Assessment of Target Organ Damage

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 ).

BOX 20.1

TOAST Classification of Ischemic Stroke

(Adapted from Reference .)

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

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 ).

TABLE 20.1

Prognostic Significance of Treatment-Induced Changes of (Asymptomatic) Target Organ Damage

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

BP, Blood pressure; ECG, electrocardiogram; Echo, echocardiography; eGFR, estimated glomerular filtration rate; IMT, intima-media thickness; LVH, left ventricular hypertrophy; MRI, magnetic resonance imaging; PWV, pulse wave velocity.

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.

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