LVH and Ventricular Repolarization

Lasse Oikarinen

Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland

Correspondence: L Oikarinen, Division of Cardiology, Department of Medicine,
Helsinki University Central Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland.
E-mail: lasse.oikarinen@kolumbus.fi, phone +358 9 47172442, fax +358 9 471 74574

1.  Introduction

Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality, including sudden cardiac death [Levy et al., 1990; Haider et al., 1998]. Therefore, detection of LVH remains clinically important. An increase in electrically active myocardium augments QRS voltages on the body surface electrocardiogram (ECG), but for detection of LVH all QRS-based LVH indexes have relatively low sensitivity at clinically acceptable levels of specificity. Experimental evidence suggests that LVH alters ventricular repolarization. LVH-induced repolarization abnormalities in the ECG may provide additional important information for detection of LVH and also for identifying patients at risk of repolarization-related arrhythmogenesis.

2.  Ventricular Repolarization and LVH

2.1. Ventricular Repolarization

Ventricular repolarization time is determined by the sum of activation time and action potential (AP) duration. At steady-state conditions, several factors affect AP duration, such as the cycle-length, ion channel composition of repolarizing currents, autonomic nervous system, electrolytes and gender differences. There are important intrinsic differences in AP characteristics in the myocardium. In the transmural axis, isolated epicardial cells, midmyocardial M-cells, and endocardial cells show different AP durations and rate dependencies [Sicouri and Antzelevitch, 1991]. Repolarization gradients have also been described between different locations in the left ventricle as well as between the left and right ventricles. However, in the intact left ventricular wall, these differences are small because of electrical coupling [Yan and Antzelevitch, 1998a] and because of the inverse relationship between activation time and AP duration [Franz et al., 1991], both of which synchronize repolarization times and recovery of excitability.

2.2. Repolarization Changes in LVH

In experimental studies, prolongation of the AP duration in response to LVH has been consistently observed [Aronson, 1980]. LVH-induced changes in AP duration may occur in a spatially nonhomogenous fashion, thus creating dispersion of repolarization [Kowey et al., 1991]. The inverse relationship between activation time and AP duration may be affected so that activation time no longer is a determinant of AP duration [Franz et al., 1991]. Interestingly, these changes may predispose to afterdepolarizations and functional reentry, and thus generate vulnerability to ventricular tachyarrhythmias [Yan et al., 2001].

Several mechanisms may explain these changes in LVH. Changes in many ion channels (for example L-type calcium current, transient outward K⁺ current (I_to), and the slow component of the delayed rectifier K⁺ current (I_Ks)), controlling for currents during phase 2 and 3 of the AP have been described [Hart, 1998; Xu et al., 2001]. These changes may dependend on the stage of LVH. In addition, interstitial fibrosis, characteristic of pathologic LVH, may cause electrical uncoupling. Other factors in LVH, such as myocardial ischemia and increased wall stress by stretch-mediated mechanisms, may regionally affect AP duration and morphology.

3.  Ventricular Repolarization and ST-T Wave

3.1. Genesis of the ST-T Wave in the Electrogram

In left ventricular wedge preparations, the ST-T segment in the electrogram, coinciding with phase 2 and 3 of AP, is generated by voltage gradients between the AP's in the epicardium and M-cell region as well as between the endocardium and M-cell region [Yan and Antzelevitch, 1998b; Gima and Rudy, 2002]. In fact, full repolarization of epicardial cells coincides with the peak of the T-wave and full repolarization of the M-cell region coincides with the end of the T-wave.

3.2. Genesis of the ST-T Wave in the Body Surface ECG

The inscription of the ST-T waveform in unipolar leads in the body surface ECG is generated by voltage gradients primarily in the transmural axis [Franz et al., 1991]. However, the observed relationships between AP's at the myocardial level and transmural electrograms are affected by the fact that each electrode on the body surface ECG records a distance-weighted integral of the voltage gradients generated by all bioelectrical sources from the entire heart. The body surface ECG recording of these gradients is also affected by the properties of the volume conductor and boundaries.

3.3. Ventricular Repolarization and Magnetocardiogram

The same myocardial ionic currents creating measurable voltage differences on the body surface ECG also generate a weak magnetic field, which can be recorded with multichannel magnetocardiography (MCG). Theoretically, the MCG signal, compared to the ECG signal, is differently affected by attenuation due to torso inhomogeneities, is more sensitive to tangential currents in relation to sensor plane, and may show complementary information concerning the repolarization phase.

3.4. ECG Measures to Detect Ventricular Repolarization Changes

The QT interval, with some limitations, is the clinical counterpart of ventricular repolarization time. Prolongation of the QT interval may reflect prolongation of the repolarization time at least in some parts of the myocardium. QT dispersion is a measure of interlead variations in QT interval duration. In an experimental study, the T-wave area in the 12-lead ECG showed a strong correlation to dispersion of repolarization [Zabel et al., 1995]. Recently, several novel descriptors of T-wave morphology, based on singular value decomposition, have been introduced [Acar et al., 1999]. Of these, the T-wave morphology dispersion and so-called total cosine R to T are likely to reflect the dipolar components of the T wave vector.

4.  LVH and ST-T Wave

4.1. Ventricular Strain Pattern

The classic strain pattern of ST depression and T-wave inversion in the ECG has long been used as a marker of the presence of anatomic LVH. Several ECG indexes, such as the Romhilt-Estes point score and the Peruggia score, have utilized the assessment of the strain pattern for detection of LVH. Two recent studies have further elucidated the relation between ECG strain and LVH. In the Losartan Intervention For Endpoint Reduction (LIFE) in Hypertension Study, which enrolled hypertensive patients with ECG-evidence of LVH, a strain pattern in leads V₅ and/or V₆ occurred in 15% of patients [Okin et al., 2001]. It occurred more commonly in patients with than without evident coronary heart disease (29% (51 of 175 patients) vs. 11% (81 of 711 patients); p<0.001). When accounting for clinical evidence of CHD, the strain pattern was likely to indicate the presence of anatomic LVH. In another recent study, the degree of the strain pattern was associated with the degree of anatomic LVH [Okin et al., 2002].

4.2. QT Interval Duration

In a LIFE substudy of 577 patients free of overt coronary heart disease, increasing echocardiographic left ventricular mass indexed to body surface area (LVMI) was associated with prolongation of the rate-adjusted QT_apex (from QRS onset to T-wave apex) and QT_end (from QRS onset to T-wave end) intervals in both genders, even after adjusting for QRS duration [Oikarinen et al., 2001]. Both concentric and eccentric patterns of LVH were associated with increased QT interval duration. In another LIFE substudy of 317 patients, regression of both echocardiographic and ECG LVH after one year of antihypertensive treatment was associated with a significant decrease in QT_apex and QT_end interval duration, even after excluding patients with a strain pattern and/or T-wave abnormalities in baseline ECGs [Oikarinen et al., 2003]. Similar, but weaker, associations were also observed between LVMI and QT dispersion as well as between reduction in QT_apex dispersion and regression of echocardiographic or electrocardiographic LVH.

4.3. Body Surface Potential Mapping of T-Wave Areas

In a body surface potential mapping study (123 electrodes) of 11 healthy controls and 42 patients with echocardiographic LVH (27 with aortic stenosis and 15 with essential arterial hypertension) without evidence of coronary artery disease (LVH group), the sum of T-wave areas (taking QRS-T discordance into account) was 413+1649 mV×s in the controls and –1223+1954 mV×s in the LVH group (p<0.05). In the LVH group, the T-wave area sum correlated with left ventricular mass (r = –0.67), LVMI (r = –0.67), and interventricular septal wall thickness (r = –0.57; p<0.001 in all). However, in this study taking T-wave areas into consideration did not improve LVH detection beyond the QRS area sum (from the body surface potential mapping or 12-lead ECG) [Oikarinen et al., submitted].

4.4. MCG Mapping of QRS-T Area Sum and QRS-T Angle

In a MCG study of 12 healthy controls and 42 patients with pressure overload induced LVH, MCG QRS- and T-wave area sums provided complementary information of left ventricular mass [Karvonen et al., 2002]. Their combination, the QRS-T area sum (the sum from 33 locations > 16000 fT×s), improved detection of LVH with 62% sensitivity and 92% specificity, and in patients with LVH correlated significantly with LVMI (r = 0.46; p = 0.002). QRS-T angle, describing the difference of the orientation of magnetic field maps of the QRS complex and the T wave, was greater in patients with LVH than in controls (93.6+56.1 vs. 44.7+48.5 degrees, respectively; p = 0.009), and in patients with LVH correlated with LVMI (r = 0.38; p = 0.013). However, neither of these MCG indexes performed substantially better than the Cornell voltage duration product from the 12-lead ECG. Based on a predefined subsample of overweight subjects, MCG QRS-T angle showed stronger correlation to LVMI than the 12-lead ECG LVH-indexes.

4.5. T-Wave Morphology Descriptors from the 12-Lead ECG

We compared T-wave morphology descriptors between a group of 35 patients with pressure-overload induced LVH (LVH group) and a group of 15 healthy controls [Oikarinen et al., 2002]. The T-wave morphology dispersion (TMD) is a measure of spatial T-wave morphological variation and total cosine R to T (TCRT) is a measure of the vector deviation between the depolarization and repolarization wave fronts. Assessed from a single beat, both TMD and TCRT were different in the LVH group than in controls (TMD: 44.3+27.8 vs. 10.2+4.2, respectively; p<0.001, and TCRT: –0.01+0.57 vs. 0.49+0.37, respectively; p = 0.005). In the LVH group, both these measures correlated with LVMI (TMD: r = 0.49, p<0.01 and TCRT: r = –0.47, p<0.01) and interventricular septal wall thickness (TMD: r = 0.50; p = 0.002 and TCRT: r = –0.48; p = 0.004). Interestingly, a preliminary analysis of a study of mildly hypertensive patients suggests that indexes of QT_apex dispersion and several of the T-wave morphology descriptors are strongly interrelated (unpublished data).

5.  Conclusions

Experimental studies have shown that LVH alters ventricular repolarization. The most consistent findings seem to be prolongation of AP duration and increased dispersion of repolarization. These changes could be expected to prolong QT interval duration and change T-wave morphology in the body surface ECG. Accordingly, we have observed QT interval to prolong as left ventricular mass increases. In addition, in patients with LVH compared to controls, changes in the classical strain pattern, T-wave areas and T-wave morphology descriptors (TMD and TCRT) have been detected and all these measures have shown a significant correlation to the degree of LVH in patients with increased left ventricular mass. However, with the approaches we have used, evaluation of the T-wave changes does not seem to substantially improve detection of anatomic LVH compared to QRS-based LVH-indexes. TMD may be a possible exception, because it showed a very low variance in healthy subjects and was increased in patients with LVH, but this finding needs to be confirmed in a larger patient population. The value of all these repolarization measures as potentially useful markers for risk of ventricular tachyarrhythmias needs to be further studied.

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