1 1.1 Pathophysiology of Cardiac Target-Organ Damage

In the pressure-loaded heart, changes in cardiac structure and function, such as left ventricular (LV) hypertrophy, initially occur as adaptive responses to reduce wall stress and maintain cardiac output. However, depending on a combination of known and lesser understood factors, e.g., antihypertensive therapy, genes, and age, the heart will at a varying pace transition towards increasing cardiac fibrosis, LV dilation, pump failure, and ultimately death [1]. Importantly, substantial evidence has documented that early identification and therapy aimed at preventing or reversing subclinical cardiac target-organ damage is associated with improved outcomes in hypertension [2]. In current practice, the treating physician is well equipped to detect and monitor temporal changes in subclinical cardiac target-organ damage. The purpose of this chapter is to give an introduction to the usefulness of electrocardiography in evaluating patients with hypertension. The first subchapter presents a brief overview of the electrocardiogram in order for the main attention to be focused on the clinical evidence pertaining to its use in assessing cardiac target-organ damage.

2 1.2 The Electrocardiogram

In spite of its centenarian status, the electrocardiogram remains one of the most ubiquitous tools in modern cardiology (>150,000,000 performed per year in the USA and the European Union). Its advantages are clear: it is widely available, can be interpreted without expert knowledge, and provides prognostic information at low cost in patients with and without established cardiovascular disease [3]. The basis for electrocardiography is the sequential depolarization of the heart, which under physiologic conditions initiates in the sinoatrial node to move through the cardiac conductive system and reach the ventricular cardiomyocytes via the Purkinje fibers. The surface electrocardiographic signal is by definition positive if the vector of electrical current points towards the electrode and negative if the net flux directs away from the electrode. Today’s standard is to use 10 electrodes to construct 12 different leads. Each lead views the depolarization and repolarization of atrial (P-wave) and ventricular (QRS-complex) cardiomyocytes from a different angle and under many circumstances allows for prediction of the anatomic localization underlying the observed electrocardiographic findings. By principle, cardiac cellular hypertrophy or a lean body stature will tend to increase QRS voltage amplitude [4]. Conversely, a loss of cardiac cells, due to, for example, cardiac fibrosis, or an increased distance from heart to the electrode, e.g., obesity or a posterior shift of cardiac positioning within the thorax, will attenuate electrocardiographic voltage [5]. Placement of the surface electrodes therefore also influences voltage-sensitive criteria for LV hypertrophy [6]. QRS duration reflects the time it takes for the initial depolarization of the LV. The latter is an integrated function of cardiac size and the speed with which the electrical pulse is propagated through the heart. Longer QRS duration may therefore be associated with intrinsic myocardial cell damage or slowing of propagation in specialized conduction tissue, perhaps due to aging in itself [7, 8]. The mechanisms underlying ST-segment deviation and T-wave inversion, although not fully understood, appear to involve a repolarization disparity between the endo- and epicardial layer induced by the effects of impaired myocardial blood flow [9]. The consequent ST/T abnormalities are not specific for underlying pathology, as they could equally reflect insufficient blood flow due to epicardial disease or an oxygen supply–demand mismatch in patients with concentric LV hypertrophy and normal coronary arteries [10, 11]. Of note, unlike ST elevation and transmural ischemia, ST depression and most instances of T-wave inversion do not localize the anatomic region with insufficient subendocardial blood flow [12]. The following subchapters highlight the clinical correlates of specific electrocardiographic findings in patients with hypertension.

3 1.3 Electrocardiographic Left Ventricular Hypertrophy

The most common criteria for assessing electrocardiographic LV hypertrophy are listed in Table 1.1 [13]. In general, the presence of electrocardiographic LV hypertrophy is regarded as highly predictive of anatomic LV hypertrophy (specificity 85–90 %), whereas the absence of electrocardiographic LV hypertrophy is considered less useful for ruling out cardiac hypertrophy (sensitivity less than 50 %) [13, 14]. As noted earlier, the latter may in part relate to the confounding effects of race, age, gender, and obesity on the diagnostic accuracy of the various electrocardiographic criteria [15–17]. In spite of its modest sensitivity, numerous studies have related electrocardiographic indices of cardiac hypertrophy to increased cardiovascular event rates in patients with hypertension [18]. It is therefore very important for the clinician to be familiar with the evidence linking electrocardiographic LV hypertrophy to target-organ damage and an independent increase in the risk of adverse outcomes including stroke, heart failure, myocardial infarction, and sudden cardiac death [19, 20]. Of equal importance is the fact that regression of electrocardiographic LV hypertrophy during antihypertensive treatment is associated with improved outcomes independent of changes in blood pressure per se [21, 22]. This suggests that LV hypertrophy is a more sensitive marker of cellular damage than brachial blood pressure. A mechanism may be that LV hypertrophy is closely associated with increased renin-angiotensin system activity and development of cardiac fibrosis (Fig. 1.1) [23, 24]. In conclusion, there is low to moderate agreement between the electrocardiographic LV hypertrophy and anatomic LV mass as determined by echocardiogram or magnetic resonance imaging (MRI) in patients with hypertension. However, strong evidence links LV hypertrophy on the electrocardiogram to risk of adverse outcomes in the same patient population. The beneficial effect of electrocardiographic LV hypertrophy regression during antihypertensive treatment suggests that electrocardiographic LV hypertrophy is a potential therapeutic target in hypertension.

Table 1.1 Electrocardiographic criteria for assessing left ventricular hypertrophy
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Fig. 1.1
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(a) Short-axis T1-weighted image of the mid-left ventricle demonstrating left ventricular hypertrophy with normal myocardial signal (arrow). (b) Corresponding midventricular MRI image with delayed gadolinium enhancement shows extensive subendocardial enhancement consistent with diffuse fibrosis (arrows). (c) Gross examination of the explanted left ventricle fixed in formalin shows extensive subendocardial fibrosis. Note the sharp demarcation from normal tan-colored myocardium (arrows). (d) Masson’s trichrome stain confirms extensive subendocardial fibrosis (S), stained blue with this stain (arrow) and sharply demarcated from normal myocardium (M), staining red (original magnification, ×40). Asterisk denotes endocardial surface (Reproduced with permission from Salvia et al. [23])

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4 1.4 Electrocardiographic ST/T Abnormalities

Electrocardiographic repolarization abnormalities are often observed in conjunction with electrocardiographic LV hypertrophy. It has been documented that adding electrocardiographic repolarization patterns to electrocardiographic voltage and QRS duration may improve the diagnostic accuracy for detection of anatomic LV hypertrophy [13]. Specifically, the additional presence of LV repolarization abnormalities is believed to be a marker of severe concentric LV hypertrophy [25, 26]. In turn, this may partly explain why the electrocardiographic “strain” pattern of lateral ST depression and T-wave inversion has emerged as an independent risk attribute even when adjusting for the presence of electrocardiographic voltage criteria for LV hypertrophy [27–29]. In the losartan intervention for endpoint reduction (LIFE) study, new development of electrocardiographic strain was a strong predictor of adverse outcome in the setting of electrocardiographic LV hypertrophy regression [30].In conclusion, electrocardiographic strain patterns refine cardiovascular risk prediction and may improve detection of anatomic LV hypertrophy when combined with electrocardiographic LV hypertrophy. The mechanisms underlying regression and development of electrocardiographic strain, at baseline and during antihypertensive therapy, require further study to fully unveil its prognostic potential.

5 1.5 QRS Duration

Longer QRS duration is an independent predictor of increased sudden cardiac death in patients with hypertension [31]. Moreover, longitudinal changes in QRS duration during follow-up in hypertensive patients are closely related to risk of incident heart failure [32]. It is less evident if QRS duration should be considered a separate risk marker as compared to electrocardiographic voltage in itself. This is further complicated by the fact that some electrocardiographic criteria for LV hypertrophy include QRS duration in their calculation, whereas others rely entirely on electrocardiographic voltage. Clearly, electrocardiographic voltage and QRS duration will be differently affected by confounding factors such as obesity and age-related calcification of conduction tissue [33]. From a pathophysiological standpoint, there may also be important differences between QRS duration and voltage, as only viable cardiomyocytes can produce electrocardiographic voltage. Conversely, longer QRS duration is in itself associated with cardiac fibrosis and LV dilatation, both of which are regarded as hallmarks of end-stage LV failure [34]. Thus, while greater QRS voltage mirrors hypertrophy of viable cardiomyocytes, longer QRS duration may reflect greater cellular hypertrophy or delayed cardiac activation due to regional or more widespread cardiac fibrosis, which may (reactive interstitial fibrosis) or may not be reversible (replacement fibrosis) [35]. Worsening fibrosis in the setting of increasing LV hypertrophy may in part explain why electrocardiographic voltage is not linearly related to cardiac mass and suggests that the current clinical standard of dichotomizing electrocardiographic criteria for LV hypertrophy may in itself lead to poor diagnostic performance of the electrocardiogram [5]. In conclusion, QRS duration is an independent predictor of heart failure and sudden cardiac death in hypertensive patients. QRS duration and QRS voltage may reflect different stages or components of cardiac maladaptations to increased LV afterload. Further studies are needed to elucidate the differential implications of longer QRS duration as compared increased QRS voltage.

6 1.6 Atrial Fibrillation

Atrial fibrillation is an independent predictor of adverse outcomes including stroke, heart failure, and cardiovascular mortality in hypertensive patients [36]. There is mounting evidence to indicate that new-onset atrial fibrillation should be regarded as target-organ damage [37]. One potential mechanism may involve increased LV pressures that translate to a dilatation of the thin-walled left atria, thereby increasing risk of atrial arrhythmia [38]. As such, regression of electrocardiographic indices of LV hypertrophy is associated with a reduced incidence of new-onset atrial fibrillation [39]. Importantly, it has been well documented that prevention of new-onset atrial fibrillation is associated with less fewer clinical endpoints, including stroke and sudden cardiac death [40, 41]. In conclusion, atrial fibrillation is a well-established marker of cardiovascular risk in hypertensive patients. Preexisting atrial fibrillation might relate to different factors than hypertension. However, there is now clear evidence to suggest that new-onset atrial fibrillation during follow-up of hypertensive patients is a sign of target-organ damage, which should elicit more aggressive lowering of blood pressure and risk factors to prevent catastrophic events like stroke and sudden cardiac death.

7 1.7 Electrocardiography vs. Echocardiography and Magnetic Resonance Imaging

Historically, the electrocardiogram has been used to detect cardiac arrhythmias and as a surrogate marker of anatomic LV hypertrophy. Based on the published evidence, sensitivity of LV hypertrophy on the electrocardiogram is too low to serve as a discriminatory marker of anatomic LV hypertrophy in patients with hypertension. The next question then becomes, is the electrocardiogram therefore a rudimentary tool that will eventually be phased out as echocardiography and cardiac MRI becomes more routine and cost is driven down. So far, the answer to that question seems to be both yes and no. Favoring a continued important role of electrocardiography in hypertension is the fact that several studies have now shown that electrocardiographic LV hypertrophy and anatomic LV hypertrophy, as determined by echocardiography or MRI, are separately predictive of adverse cardiovascular outcomes [37, 42]. It has therefore been proposed that anatomical and electrical hypertrophy might reflect different aspects of cardiac maladaptations to increased LV afterload [43]. Novel cardiac MRI measures, such as extracellular volume mapping and pixel-wise quantification of myocardial blood flow, are likely to provide further insight into the mechanisms underlying electrocardiographic abnormalities in the hypertensive heart [44]. On the other hand, there is now sufficient evidence to conclude that electrocardiogram is not useful tool to screen for anatomic LV hypertrophy and that many electrocardiographic changes overlap with changes in cardiac structure and function that are not specific to cardiac organ damage induced by hypertension. Thus, the electrocardiogram cannot stand alone in cardiovascular risk stratification of hypertensive patients, but it can provide low-cost and very valuable prognostic information when ordered and interpreted in light of its strengths and limitations. There is no randomized comparison of antihypertensive management with and without guidance from the electrocardiographic findings. Thus, until new evidence becomes available, the clinician must rely on observational evidence as presented in this chapter.