Hypertension-induced cardiovascular (CV) morbidity and mortality is caused by structural and functional alterations of the brain, heart, eyes, kidneys, and vasculature. Importantly, these hypertensive target organ damage (TOD) can be detected in an early subclinical stage, that is, as an asymptomatic and reversible stage of disease before fatal and nonfatal CV events occur. The classical score systems used to estimate the total CV risk do not take TOD into account because these score systems are only valid in hypertensive patients without TOD. Once TOD, even intermediate, has developed (e.g., decreased estimated glomerular filtration rate [GFR], left ventricular hypertrophy [LVH]), these conditions are by far overwriting any risk prediction from the CV risk factor scores. TOD represents an intermediate stage in the CV, cerebrovascular, and renal continuum and its progression depends on both the duration and severity of high blood pressure (BP). Although there is no doubt that arterial hypertension has an independent relationship on several TODs, the individual impact of hypertension is diverse. Hence, this chapter mainly addresses TODs with arterial hypertension being the most important attributable risk factor.
From a therapeutic perspective it is essential to treat hypertension at a stage when TOD changes are reversible, and to be aggressive to achieve BP control rapidly.
A variety of techniques are available nowadays to diagnose TOD in different organs but with differences in sensitivity and specificity. TOD can be routinely assessed in the clinical work up, but the applicability is limited depending on the availability of the various techniques and the reimbursement strategy of health care systems. The clinical importance of TOD is also underlined by the fact that TOD requires not only more aggressive and immediate drug therapy, but also by the clear perspective to reduce TOD and the associated risk. Thus, regression of TOD is clinically a useful tool for evaluation of the efficacy of antihypertensive treatment in individual patients. Therefore this chapter also emphasizes the consequences of TOD regression by antihypertensive treatment, and attempts to establish whether or not changes of TOD have related prognostic significance.
Target Organ “Brain”
In general, the brain is highly vulnerable to the deleterious effects of elevated BP and represents the classic target organ of BP-induced damage. Arterial hypertension, beyond its well-known effect to cause clinical (ischemic and hemorrhagic) stroke, is also associated with the risk of asymptomatic (subclinical) brain damage, such as cerebral small vessel disease (SVD). Widespread use of magnetic resonance imaging (MRI) applied to search for cerebrovascular and brain damage has limited availability (in some countries) and high costs in the evaluation of hypertensive patients, although silent brain infarction should be searched for in all hypertensive subjects with disturbances, cognitive impairment, and, particularly, memory loss.
Stroke
Stroke incidence has declined by over 40% in the past 4 decades in high-income countries, but over the same period, incidence has doubled in low-income and middle-income countries. Because age is one of most important risk factors for stroke it has been proposed that aging of the world population implies a growing number of persons at risk. The decline of stroke incidence in high-income countries is also thought to be related to better CV risk management. In Western countries about 80% of strokes are ischemic and the remaining 20% are hemorrhagic. This distinction between hemorrhagic and ischemic stroke is critical for stroke management and treatment decisions.
The main mechanisms causing ischemic stroke are thrombosis and embolism. Atherosclerosis is the most common feature, and a plaque rupture causes downstream ischemic stroke. Pathological conditions causing thrombotic ischemic stroke are high-grade stenosis of the internal carotid artery, fibromuscular dysplasia (FMD), arteritis (i.e., giant cell and Takayasu), and vascular dissection. Embolic stroke may occur as a result of embolization from a variety of sources (e.g., left atrium, mitral valve disease, atherothrombotic plaques in the aortic area), but the most common underlying cause is atrial fibrillation.
Multiple infarct locations (in different vascular beds) suggest the heart (and aorta) as the origin of the embolism. Ischemic stroke can be subdivided according the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, which is based on clinical symptoms as well as results of further investigations ( Box 20.1 ).
1
Large Artery Atherosclerosis (Embolus/Thrombosis)
Features:
- 1.
Clinical: cortical or brainstem or cerebellar dysfunction
- 2.
Imaging: cortical, cerebellar, brainstem, or subcortical infarct greater than 1.5 cm on computed tomography (CT) or magnetic resonance imaging (MRI)
- 3.
Test: stenosis (greater than 50%) or occlusion of a major brain artery or branch cortical artery evidenced by duplex ultrasound imaging or arteriography.
2
Cardioembolism (High Risk/Medium Risk)
Features:
- 1.
Clinical: cortical, brainstem or cerebellar dysfunction or the evidence of a previous transient ischemic attack or stroke in more than one vascular territory
- 2.
Imaging: cortical, cerebellar, brainstem, or subcortical infarct greater than 1.5 cm on CT or MRI
- 3.
Test major cardiac source of emboli (e.g.,):
- a.
mechanical prosthetic valve
- b.
atrial fibrillation
- c.
left atrial/atrial appendage thrombus
- d.
left ventricular thrombus
- e.
dilated cardiomyopathy
- f.
akinetic left ventricular apex
- g.
atrial myxoma
- h.
infective endocarditis
- a.
3
Small-Vessel Occlusion (Lacunae)
Features:
- 1.
Clinical: lacunar syndromes without evidence of cortical or brainstem or cerebellar dysfunction (a history of diabetes mellitus or hypertension supports the clinical diagnosis)
- 2.
Imaging: normal CT/MRI examination or a relevant subcortical or brainstem infarct smaller than 1.5 cm
- 3.
Test: potential cardiac sources for embolism should be absent, and evaluation of the large extracranial arteries should not demonstrate a stenosis of greater than 50% in an ipsilateral artery.
4
Stroke of Other Determined Etiology
Blood tests or arteriography should reveal one of the following unusual causes of stroke
- a.
nonatherosclerotic vasculopathies
- b.
hypercoagulable states
- c.
hematologic disorders
Patients in this group should have clinical and CT/MRI findings of an acute ischemic stroke, regardless of the size or location.
5
Stroke of Undetermined Etiology
- a.
two or more causes identified
- b.
negative evaluation
- c.
incomplete evaluation
Prognostic Value of Change
In primary and secondary prevention of stroke, antihypertensive treatment represents a cornerstone of treatment options. A continuous relationship between BP and the occurrence of stroke has been documented and, conversely, clinical trials and meta-analyses have revealed that lowering BP results in a substantially reduced risk of stroke in both primary and secondary prevention.
Small Vessel Disease
It has to be taken into account that the terminology and definitions for SVD varies between studies (e.g., white matter lesions, -hyperintensity, -changes, -disease). Hence, the STandards for ReportIng Vascular changes in nEuroimaging (STRIVE) have proposed MRI-terminology and lesion findings ( Fig. 20.1 ).
White Matter Hyperintensity
Among all subtypes of SVD, white matter hyperintensity (WMH) is the most prevalent lesion in the general population. About every second patient in their forties, and more than 90% aged over 80 years of age have WMH.
Hypertension is considered to be an important risk factor for both WMH volume and progression. Importantly, a systematic review and meta-analysis revealed that WMH predicts a three-fold increased risk of stroke, and double increased risk of both dementia and mortality.
Prognostic Value of Change
Increasing evidence suggests that BP control may reduce the course of WMH progression. Moreover, it was shown that uncontrolled patients with untreated hypertension had significantly more WMH progression than subjects with uncontrolled treated hypertension and controlled treated hypertension. These data indirectly suggest that antihypertensive therapy may prevent WML progression in the hypertensive population. However, until today, there is not a single study demonstrating that decrease of WMH induced by effective antihypertensive therapy is associated with improved prognosis ( Table 20.1 ).
| Target Organ Damage | Sensitivity for Changes | Time of Change | Prognostic Significance of Changes |
|---|---|---|---|
| Brain | |||
| Small vessel disease | No data | No data | No data |
| Heart | |||
| LVH | |||
| ECG | Low | >6 months | Yes |
| Echo | Moderate | >6 months | Yes |
| MRI | High | >6 months | No data |
| Eye | |||
| Qualitative signs | Low–high | Weeks–months | No data |
| Quantitative signs | No data | No data | No data |
| Kidney | |||
| eGFR | Moderate | Month–years | Yes |
| Albuminuria | High | Weeks–months | Yes |
| Vasculature | |||
| IMT | Very low | >12 months | No |
| PWV | High | Weeks–months | Limited data |
| Central BP | High | Days–weeks | No data |
Microbleeds
Similarly, aging and hypertension are independently associated with cerebral microbleeds (MB). Importantly, higher BP (e.g., odds ratio [OR] 2.69; 95% confidence interval [CI], 1.40 to 5.21 per standard deviation [SD] increase for 24-hour BP) was associated with new development of MB. Presence of MB is associated with increased risk of incident intracerebral hemorrhage, in particular in patients on anticoagulation therapy. Presence of MB increased the risk of both hemorrhagic and ischemic stroke in patients after ischemic stroke. Studies revealed that MB is associated with increased risk of stroke-related death as well as all-cause and CV mortality.
Prognostic Value of Change
Although the magnitude of BP elevation is associated with the occurrence of MB, effective BP reduction had surprisingly no clear impact on MB progression during follow-up.
Small Subcortical Infarcts
Small subcortical infarcts (SSI), historically commonly called “lacunar stroke,” are primarily located in the motor and sensory pathways and explain the clinical symptoms despite lacunar size. Only half of SSI are detected on computed tomography (CT), but at least 70% are visible on diffusion-weighted MRI. Although pathogenetic mechanisms between hypertension and SSI are largely unknown, the prevalence of hypertension is highest in patients with SSI compared with any other subtype of ischemic stroke. The presence and progression of SSI is an independent risk factor for cerebrovascular disease and impairment of cognitive function.
Prognostic Value of Change
In the recently published “Secondary Prevention of Small Subcortical Stroke (SPS3)” trial, a systolic BP target of less than 130 mm Hg was accompanied by a nonsignificant reduction in all stroke, disabling or fatal, but with a significant reduction of intracerebral hemorrhagic stroke compared with a systolic BP target of 130 to 149 mm Hg. In the European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines BP reduction less than 140/90 mm Hg is recommended for primary and secondary stroke prevention, but no specific recommendation is made for WMH, MB, and SSI.
Lacunes
Previous SSI, silent brain infarction (SBI), and hemorrhage (territory of one penetrating arteriole) are vascular causes of lacunes, but shrunk striatocapsular strokes may also form a lacunar-like cavity. Although an association between BP and incident lacunes was seen in patients without baseline documentation, higher BP did not contribute to lesion progression in patients with already severe findings at baseline.
Prognostic Value of Change
Because SBI increases the risk of stroke up to five times, indirect evidence based on a small Japanese study demonstrates that BP control reduced the risk of SBI. Whether or not such a reduction of SBI is related to improved survival remains to be proven.
Perivascular Space
The fluid-filled space surrounding the path of penetrating arteries is named perivascular space (PVS). In the Northern Manhattan Study it was recently shown that dilated PVS is more common in patients with higher peripheral pulse pressure (PP) and systolic BP, the pulsatile components of BP.
Prognostic Value of Change
Compared with normotensive patients, uncontrolled hypertensive patients during follow-up were at increased risk of dilated PVS. Studies analyzing whether an increase or decrease of PVS bears any prognostic information are missing.
Dementia
The link between hypertension and the incidence and prevalence of dementia is well established. Hypertension is either a causal risk factor or an indirect promoter of dementia. Studies assessing the midlife BP (measured between 40 and 65 years) revealed a relationship between higher midlife BP and risk of incident vascular dementia. Of note, however, no clear association with late-life BP and the development and prevalence of dementia was found. Regarding both main subtypes of dementia, namely Alzheimer disease and vascular dementia, there was a clear association for hypertension and vascular dementia (e.g., Hiyasama study: hazard ratio [HR]: 10.07 [3.25 to 31.25] for BP range 160 to 179/100 to 109 mm Hg versus normal BP range [<130/85 mm Hg]), but less clear for Alzheimer disease (e.g., Hiyasama study: HR 1.05 [0.50 to 2.22] BP range 160 to 179/100 to 109 mm Hg versus normal BP range [<130/85 mm Hg]). In contrast, Launer et al. observed a significant relation between hypertension and Alzheimer disease (OR 4.47 [1.53 to 13.09] for diastolic blood pressure [DBP] ≥ 95 mm Hg versus 80 to 89 mm Hg), supporting the hypothesis that vascular factors cause or at least accelerate Alzheimer disease.
Alzheimer disease and vascular dementia may often coexist and thus, misclassification may happen (e.g., vascular dementia or a mixed dementia rather than Alzheimer disease).
Although not directly recommended in most guidelines, the cognitive assessment instruments, particularly in patients with increased risk or based on clinical assumptions, may reasonably be part of routine clinical work up of hypertensive patients. Different screening questionnaires are available, such as the Mini-Mental State Examination (MMSE), the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and the Montreal Cognitive Assessment (MoCA) (Screening for cognitive impairment in older adults: and evidence update for the U.S: Preventive Services Task Force, 2013. www.ahrq.gov .).
Although MMSE is the most widely used test (including five sections, namely orientation, registration, attention and calculation, recall and language), it cannot evaluate executive function and cognitive impairment only with low sensitivity. The MoCA, which incorporates subtests for executive function and psychomotor speed (often impaired in cognitive impairment), is specially designed for detecting mild cognitive impairment. Compared with MMSE, the MoCA test showed remarkably improved sensitivity and specificity for cognitive impairment (18% versus 90%). Moreover, sensitivity of detecting cognitive impairment was greater with MoCA than with MMSE in patients with acute transient ischemic attack or minor stroke, even when other neurologic deficits were not evident.
Prognostic Value of Change
Longitudinal observational studies found benefits of BP reduction for the risk of incident vascular dementia, but results are uncertain with respect to BP reduction and Alzheimer disease. Longer duration of BP reduction was associated with less risk of dementia. In contrast, pooled analysis with meta-regression technique of large-scale randomized controlled trials (mainly active treatment versus placebo) revealed that risk of cognitive impairment was not clearly reduced by active treatment, probably attributed to the relatively short treatment duration of 2 to 5 years. It remains to be proven whether or not improvement or stabilization in the MoCA score (by BP reduction) is associated with improved neurologic outcome, cognitive impairment, and risk of stroke and mortality. Nevertheless, despite the lack of clear evidence, BP lowering is thought to decrease or stop the process and progression of dementia.
Target Organ “Heart”
Longstanding hypertension leads to LVH modified by various pathogenetic factors and, if untreated, to congestive heart failure (CHF).
Left Ventricular Hypertrophy
Initially, LVH occurs as an adaptive process to the pressure-load imposed on the heart to reduce wall stress and maintain LV pump function and ejection fraction (EF). As a consequence, wall thickness increases on the expanses of the LV internal diameter and relative wall thickness (ratio of wall thickness [RWT] to LV internal diameter) increases as well, so-called concentric pattern of LVH. Over time, LV remodeling processes aggravate, hypertrophied muscle fibers become thickened and shortened, and perivascular and interstitial collagen content increases, ultimately resulting in LV dilation, so-called pattern of eccentric LVH. However, only a small portion of left ventricular mass (LVM) variation are explained by BP (only 10% with office systolic BP over 30 years and up to 25% with 24-hour ambulatory BP), and solid evidence is available that several nonhemodynamic factors (e.g., body mass index, dietary salt intake, genetic factors, activation of the sympathetic nervous system, and renin-angiotensin-system [RAS] ) determines the development as well as the degree of LVM ( Fig. 20.2 ).
Several methods, with different sensitivity and specificity are available for the assessment of LVH in hypertension. From some decades ago, epidemiological studies have revealed that LVH is one of the independent risk factors determining prognosis of hypertensive patients. Both clinical and epidemiological studies have shown that LVH, irrespective of whether assessed by electrocardiogram (ECG) or echocardiography, is associated with a several-fold increase in CV and all-cause mortality. Interestingly, LVH diagnosed by ECG and by echocardiography does not encompass the same entity; that is, they reflect different pathogenetic aspects related to LVH adaptive process because LVH by ECG and by echocardiography are independently associated with mortality.
Electrocardiography
In hypertension guidelines, ECG is recommended as the primary diagnostic tool to detect LV remodeling and LVH, and in a recent analysis of 26 studies, the role of ECG as a first-line examination for identifying subclinical cardiac organ damage has been highlighted.
There are several criteria for detecting LVH by ECG based on voltage and in part, repolarization patterns and/or QRS duration. The most common criteria are (modified) Sokolow-Lyon index as S V1 + R V5 > 3,5 mV and the Cornell product criteria (S V3 + R aVL ∗ QRS-duration >244 mV∗ms) ( Table 20.2 ). In obese patients the Cornell product and, if left anterior fascicular block is evident, other criteria (e.g., Siii + max. R/S any lead >30 mV men [>28 mV women]; for details see Hancock et al. ) may be preferred, because voltage, repolarization pattern, and QRS duration may be differently affected as a result of these conditions.
| Electrocardiography | ||
| Sokolow-Lyon Index | S V1 + R V5 | >3,5 mV |
| Cornell voltage criteria | S V3 + R aVL | >2,8 mV |
| QRS duration product | (Cornell voltage ∗ QRS-duration) | >244mV∗ms |
| Echocardiography | ||
| LV mass (BSA, g/m 2 ) | >95 (♀)/>115 (♂) | |
| LV mass index (height 1.7 , g/m 1.7 ) | >60 (♀)/>81 (♂) | |
| Type | ||
| (LVH and) RWT | >0.42 |
| (LVH and) RWT | ≤0.42 |
| (no LVH) RWT | >0.42 |
| Magnetic Resonance Imaging | ||
| LV mass (BSA, g/m 2 ) (without papillary muscle mass) | >85 (♀)/>108 (♂) | |
| LV mass (BSA, g/m 2 ) (with papillary muscle mass) | >89 (♀)/>112 (♂) | |
Regardless of used criteria, the sensitivity in detecting LVH is at best about 50% to 60%, but of high specificity (about 85% to 90%). Nevertheless, a 12-lead ECG should be performed in all hypertensive patients, because other signs of hypertensive damage to the heart and/or CV complications (e.g., atrial fibrillation) can be detected. Notably, there is evidence that new-onset of atrial fibrillation must be considered as TOD and specific antihypertensive therapy is recommended.
Echocardiography
Echocardiography is more sensitive than ECG in detecting LVH and is the gold standard for quantifying cardiac structural and functional changes of the LV in hypertensive patients. Echocardiographic evaluation allows quantitative measurements of interventricular septum wall thickness (IVST), left ventricular internal diameter (LVID), and posterior wall thickness (PWT) in diastole (d) and systole (s). LVM is calculated under the assumption of a prolate ellipsoid shape of the LV according a mathematical formula of the American Society of Echocardiography (LVM = 0.8 × (1.04 [(LVIDd + PWTd + IVSTd) 3 − (LVIDd) 3 ] + 0.6g). A normalization of LVM for various body constitutions is necessary to avoid underestimation and overestimation, and the indexation to height 1.7 (g/m 1.7 ) appears to be best, although the standard index based on body surface area (BSA) is still used in clinical practice. More recently, data from the Echocardiographic Normal Ranges Meta-Analysis of the Left Heart (EchoNoRMAL) project suggest that different allometric power for BSA and height should be applied according to gender and ethnic group, but these complex algorithms have not found general acceptances. Calculation of RWT (as 2 × PWTd/LVIDd) with its cut-off value of 0.42 permits the classification of concentric (RWT > 0.42) or eccentric (RWT ≤ 0.42) hypertrophy as well as concentric remodeling (normal LVM, but RWT > 0.42). This is of importance because the patterns of LVH are differently associated with CV risk, with concentric LVH to have the greatest risk. Finally, it needs to be stressed that echocardiography offers the opportunity to assess additional information on anatomy and function of the heart as well as valves and thereby allows the diagnosis of other hypertensive-related TOD, such as CHF with reduced or preserved EF and coronary heart disease among others.
Magnetic Resonance Imaging
It has been proposed that MRI is the new “gold-standard” for noninvasive evaluation of LVH, but the low availability and high cost clearly argue against this claim and has to be refuted. Nevertheless, MRI should be considered in patients with poor echocardiographic quality. Notably, MRI enables an answer regarding LVH pattern and its cause. Detailed protocols and reference values (partly given in Table 20.2 ) have been published.
Prognostic Value of Change
It was repeatedly shown that regression of LVH, irrespective of whether assessed by ECG or echocardiography, conferred an improvement of associated CV risk. In the echocardiographic substudy of the LIFE trial, LVM reduction of one standard deviation (i.e., 25 g/m 2 ) results in a 20% decrement of the primary endpoint (death, nonfatal MI, and stroke). For a single patient, it is proposed that LVM changes of 10% to 15% may have clinical significance. A meta-analysis directly comparing regression of LVH among different antihypertensive classes revealed that RAS blockers (angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB]) and calcium channel blocker (CCB) exhibited the most pronounced effect, which was found to be superior to those of beta-blockers and diuretics. Subsequently, a more recently published meta-analysis confirmed that RAS blockers are better able to reduce LVH than beta-blockers. Nevertheless, achievement of BP control is the most important target in obtaining LV reduction. Interestingly, besides the rapidly proven relationship that LVM reduction results in less CV events, regression of LVH in hypertensive patients still has an adverse CV prognosis compared to those who never had LVH; that is, the CV prognosis improves but is still elevated after reduction of LVM.
Heart Failure
Epidemiological studies have shown that hypertension is the most frequent underlying cause of CHF. Notably, in a large proportion of patients, antihypertensive drugs (ACE inhibitor, ARB, aldosterone-antagonist, beta-blocker, diuretic), and angiotensin receptor Neprilysin inhibitor are now standard of care not only to lower afterload but also to counteract neuroendocrine stimulation (inherent in CHF).
Heart Failure With Preserved Ejection Fraction
Alterations in LV relaxation and filling pattern are main features of diastolic dysfunction in hypertension, which may precede alteration in systolic dysfunction. Diastolic dysfunction, often associated with LV remodeling and concentric LVH, may result in clinical symptoms of CHF, although EF is preserved (HFpEF). The diagnosis of HFpEF is challenging because it is largely based on the exclusion of other noncardiac causes of symptoms suggestive of CHF.
Both diagnosis and grading of diastolic dysfunction is based on Doppler tissue analysis (E/e′ ratio), preferably assessed at septal and lateral mitral annulus. Additional indicators of impaired diastolic filling are the ratio between transmitral peak early and late filling velocity (E/A ratio) and atrial size, an indicator of diastolic dysfunction. Of all Doppler parameters, the E/e′ ratio has been shown to be the strongest predictor of first cardiac events in hypertensive patients independent of LVM and RWT. Likewise, left atrial (LA) enlargement, reflecting increased left ventricular filling pressure, indexed by volume (LAVi >34 mL/m 2 ), is also predictive of CHF and mortality.
Heart Failure With Reduced Ejection Fraction
Global alteration of LV systolic function is the key diagnostic criteria of heart failure with reduced EF (HfrEF) whose two major underlying diseases are nowadays hypertension and coronary artery disease. Two-dimensional echocardiography using the modified Simpson method (average of apical four- and two-chamber views) is the traditional measurement of systolic LV function, and EF above 55% is defined as normal, between 55% and 45% as moderate, and below 35% as severe LV systolic dysfunction.
Nowadays, three-dimensional technology allows frame-by-frame detection of the endocardial surface from real-time three-dimensional datasets. An improved accuracy and reproducibility of three-dimensional measurements of LV volumes and LVEF compared with two-dimensional have been demonstrated by using independent reference technique (e.g., MRI).
Prognostic Value of Change
Prevention of CHF represents the largest benefit that is associated with the use of BP-lowering drugs. A meta-analysis of major interventional randomized trials comprising patients with hypertension has revealed that not only BP reduction but also the used class of antihypertensive drugs are related to decreased incidence of CHF. In contrast, only a few studies have investigated the effect of BP reduction in patients already suffering from CHF and up-to-date, no efficacious therapy have been identified for HFpEF. On the contrary, a subanalyis of the I-PRESERVE study showed that HFpEF patients hospitalized for any reason, and especially for HF, were at increased risk for subsequent death. Randomized controlled trials have mainly enrolled patients with HFrEF. Efficacious therapies for treating HFrEF in hypertensive patients are the preferential use of ACEs, ARBs, beta-blockers, diuretic, and aldosterone-antagonists.
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