Introduction

Hypertension is a common clinical condition related to higher risk of stroke, heart failure, myocardial infarction, and renal disease [1, 2]. Despite successes in prevention and treatment, hypertension currently remains a major cause of morbidity and mortality [3]. It was estimated that in 2025, there will be approximately 1.5 billion adults with hypertension worldwide [4], which determines a huge importance in health and economics aspects considering that high blood pressure (BP) is one of the leading risk factors for global disease burden [5].

A considerable proportion of general hypertensive patients, estimated between 10 – 20 %, are defined as resistant hypertension (RHT), diagnosed when there is failure to reach office BP control despite using at least three anti-hypertensive medications in adequate dosages, ideally including one diuretic. Patients using at least four anti-hypertensive drugs to control BP also are considered RHT [6•]. These patients have higher prevalence of diabetes, dyslipidemia, physical inactivity, and sleep apnea [6•, 7–9], and develop more target organ damage (TOD) in the heart, brain, kidneys, and blood vessels when compared with patients with controlled hypertension [7, 10–14]. Consequently, they have a higher incidence of major cardiovascular events such as coronary artery disease, stroke, and heart failure [15••, 16, 17]. As was pointed out in a recent review, the relationships between cardiovascular disease and TOD can be bidirectional in RHT [18]. Persistently high BP is implicated in structural and functional changes leading to development of left ventricular hypertrophy, increased aortic stiffness, atherosclerotic plaques, microvascular disease, and renal dysfunction, and turns hypertension gradually more resistant to treatment [18]. It may sound redundant, but that is exactly the meaning: RHT aggravates RHT. The more severe and longer is the sustained hypertension, the worse will be TOD development. Reciprocally, with more established TOD, the worse will be the treatment resistance.

More recently, a new subgroup was defined called refractory hypertension. The term “refractory” was formerly used as a synonym of “resistant”, but Acelajado and colleagues used it to define an “extreme phenotype of anti-hypertensive treatment failure” [16]. In two previous studies, the prognosis of refractory hypertension could be evaluated. [17, 19••]. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) [20] is a longitudinal population-based study of 30,000 African-American and white adults aged > 45 years that looked for the causes for the excess stroke mortality in the Southeastern US and among African-Americans. In the analysis of patients from this study [19••], uncontrolled hypertension despite using at least five drugs, was related to higher cardiovascular risk. The other one, the Reduction of Atherothrombosis for Continued Health (REACH) registry [21], evaluated over 67,000 patients (>45 years) in 44 countries with at least 3 risk factors for atherothrombosis and/or established arterial disease. The main purpose of the study was to evaluate if cardiovascular risk factors present comparable patterns in different countries around the world. In this study, after a follow-up of 4 years, patients with refractory hypertension (using five or more anti-hypertensive drugs) had higher risk of CV mortality compared with those on three or fewer agents [17].

Despite pharmacological interventions, BP control in RHT patients remains challenging, and new interventional procedures, such as renal sympathetic denervation, have been recently been proposed and extensively discussed, although some doubts still remain regarding the sustained effect in decreasing BP and the possibility of reversing sub-clinical damage with prognostic impact on cardiovascular outcomes [22]. Although not fully established, it reopens the discussion whether we should have as aims of treatment (pharmacological or not) the regression of TOD, especially sub-clinical alterations, beyond and despite the BP goal to be achieved [23]. Because of the relevance of this topic, the objective of this review is to update data available related to RHT and TOD with emphasis on cardiovascular and renal complications, including sub-clinical damage and prognostic aspects.

Resistant Hypertension and Cardiovascular Complications

Left Ventricular Hypertrophy

Left ventricular hypertrophy (LVH) is a structural remodeling of the heart. The thickening of ventricle walls in response to pressure overload results in an increase of left ventricular mass (evaluated by left ventricular mass indexed to body surface area - LVMI). It is one of the most frequent cardiac complications due to persistent high BP levels. Assessed by echocardiography or electrocardiography, it is considered an asymptomatic TOD and equally a risk factor predictive of worse prognosis [2, 23, 24]. Based on updated criteria, the prevalence of echocardiographic LVH in RHT patients ranges from 55 to 75 % [6•, 8, 25], and may vary depending on the method used to calculate LV mass. The most recent definition of LVH is based on LVMI >115 g/m2 for men and >95 g/m2 for women [2, 26], but many studies used older values with LVMI > 125 and > 110 g/m2, obviously reducing the estimated prevalence.

Concentric hypertrophy (represented by a left ventricular wall-to-radius ratio of ≥0.42) is the most common type of LVH found in RHT [11, 18]. In previous studies with general hypertensives, concentric hypertrophy was more consistently associated with increased cardiovascular risk [2, 27] and with the degree of BP load [28]. LVH is also related to other TOD and cardiovascular markers of worse prognosis [8, 29]. In a cross-sectional study with 705 RHT patients, 534 with echocardiographic LVH, microalbuminuria, and high C-reactive protein were independently associated with LVH diagnosis [29].

When LVH is assessed by electrocardiography (ECG-LVH), although it has less sensitivity, it keeps its prognostic importance. The presence of ECG-LVH, usually detected by Sokolow-Lyon index (SV1+ RV5 or V6 > 35 mm) or by the Cornell voltage QRS duration product (>244 mV*ms-1), is an independent predictor of cardiovascular events in RHT patients [30••]. In a large study with RHT patients, using 24-h ambulatory blood pressure monitoring (ABPM), ECG- LVH criteria were fulfilled in 18.5 % of patients with true RHT [31••]. Studies conducted in a Brazilian cohort of RHT patients demonstrated an ECG-LVH prevalence varying between 26 to 29 % [30••, 32]. Although echocardiography has an obvious higher sensitivity to detect LVH than ECG, it was previously observed that some electrocardiographic alterations as QTc interval prolongation (>440 ms) and a Cornell product >240 mV*ms-1 were associated with increased risk of LVH measured by echocardiogram. When these two alterations are combined, the risk of a high LVMI increases about nine-fold [32]. Furthermore, these ECG measurements are cheaper and easily available, and it was demonstrated that the regression of these electrocardiographic abnormalities during treatment of RHT patients also can improve cardiovascular outcomes and may constitute additional therapeutic goals in RHT management [30••, 33, 34].

In addition, echocardiography provides information about left ventricular diastolic filling and diastolic function. Diastolic dysfunction is a very important condition closely related to hypertension, explaining about 50 % of heart failure occurrence. Most relevant, these alterations may occur in the absence of systolic dysfunction and even without LVH [2], and are associated with increased risk of cardiovascular events, independent from left ventricular mass and ambulatory BP [35]. However, there are no studies evaluating the prognosis of diastolic function in RHT.

Studies recently conducted in patients after renal sympathetic denervation have demonstrated that left ventricular mass and diastolic dysfunction can be reverted, independent from BP reduction, which may reveal a new bridge between cause-and-effect in TOD development [22]. Aldosterone levels and the effects of spironolactone were also evaluated in the regression of left ventricular mass, measured by cardiac magnetic resonance, in RHT patients. After 3 months of treatment, the authors demonstrated a higher reduction of left ventricular mass and volume, left atrial volume and wall thickness in high aldosterone patients compared to group with normal aldosterone levels [36].

Similarly, in a case-control study, patients with primary aldosteronism had significantly greater left ventricular measurements including LVMI compared with control group. High salt intake determined by 24-h urinary sodium excretion, was an independent predictor for left ventricular wall thickness and mass among these patients, but not in those with essential hypertension. In this way, aldosterone blockade associated with low salt-intake probably results in target organ protection and lower cardiovascular risk. [37]

These arguments sustain that not only the duration and degree of BP elevation, but other neuro-humoral factors, such as activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, are involved with myocardial hypertrophy pathophysiology [38].

Coronary Artery Disease

The prevalence of atherosclerotic coronary artery disease (CAD) varies in different series of RHT patients from 10 % [31••] to 37 % [8, 19••] and it seems to be directly associated with high BP [19••]. In a previous RHT cohort study [15••] in which 556 patients were evaluated after a median follow-up of 4.8 years, the crude incidence rate of total cardiovascular events was 4.32 per 100 patient-years of follow-up, with a total of 44 CAD events (23 acute myocardial infarction, 16 myocardial revascularization, and five sudden deaths). Evaluating the prognostic value of ABPM parameters, the presence of non-dipping pattern duplicated the risk of CAD events [39].

Regarding heart complications in RHT, many analyses have been recently published confirming the poor prognosis, mainly related to cardiac mortality. Three studies [17, 19••, 40] published in the last year have evaluated the higher cardiovascular risk in RHT patients compared with control or non-resistant patients. All studies analyzed data from large hypertensive populations (from the REACH study, the REGARDS study, and the International Verapamil SR-Trandolapril Study [INVEST]) using the traditional definition of RHT, and all of them have equally demonstrated a higher risk of adverse outcomes (including cardiovascular mortality, myocardial infarction, and stroke). INVEST is a randomized, open label, blinded endpoint study that enrolled 22,576 patients (>50 years) with hypertension and coronary artery diseases at 862 centers in 14 countries [41]. The study compared cardiovascular outcomes in patients treated with a therapeutic scheme including a calcium antagonist or not. In a post hoc analysis, it was demonstrated that patients with RHT (6,490 from a total of 17,190 patients) had a 47 % higher risk of cardiovascular mortality and 61 % higher risk for nonfatal stroke than patients with controlled BP. Moreover, nonfatal stroke was the only adverse outcome that differed in RHT patients compared to uncontrolled hypertensives [40]. In another study performed specifically in patients with coronary heart disease, 11.1 % of 10,001 individuals were considered as having “apparent treatment-resistant hypertension”. This group had a 69 % increased risk of coronary heart disease mortality and a 53 % higher risk of any cardiovascular event in comparison to the non-resistant subgroup [42].

Cerebral and Vascular Disease

The brain is the most notable of the target organs related to high BP; arterial hypertension is directly involved in the pathogenesis of stroke and dementia [43]. It was previously demonstrated that the risk of stroke increases continuously above BP levels of approximately 115/75 mmHg.

In RHT patients, these figures seem to be much higher. In a recent prospective evaluation, after a follow-up of 4 years, the risk of non-fatal stroke in the RHT group was 26 % higher than in the non-resistant group [17]. In the same study, it was demonstrated a higher risk associated with the numbers of anti-hypertensive drugs in use (higher in the group on at least five drugs) [17]. Another prospective study [15••] with more than 500 RHT patients showed that higher 24-h systolic and diastolic BP increased the risk of stroke in 42 % and 62 %, respectively, and the baseline diagnosis of true RHT triples this risk. Similarly, Calhoun and colleagues [19••] compared refractory hypertension (at least five drugs) with resistant hypertension (traditional definition, at least three drugs) and non-resistant hypertensive patients. The median Framingham 10-year coronary disease and stroke risk score for all patients with refractory hypertension was, respectively, 50 % and 28 % higher than the risk score for individuals with classic resistant hypertension and more than two-fold the risk score of all participants treated for hypertension. After adjustment for age, race, sex, and geographic region of residence in North America, the median 10-year predicted stroke risk was 8.1 % (95 % CI: 5.9–10.3) higher among those with refractory hypertension than in all treated hypertensive individuals [19••].

Otherwise, there were some subclinical markers of cerebrovascular disease, such as increased common carotid artery intima-media thickness (IMT ≥0.9 mm), with or without carotid plaques, presence of white matter lesions on brain magnetic resonance imaging (MRI), or increased central aortic stiffness (measured by carotid-femoral pulse wave velocity [PWV] >10 m/s), which may help to identify individuals at higher risk for stroke [2].

During the last decade, it had already been demonstrated that RHT patients had increased carotid IMT and higher prevalence of carotid plaques than non-resistant hypertensive individuals [11]. The European Lacidipine Study on Atherosclerosis (ELSA) [44], although not specifically in RHT, confirmed the relationships between increased carotid IMT and adverse cardiovascular outcomes. Curiously, the relation between any IMT measurement and stroke did not attain statistical significance in this study, probably because of the small number of incident strokes during follow-up (only 25 strokes).

More recently, a cross-sectional study with 42 RHT patients showed that cerebral microangiopathy, diagnosed by white matter lesions on MRI, in 19 patients was related to lower heart rate and higher nighttime systolic BP. Compared to 23 RHT patients without cerebral lesions, patients with cerebral microangiopathy had similar carotid IMT, but higher aortic stiffness [45].

Aortic Stiffness

Carotid-femoral PWV is the best indicator of increased aortic stiffness and its association with worse cardiovascular prognosis in several clinical conditions is consistently demonstrated, including in hypertensive patients, and particularly for stroke occurrence. [46]. In a large cross-sectional study [47] including 600 patients with RHT, we had previously reported that 168 patients (28 %) exhibited increased aortic stiffness; and that diabetes, microalbuminuria, low level of HDL-cholesterol, widened 24-h pulse pressure, and a blunted nocturnal BP fall were the covariates independently associated with increased aortic stiffness.

Recently, Muiesan and colleagues [18], in a review of their own data, evaluated the prevalence of simultaneous TOD in RHT, including the subclinical alterations discussed before. They analyzed 317 hypertensive individuals selected from a larger general population sample living in northern Italy and who were participating in an epidemiological study which investigated the association between cardiovascular risk factors and TOD (the Vobarno Study). RHT patients represented 9.5 % of the total sample or 17.3 % considering only those with treated hypertension (n = 173). Carotid IMT, aortic PWV, left ventricular mass, and renal function parameters were significantly more abnormal in RHT patients than in controlled hypertensive individuals. There was a high prevalence of carotid plaques observed in the entire population; nevertheless, it was significantly greater in the group of RHT patients (97 % vs. 83 %, p = 0.04). Increased aortic stiffness was found in 71 % of RHT group and 44 % of controls.

Nevertheless, none of the sub-clinical cerebrovascular TOD had yet their prognostic importance examined in patients with RHT, which is clearly needed to recommend their routine use in the clinical management of resistant hypertensives.

The principal findings of cardiovascular complications in RHT patients are summarized in Table 1.

Table 1 Studies performed in patients with resistant hypertension investigating the prevalence and/or incidence of major cardiovascular complications
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Resistant Hypertension and Renal Complications

Reduced glomerular filtration rate (GFR) (30 – 60 mL/min/1.73 m2) and microalbuminuria (MA) (30 – 300 mg/24 h) are considered asymptomatic organ damage used for cardiovascular risk stratification in general hypertensive subjects [2] and also in RHT patients [6•, 7, 8]. Its screening should be considered a routine procedure in the diagnostic approach of these patients [48], as it is known that MA is a reversible condition [2,49••,50] and can reduce cardiovascular risk.

Microalbuminuria

It is well-known that MA is more prevalent in patients with RHT [7, 10, 11, 14] than non-resistant hypertensives, and this prevalence is strongly associated with higher BP, such as in true uncontrolled RHT [49••, 50] and refractory RHT [19••]. Moreover, there is a high association between MA and other ABPM parameters related to a high cardiovascular risk such as increased nighttime systolic BP [51], enlarged pulse pressure, and non-dipper pattern [8]. A cross-sectional study in a large cohort of RHT patients showed that MA was independently associated with LVH occurrence [34] and with increased arterial stiffness [47].

Prospective studies also confirmed the prognostic importance of microalbuminuria in RHT patients [49••, 52••]. We evaluated prospectively 531 patients with a median follow-up of 4.9 years [49••], and found that baseline MA nearly doubled the risk of any fatal and non-fatal cardiovascular event occurrence and tripled the risk for cardiovascular mortality. Moreover, it was shown that the risk begins with albuminuria values lower than the classic MA cut-off (30 mg/24 h). This study also evaluated prognostic influence of changes in albuminuria during the follow-up, independent of ambulatory BP or serum creatinine changes. Patients who regressed MA, had a 27 % decrease in cardiovascular risk, while those who developed MA presented a 65 % greater CV risk. Recently, Oliveras and colleagues [52••] evaluated 133 RHT patients during a median follow-up of 73 months and observed that baseline MA was not a prognostic marker of fatal and non-fatal cardiovascular events, but persistence or new-appearance of MA predicts cardiovascular diseases. In this way, MA prevention and reduction may be a therapeutic target in RHT patients [49••, 52••].

Moreover, cardiovascular and renal effects of aldosterone excess seem to be dependent on high dietary salt intake. Pimenta et al [53] evaluated prospectively 84 RHT patients according their aldosterone status, sodium and protein excretion, and observed a positive correlation between protein and sodium excretion in patients with high 24-h urinary aldosterone, but not in patients with normal aldosterone status. These findings suggested that the combination of high dietary salt and aldosterone excess should increase urinary protein excretion.

Chronic Kidney Disease

The presence of chronic kidney disease (CKD), defined as an estimated GFR <60 mL/min/1.73 m2, is considered the strongest predictor of RHT [6•, 14, 17]. This is one of the well-established characteristics of patients with RHT [7, 14, 54], is associated with the severity of RHT [19••, 36], and also with other ABPM parameters known to be associated with worse prognosis, such as an adverse dipping pattern [8, 51]. Oliveras et al. [51] had shown a strong association between albuminuria and renal function impairment in RHT patients.

Recently, the REGARDS study [54], comparing 2,147 RHT patients and 7,827 patients without treatment-resistance during a follow-up of 6.4 years, showed that RHT presented an increased risk (6.32; 95 % CI: 4.30 – 9.30) for end-stage renal disease.

Our group evaluated [55••] prospectively 531 RHT patients (median follow-up 4.9 years) and showed that a GFR < 60 mL/min per 1.73 m2, either estimated by the Cockroft-Gault equation or by the MDRD formula, presented a incidence rate of fatal and non-fatal cardiovascular events significantly higher than patients with GFR > 60 mL/min per 1.73 m2 (6.13 vs. 3.54 and 5.88 vs. 3.05, respectively). A low GFR estimated by the MDRD formula was an important prognostic marker for cardiovascular events in the three stages of decreasing GFR compared with a GFR > 90 mL/min per 1.73 m2. Moreover, the combination of a reduced estimated GFR (<60 mL/min per 1.73 m2) and MA (>30 mg/24 h) tripled the risk of total cardiovascular events and all-cause mortality and quadrupled the risk of cardiovascular mortality. These results pointed to the importance of a different approach for RHT patients with CKD [56], focusing on persistent volume overload, more intensive renin-angiotensin-aldosterone system blockade, and nocturnal BP control. The principal findings of renal complications in RHT patients are summarized in Table 2.

Table 2 Studies performed in patients with resistant hypertension investigating the prevalence and/or incidence of renal complications
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In conclusion, resistant hypertension is an increasingly clinical condition that carries a high morbidity and mortality compared with patients with controlled hypertension. All efforts should be focused on achieving a better BP control, with a comprehensive diagnostic and treatment approach [48], including strategies to increase drug adherence, change in lifestyle, investigation of secondary causes of hypertension, and appropriate anti-hypertensive drug combination with emphasis on the use of diuretics (ideally chlorthalidone) and a mineralocorticoid receptor antagonist. Furthermore, BP control should be based on out-of-office blood pressure measurements, preferably by ABPM, during the whole follow-up. Moreover, the investigation of asymptomatic and established TOD is extremely necessary in this group of patients (Fig. 1). Such an approach may lead to cardiovascular and renal TOD regression and improved prognosis.

Fig. 1
figure 1

Diagnostic approach of patients with resistant hypertension

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