology and development of LVH (Figure  1). Sympathetic activation may trigger ventricular arrhythmias.⁹ Prolongation and dispersion of repolarization is another feature of the pro-arrhythmogenic impact of LVH.^10,11 Nocturnal arrhythmias, including sinus arrest, second-degree AV block, ventricular premature beats (VPBs) and non-sustained ventricular tachycardia (NSVT) have been reported in up to 50% of sleep apnoea patients. Sleep apnoea is known to predispose to the development of AF. About 50% of sleep apnoea patients are hypertensive,¹² and about 30% of hypertensive patients also have sleep apnoea.^13,14

Figure 1.

Mechanisms of arrhythmias in hypertension. LA, left atrium; LVH, left ventricular hypertrophy; RAAS, renin-angiotensin-aldosterone system.

At the cellular level, structural remodelling induced by HT is associated with impaired cell-to-cell communication at gap junctions, and is the basis of non-homogenous impulse propagation and re-entrant ventricular arrhythmias.^7,15 Left ventricular hypertrophy is also a source of myocardial ischaemia due to the mismatch of oxygen supply and demand, which may trigger of ventricular arrhythmias and SCD in some cases.^1,11,16

Supraventricular arrhythmias

Supraventricular ectopics

Studies show that supraventricular ectopics (SVPBs) and VPBs occur frequently in hypertensive patients with LVH.¹⁷ A non-dipping profile (nocturnal BP reduction <10% vs. diurnal BP) and increased nocturnal BP are markers of more advanced target organ damage; thus, non-dipping is commonly associated with arrhythmias.¹⁸

Recovery from exercise may be another triggering factor for SVPBs and the subsequent occurrence of AF.¹⁹ Patients with excessive SVPBs and LVH have a greater risk of developing AF, which is associated with increased age, SBP, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels.²⁰ Interestingly, stroke was commonly the first clinical presentation, beyond manifest AF in these study subjects. Even short runs of 20–50 SVPBs are associated with AF or some cryptogenic stroke events and ischaemic stroke.²¹

Consensus statements		References
Patients with frequent SVPBs and LVH have a higher probability of AF, and prolonged ECG monitoring to detect AF may be used		20
Lifestyle changes may be introduced in the management of most patients with SVPBs, including addressing precipitants relevant to some patients (e.g. alcohol, caffeine) and optimizing BP control, especially in patients with LVH		17

ECG, electrocardiogram.

Atrial fibrillation

Due to its high prevalence in the general population, HTN is the most significant population-attributable risk for AF and has been estimated to be responsible for 14% of all AF cases.²² HTN was present in >70% of AF patients in epidemiological studies²³ and recent AF real-world registries,²⁴ and in 49–90% of patients in randomized AF trials.²⁵ An increased AF risk was also reported in individuals with upper normal BP.²⁶

Hypertension has been identified as an independent risk factor for incident AF²⁷ or AF progression,²⁸ AF-related stroke, silent lacunar infarcts and mortality,²⁹ and bleeding complications of oral anticoagulant therapy in AF patients,³⁰ and a contributor to an increased risk of poor quality of treatment with vitamin K antagonists, as predicted by the SAMe-TT₂R₂ score.³¹ AF may be asymptomatic in up to 35% of patients (including those with symptomatic AF episodes),³² particularly in patients with less comorbidity (e.g. with HTN only).³³

Consensus statements		References
AF should be considered as a manifestation of hypertensive heart disease, and HTN management should be optimized		22 , 26
Given that stroke prevention is central to the management of AF patients, the detection of HTN and good BP control should be made to minimize the risk of stroke and thromboembolism, and the bleeding risk of patients on antithrombotic therapy		29

Supraventricular tachycardia

Left ventricular hypertrophy is the most important predictor for supraventricular arrhythmias. In a recent meta-analysis of 10 studies with 27 141 patients the incidence of supraventricular tachycardia (SVT) (especially atrial tachycardia, AF or flutter) in patients with LVH was 11.1% compared with 1.1% in patients without LVH (P < 0.001).³⁴ Patients with LVH have a 3.4-fold greater odds of developing SVT [odds ratio (OR) 3.39; 95% confidence interval (CI), 1.57–7.31] than those without LVH.³⁴

Other arrhythmias

Bradyarrhythmias

Drug-related

While dihydropyridine calcium channel blockers (CCBs) combine well with β-blockers in the management of HTN, caution should be exercised when combining non-dihydropyridine CCBs with beta-blockers.³⁵ There is a risk of bradycardia and AV block with non-dihydropyridine CCBs, particularly with verapamil, but also with diltiazem at higher doses.^36,37

In patients with chronic kidney disease, the accumulation of beta-blockers or active metabolites could exacerbate concentration-dependent side effects, such as bradyarrhythmias.³⁸

Sick sinus syndrome and atrioventricular conduction disturbances

The association of LVH with bradyarrhythmias, including complete atrioventricular block and symptomatic sick sinus syndrome requiring permanent pacemaker implantation, has been observed in several studies.^39,40 Thus, AV conduction disturbances may occur in hypertensive patients with LVH and sinus node dysfunction may occur. Both conditions may be encountered in the subgroup of hypertensive patients with sleep-disordered breathing.⁴¹

In these situations, the electrophysiological properties of the sinus node and AV conduction system in obstructive sleep apnoea (OSA) patients with nocturnal bradyarrhythmias are usually normal while awake, and thus the primary therapy of bradyarrhythmias in the setting of sleep apnoea and normal AV conduction should be the treatment of OSA with continuous positive airway pressure, which can reverse these bradyarrhythmias and reduce BP.⁴¹

Intra- and interatrial/inter- and intra-ventricular conduction delays

Interatrial and intra-atrial conduction delays have been reported to be longer in patients with HTN compared with controls.⁴² In HTN with LVH on ECG, left bundle branch block (LBBB) and fragmented QRS identifies patients at increased risk of CV mortality, SCD, and HF.⁴³

Elevated resting heart rate in sinus rhythm

A high resting heart rate (HR) has been associated with an adverse prognosis in patients with CAD and HF.⁴⁴ In HTN patients free from other overt cardiac disease this is less clear, and an elevated resting HR in these patients seems to be more of a risk marker than a risk factor.⁴⁵

A resting HR >80–85 bpm may be used as a guide to investigate for occult HF symptoms by clinical examination or determination of biomarkers (such as BNP) or by echocardiogram, or searching for associated comorbidities, such as arrhythmias (e.g. AF and atrial flutter), anaemia, hyperthyroidism, and sepsis.⁴⁶

In AF, rate control should initially aim for a HR <110 bpm, with stricter rate control if symptomatic or LV function deteriorates.⁴⁷ The beneficial effects of beta-blockers on outcomes may be less apparent in patients with AF and reduced LV systolic function.⁴⁸

Consensus statements		References
Sinus node and AV conduction disturbances (particularly in patients with LVH) may occur in HTN patients as a consequence of sleep apnoea, and sleep disordered breathing is more common in these patients. Thus, HTN patients should be assessed for these conditions.		39–41
Conduction delays occur both at the atrial and ventricular level in HTN patients, particularly those with LVH leading to AF or SCD. LBBB in HTN, especially with LVH, identifies patients at increased cardiovascular risk. Thus, HTN patients should be assessed for these conditions.		42
An increased resting heart rate (>80–85 bpm), portends an adverse prognosis, not only in patients with CAD and HF but also in HTN patients. Routine HR lowering using beta-blockers or other agents may be considered in HTN subjects uncomplicated by other comorbidities (e.g. impaired LV function).		44

Proposal for a standardized ‘workup’

In most patients with HTN and suspected arrhythmias, all efforts should be made to obtain a diagnosis by documenting the arrhythmia.

Regular SVTs, including atrioventricular nodal re-entrant tachycardia, atrioventricular re-entrant tachycardia, atrial flutter, and focal atrial tachycardia may lead to severe symptoms in patients with HTN, in whom curative treatment with catheter ablation as well as medical therapy may have high success and low-complication rates.⁴⁹

The increasing evidence that silent AF is associated with a higher stroke risk⁵⁰ has led to a recommendation of ‘opportunistic screening’ for AF using pulse-taking or ECG in the most recent guidelines.⁵¹ This recommendation is clearly also valid in HTN patients because they are at greater risk of stroke, although further research is needed to define best practice for younger patients with HTN and asymptomatic organ damage.⁵²

A number of studies suggest that lower BP goals reduce the frequency of episodes with paroxysmal SVT.^5,6 Lifestyle changes reducing the BP and AF burden may also contribute.⁵³

The order and type of workup of patients with arrhythmias and HTN depends on various factors including the duration and severity of symptoms, the frequency of episodes and the potential therapeutic implications. A proposal for a standardized initial work up is shown in Figure  2. With a CHA₂DS₂-VASc score ≥2 (i.e. ≥2 stroke risk factors) there is sufficient risk to either consider or recommend stroke prevention in patients with AF or suspected AF on the basis of (prolonged) AHRE.

Figure 2.

Proposal for a standardized initial work up in patients with arrhythmias and hypertension depending on the duration and severity of symptoms, the frequency of episodes and the potential therapeutic implications.

As a final step, 30-day event monitoring or an implantable cardiac monitor may be used to detect rare arrhythmias. The optimal cut-off for the definition of device-detected AF however, currently remains elusive; a 6-min cut-off is the mostly widely used, based on the findings of the ASSERT trial (ASymptomatic AF and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing).³² Closely connected to this is the question of the necessary AF burden to initiate anticoagulation, but a >5–6 min burden is generally considered as ‘significant’. Finally, the use of new technology that may be incorporated into a smartphone may be another option for recording an infrequent arrhythmic event or detecting silent AF.⁵⁴

Consensus statements		References
Silent AF is common, and opportunistic screening for underlying AF should be made in HTN patients. In HTN patients with symptoms suggestive of a cardiac rhythm disorder, the presence and type of arrhythmia should be documented for adequate management of the arrhythmia.		52 , 53

Management approaches

As seen in Figure  3, the management of patients with HTN and SVT is primarily driven by the type of arrhythmia. HTN should be proactively managed, with the type of treatment determined by associated compelling indications and/or comorbidities.⁵⁵ In general, RAAS blockade with ACE inhibitors or angiotensin II receptor blockers (ARB) should be considered in patients with LVH.

Figure 3.

Proposed algorithm for management of patients with hypertension and supraventricular tachycardia.

Supraventricular tachycardia

For the acute management of SVT, patients are treated like patients with no HTN according to published guidelines.⁵⁶ Vagal manoeuvres or intravenous adenosine are recommended as initial therapy.⁵⁷ In hemodynamically unstable patients, synchronized cardioversion is recommended.⁵⁸ Intravenous diltiazem, verapamil, or beta-blockers are recommended for patients with hemodynamically stable patients.⁵⁷ Intravenous esmolol is especially useful for short-term control of SVT and HT.⁵⁹

Catheter ablation is the first choice therapy for the management of more chronic management of SVT.^58,60 Similarly, focal ectopic atrial tachycardia can usually be treated by ablation. For patients who refuse catheter ablation, possible options in symptomatic patients without ventricular pre-excitation during sinus rhythm include oral beta-blockers, diltiazem, or verapamil. Flecainide, propafenone, or sotalol are reasonable choices in patients without structural heart disease (e.g. severe LVH) who have symptomatic SVT and are not candidates for, or prefer not to undergo, catheter ablation.⁵⁸

Atrial fibrillation

The priority in the treatment of patients with AF is stroke prevention.^51,61 The default is to offer oral anticoagulation (OAC) to all AF patients except for those at low risk (defined as a CHA₂DS₂-VASc Score 0 in males, 1 in females).⁶² Thus, the initial step is to identify ‘low risk’ patients in whom no antithrombotic therapy is recommended, following which OAC can be considered for those with ≥1 additional stroke risk factors.⁶² Even a single stroke risk factor confers excess risk of stroke and mortality, and the net clinical benefit of treating these patients is positive.⁶³

Uncontrolled HTN (e.g. SBP >160 mmHg) and other modifiable risk factors (e.g. concomitant aspirin or non-steroidal anti-inflammatory drug treatment, excessive alcohol use) should be addressed to minimize the risk of bleeding.⁶⁴

Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred treatment modality over vitamin K antagonists for anticoagulation,⁶¹ based on the results of four independent large-scale clinical trials.⁶⁵ Subgroup analyses in patients with HTN have mostly been consistent with the main outcome of the trials. ⁶⁶ The use of aspirin for stroke prevention in AF is associated with minimal efficacy but has a substantial bleeding risk; thus, aspirin is therefore no longer recommended.⁶¹

Persistent as well as permanent AF is common in elderly hypertensive patients, often associated with HfpEF, where rhythm control may not be an option. A beta-blocker or non-dihydropyridine calcium blocker may be considered for rate control in these patients, although RAAS blockade may aid LVH regression. Digoxin may be a second-line option.

Atrial fibrillation ablation has emerged as an effective method for the treatment of AF. In paroxysmal AF with normal sized atria, long-term freedom from symptoms can be achieved in up to 80% of patients, but may require multiple procedures.⁶⁷ In patients with persistent AF and diseased atria, long-term success rates are substantially below 70%.⁶⁷

Consensus statements		References
Oral amiodarone should be used for ongoing management in patients with symptomatic SVT who are not candidates for, or prefer not to undergo, catheter ablation and in whom beta blockers, diltiazem, flecainide, propafenone, sotalol, or verapamil are ineffective or contraindicated.		56–58 , 68
The priority in the treatment of patients with AF is stroke prevention, and AF patients with HTN have a CHA2DS2-VASc score of at least 1; thus, effective stroke prevention may be considered with OAC in addition to good BP control. With additional stroke risk factors, and a CHA2DS2-VASc score ≥2, OAC should be used, as well as controlled VKA (TTR >70%) or non-vitamin K antagonist oral anticoagulants (NOAC), with a preference for the latter.		63
Bleeding risk should be assessed with a focus on modifiable bleeding risk factors, most of which may be identified using the HAS-BLED score.  – The HAS-BLED score should be used to identify ‘high risk’ patients (score ≥3) for more careful review and follow-up, and to address reversible bleeding risk factors (e.g. uncontrolled HTN). A high HAS-BLED score alone is not a reason to withhold OAC.		64 , 69
AF ablation should be used in hypertensive patients with symptomatic recurrences of AF on antiarrhythmic drug therapy who prefer further rhythm control therapy, and is the first therapy in selected individuals as an alternative to antiarrhythmic drug therapy depending on patient choice, benefit, and risk.  – In patients with re-entrant SVT and isthmus dependent flutter, catheter ablation should be used as it has high success and low complication rate.		70
In patients with severe structural heart diseases, such as severe LVH, a history of myocardial infarction and HF, or hemodynamically-significant valvular disease, do not use flecainide or propafenone. Do not use sotalol in LVH patients, or diltiazem and verapamil in HfrEF patients.		71

Ventricular arrhythmias

Ventricular ectopics

Ventricular arrhythmias are common in HTN patients and this association may have important clinical implications.^34,72–74 High BP is not arrhythmogenic per se but may induce ventricular overload. Ventricular arrhythmias are commonly observed in aortic stenosis, even when peripheral BP is low; the frequency of these arrhythmias has been shown to be reduced after transcatheter aortic valve implantation.⁷⁵

Ventricular tachycardia, ventricular fibrillation, and sudden death

Hypertension is a risk factor for SCD, particularly in the context of increased LV mass.⁷⁶ Left ventricular hypertrophy is associated with a long-term risk of SCD independent of BP, and the risk of SCD increases progressively with LV mass.⁷⁷

There is evidence that optimal BP control and regression of LVH by antihypertensive treatment can help prevent cardiac arrhythmias.^78,79 Although an effect on the burden of ventricular ectopy has not been consistently observed even in the context of LVH reversal,⁸⁰ a reduced incidence of SCD has been demonstrated with effective BP control and LVH regression.⁸¹

However, the potential influence of antihypertensive drugs on the risk of SCD should be considered. Thiazide diuretics have been associated with an increased risk of cardiac arrhythmias, with a dose-dependent increase in SCD.⁸² Although the exact mechanism is unknown, hypokalaemia may be involved, with increased risk for QT prolongation, QT dispersion, and a propensity for arrhythmogenic early and delayed after depolarizations.⁸³ Although BP lowering itself may be important in affecting the SCD risk⁸⁴ in patients with HTN and diabetes blockade of the RAAS seems superior to other strategies to prevent SCD.^85,86

Proposal for a standardized ‘workup’

Frequent NSVT or single VPBs in patients with HTN are treated similarly to those found in patients without HTN. A 12-lead ECG and a 24-h Holter recording may help potentially localize site(s) of origin and quantify VPBs. Transthoracic echocardiography may be useful to assess other signs of hypertensive or structural heart disease and left ventricular systolic function. The latter is particularly important to identify, especially when a high VPB burden, defined as >20% of all beats in a 24-h recording, is documented.⁸⁷ If underlying coronary disease is suspected, with frequent VPBs, associated symptoms, or LV systolic dysfunction, exercise testing may be useful to assess the effect on VPBs and evaluate the presence of myocardial ischemia (Figure  4).

Figure 4.

Proposal for a standardized workup . Only in rare cases does myocardial biopsy change management, and the benefit:risk of this is low. Consider ICD implantation if LVEF <35% despite goal-directed medical therapy and sustained HTN control.

Since the presence and number of VPBs may be modulated by many factors, a blood biochemistry profile, including electrolytes (potassium, magnesium, calcium), renal function, thyroid function and glucose should be made. Moreover, it is necessary to review prescriptions and over-the-counter agents that may lengthen the QT interval or induce sympathetic stimulation, particularly if LVH is evident on ECG or echocardiography.⁸⁸ Excessive intake of alcohol or caffeine or other non-pharmacologic stimulants and recreational drug use should be investigated and corrected appropriately. Identification of chronic exposure to high-stress conditions is important in order to counsel avoidance or ways to mitigate the stress, in view of the facilitating effect of adrenergic stimulation on arrhythmogenesis.

Consensus statements		References
Frequent VPBs, couplets, or non-sustained ventricular arrhythmias require a careful clinical history and examination, blood chemistry, a 12-lead ECG, and a 24-h Holter recording.		72 , 73
Transthoracic echocardiography should be used to assess HTN patients with arrhythmias for signs of hypertensive or structural heart disease.		34
Findings of frequent VPBs and/or NSVT should lead of investigation for structural heart disease, including transthoracic echocardiography or cardiac MRI.		88
Exercise testing or other functional testing for ischaemia may be used for patients with suspected coronary disease and frequent VPBs or associated symptoms, both to assess suppression or worsening of VPBs and to evaluate the presence of myocardial ischaemia. Further non-invasive testing or coronary angiography may be used if required.		87
Serological studies, including electrolyte levels, glucose, and thyroid studies may be used to assess reversible, secondary causes of increased ventricular ectopy.		88
Identification of non-prescription or non-pharmacologic sources of increased adrenergic stimulation, including intake of alcohol, caffeine, and other stimulants including recreational drugs, should be documented in the history in order to provide appropriate counselling and/or help as needed.		88

Management approaches

Management approaches for ventricular arrhythmias in HTN patients may vary widely based on the primary presentation. The most common ventricular arrhythmias associated with HTN are VPBs, although NSVTs have also been observed and can affect the prognosis, particularly in the context of LVH.⁸⁹

Although a direct relationship between VPB reduction and antihypertensive treatment has not been clearly shown, a reduced fatal ventricular arrhythmia event risk has been demonstrated, and efforts to control BP remain important. Beta blockers seem to be inferior to other major antihypertensive drug classes in reducing LV mass and the major CV event risk.^90,91 However, other studies have indicated overall benefit in SCD reduction with BP lowering, regardless of drug class, and have demonstrated additional benefit with the use of beta-blockers in patients with concomitant CAD.⁹² There is also agent-specific evidence of SCD reduction using ACEI or ARB, which appears to be independent of BP reduction.^85,92 Thus, ACEI and ARB are also recommended in HTN patients at high risk for SCD.

Patients with HT-induced LVH may have greater QTc dispersion, particularly in the context of hypokalaemia.⁸⁸ A relationship between QT and RR intervals has been observed in hypertensive patients with LVH, which is similar to other conditions with proarrhythmic potential, including subsets of long QT syndrome.¹¹ Thus, avoiding marked hypokalaemia or anything that prolongs repolarization time may be important.

In asymptomatic HTN patients with normal LV systolic function and non-sustained ventricular arrhythmias, there is no role for the prophylactic use of antiarrhythmic drugs.

Antiarrhythmic drugs, e.g. class IC agents such as flecainide, are not recommended, especially where structural heart disease, such as severe LVH or LV systolic dysfunction, is evident. In addition to beta-blockers and ACEi or ARB, catheter ablation should be considered in these patients, as well as an implantable cardioverter defibrillator (ICD).⁹³ Similarly, in patients with a low ejection fraction and persistently high frequency of ventricular ectopic beats (>15–20% of total beats in a day, or >10 000 PVCs/24 h) and/or associated symptoms, antiarrhythmic drugs (e.g. beta-blockers, amiodarone) or catheter ablation should be considered to potentially reverse tachycardia-induced cardiomyopathy.⁹⁴

Finally, achieving adequate BP control and promoting LVH regression is a central management goal and any combination of antihypertensive drug classes should be considered as needed to achieve this goal, with the considerations as discussed above. In the context of persistently-severe LV systolic dysfunction (EF <35%) despite adequate medical management, including BP control, ICD implantation should be considered, although in the absence of CAD the prognostic benefit is not evident.^95,96

Consensus statements		References
Achieving and maintaining adequate BP control should be a priority when managing patients with HT and ventricular arrhythmias, especially those with severe LV systolic dysfunction (EF < 35%)		80 , 85 , 92
Beta-blockers should be used for the management of HTN in the setting of CAD and HF		92
ACE inhibitors and ARB should be used for HTN management in patients at high risk for SCD		85 , 92
Avoiding hypokalaemia or QT-prolonging drugs should be a priority in the context of HTN and LVH		11 , 88
In patients with sustained ventricular arrhythmias or frequent non-sustained ventricular arrhythmias with LV systolic dysfunction  – Treatment with beta-blocker, MRA and sacubitril/valsartan reduces the risk of sudden death and should be used in patients with HFrEF and ventricular arrhythmias Catheter ablation, and/or ICD implantation should be used in addition to antihypertensive therapy		95
An ICD should be used to reduce the risk of sudden death and all-cause mortality in patients who have recovered from a ventricular arrhythmia causing haemodynamic instability, and who are expected to survive for >1 year with good functional status  – In persistent, severe LV systolic dysfunction, despite adequate BP control and other HF management, with frequent VPBs in patients thought to have a PVC induced cardiomyopathy, ICD implantation may be used, if significant ischaemic heart disease is evident An ICD should be used to reduce the risk of sudden death and all-cause mortality in patients with symptomatic HF (NYHA Class II–III), and an LVEF ≤35% despite ≥3 months of OMT, provided they are expected to survive substantially longer than one year with good functional status, and they have: (i) IHD (unless they have had an MI in the prior 40 days and (ii) dilated cardiomyopathy		95
Antiarrhythmic drugs should not be used routinely in patients with HF and asymptomatic ventricular arrhythmias due to safety concerns (worsening HF, proarrhythmia, and death)		96

Complications related to arrhythmias and hypertension

Heart failure

Hypertension is one of the most common causes of HF and antihypertensive therapy markedly reduces the incidence. About half of all HF patients present a reduced ejection fraction. In general, AF is predicted by the same risk markers predicting HF, including target organ damage.⁹⁷ In the context of HTN, the association with HFpEF is particularly important because the LV filling pattern is always abnormal, requiring a greater atrial contribution.⁹⁸ Although uncontrolled HTN is certainly a trigger for AF, consolidated organ damage is the hallmark of risk.⁹⁷ Thus, attention should be paid to the global management of risk (including metabolic factors and obesity) in addition to the aggressive antihypertensive therapy that is always required.

A rate control strategy is mandatory in persistent/permanent AF to facilitate LV filling, and is obtained more frequently using cardiospecific beta-blockers.⁴⁷ An uncontrolled HR may lead to tachycardia-induced cardiomyopathy, with LV dilatation and impairment. In patients with systolic HF, the combination of digoxin and a beta-blocker could be effective. In patients with HFpEF, non-dihydropyridine CCBs could be an alternative to beta-blockers. In patients with chronic HF, a rhythm-control strategy has not been demonstrated to be superior to a rate-control strategy in reducing mortality or morbidity. In acute HF, emergency cardioversion may be required due to hemodynamic instability.

Postural hypotension

Postural (orthostatic) hypotension is usually defined as drop of 20 mmHg in SBP or 10 mmHg in DBP within 2–5 min of standing up, and with light-headedness lasting a few seconds to several minutes.⁹⁹

Orthostatic hypotension (OH) is common in elderly HTN patients, with a reported prevalence ranging from 6% to 30%. Due to its association with an increased risk of falling, OH in elderly patients with HTN and AF may inappropriately prevent the use of OAC for stroke prevention. Hypertension itself and commonly used antihypertensive drugs increase the incidence of OH. The risk for OH increases with ageing and diabetes due to slower baroreceptor function, impaired cardiac performance, and stiffer arteries.¹⁰⁰ Some antihypertensive and cardiodepressant medications (e.g. diuretics, alpha and beta blockers, CCBs, RAAS blockers and nitrates), drugs for Parkinson’s disease, and certain antidepressants and antipsychotics may increase the risk of OH.¹⁰¹

Thromboembolism and bleeding risk, including safe use of antithrombotic therapy in hypertension

Increased BP (SBP >130 mmHg or a diagnosis/history of HTN) doubles the risk of stroke in patients with AF.¹⁰² Oral anticoagulation/oral anticoagulant with VKAs or NOACs reduces the stroke risk and mortality in AF¹⁰³ but their benefit must be balanced against the risk of OAC-related major bleeding (especially ICH, due to its high-fatality rate)¹⁰⁴ because uncontrolled HTN (but not a diagnosis/history of HTN) increases the bleeding risk.¹⁰⁵

Optimal BP control is crucial for both stroke and bleeding risk reduction in AF patients taking OAC. Available evidence from randomized trials clearly shows a substantial increase in stroke risk (including both ischemic and haemorrhagic stroke) at SBP values >140 mmHg in AF patients taking warfarin.¹⁰⁶ In a post  hoc analysis of the ARISTOTLE (Apixaban for Reduction In STroke and Other ThromboemboLic Events in Atrial Fibrillation) trial, elevated BP (SBP ≥140 mmHg and/or DBP ≥90 mmHg) at any point during the trial was associated with an increased risk of stroke or systemic embolism (HR 1.53; 95% CI 1.26–1.86), haemorrhagic stroke (HR 1.85; 95% CI 1.26–2.72) and a composite of major and clinically relevant non-major bleeding (HR 1.14; 95% CI 1.01–1.28) in both treatment arms (i.e. apixaban or warfarin), while a history of HTN was significantly associated with increased stroke but not major bleeding.

Patients with uncontrolled HTN, defined as a SBP ≥170–180 mmHg and/or DBP ≥100 mmHg, were excluded from all four NOAC trials, while HTN, defined as the use of antihypertensive medications¹⁰⁷ (or persistent SBP >140 mmHg or DBP>90 mmHg),¹⁰⁸ was present in 78.8–93.7%^108,109 of participants. Most AF guidelines now favour the use of NOACs over VKAs (Figure  5).³¹

Figure 5.

Proposed algorithm for antithrombotic management of patients with hypertension and non-valvular atrial fibrillation. ASA, acetylsalicylic acid; NSAID, non-steroidal anti-inflammatory drug; OAC, oral anticoagulant; VKA, vitamin K antagonist; NOAC, non-vitamin K oral anticoagulant. SAMe-TT₂R₂, sex female, age 60 years, medical history (more than two comorbidities), treatment (interacting drugs, e.g. amiodarone for rhythm control), tobacco use (doubled), race (doubled); TTR, time in therapeutic range.

Given its high prevalence in AF patients, HTN may often be the single risk factor requiring a decision on OAC use, and data from contemporary real-world AF registries show that physicians often underestimate the significance of HTN as a stroke risk factor¹¹⁰ despite clearly positive net clinical benefit (the balance of stroke reduction against serious bleeding) of OAC in patients with ≥1 stroke risk factor in large contemporary AF cohorts.¹¹¹

A recent analysis showed that the threshold for OAC use at ≥1.7%/year annual stroke risk for VKAs should be decreased to ≥0.9%/year annual stroke risk with the safer NOACs.¹¹² Two recent analyses of large AF cohorts of untreated patients with one stroke risk factor reported annual stroke rates well above the NOACs threshold (1.55%¹¹³ and 2.55–2.75%¹¹⁴), and HT was associated with a significant increase in stroke risk [HR 1.71; 95% CI 1.48–1.98 (females), and 1.95; 95% CI 1.73–2.19 (males)].¹¹⁴ The presence of one stroke risk factor in untreated AF patients was associated with increased rates of stroke, bleeding and death,¹¹³ and warfarin use was associated with a positive net clinical benefit compared with no therapy or aspirin.⁶³ In clinical practice, shared informed decision-making is useful, as AF patients commonly attribute stronger value to the avoidance of stroke than the risk of bleeding.⁶³

Consensus statements		References
OAC should be used to reduce the stroke risk in most AF patients with HTN, including those with AF in whom HT is the single additional stroke risk factor Shared, informed decision-making on the risks and benefits of OAC therapy should be used, especially where HT is the single additional stroke risk factor		62 , 102
Well-controlled anticoagulation intensity (i.e. a TTR of ≥ 65–70%) should be used to achieve the optimal risk/benefit ratio with VKA therapy Compared with VKAs, NOACs offer additional safety benefits when there is good adherence to treatment		31 , 62
Optimal BP control should be used to minimize the risks of AF-related stroke and OAC-related bleeding. Until more data are available, target BP values in AF patients taking OAC should be < 140 mmHg SBP and <90 mmHg DBP OAC should be used with caution in patients with persistent uncontrolled HTN (SBP ≥180 mmHg and/or DBP ≥100 mmHg) but strenuous efforts to control BP should be made		62 , 105

Health economic considerations

Taking into account the risk of CV events linked to high BP, the costs of untreated or inadequately controlled HTN are of great relevance for any health care system.¹¹⁵ According to meta-regression analyses, for every 10 mmHg reduction in SBP the risk of major CV disease events is reduced by 20%, the risk of CAD by 17%, the risk of stroke by 27%, the risk of HF by 28% and the risk of all-cause mortality by 13%.¹¹⁶ The high prevalence of both HTN and AF and the increasing costs of their treatment are an important financial burden and therefore many economic analyses have aimed to assess the cost-effectiveness of treating these diseases.⁹⁰

For stroke associated with AF, the direct costs per patient are approximately 33% greater than the costs for stroke unrelated to AF¹¹⁷ and are in the range of €30 000 over a 2-year period for a severe ischemic stroke.¹¹⁸ In this scenario, the use of NOACs in patients with non-valvular AF has been found to be cost-effective.^119–121 In a series of cost effectiveness and cost-benefit analyses, the higher initial cost of NOACs compared with warfarin was offset by the reduction in intracranial bleeding and stroke prevention, making these agents cost-effective in the long-term.^119–121

Areas for further research

Many areas linking HTN and cardiac arrhythmias merit additional clarification and further study. While perhaps rather selective, some areas of uncertainty are summarized as follows:

• How different circadian BP profiles, particularly blunted nocturnal BP, influence the presence of different arrhythmias.

• Detection and management of HTN patients with silent AF to prevent stroke risk, and whether the use of OAC in patients with HTN and silent AF results in a meaningful stroke reduction.

• Antihypertensive drugs and regression of myocardial fibrosis in patients with HTN and LVH.

• Primary prevention of arrhythmias in patients with uncomplicated HTN: Is there a preferred antihypertensive drug or combination?

• Optimal antihypertensive treatment in patients with HF and preserved ejection fraction.

• Optimal BP targets in patients with HTN and OAC therapy.

• AF management in asymptomatic cases detected by remote monitoring by implantable cardiac devices.