diastolic dysfunction and hypertension, left ventricular stiffness, P-wave dispersions, P-wave terminal force in V1, ventricular activation time
2D echo two-dimensional echocardiography study
DD diastolic dysfunction
LV stiffness left ventricular stiffness
LVH left ventricular hypertrophy
LVMI left ventricular mass index
PTFV1 P-wave terminal force in V1
PWD P-wave dispersions
TDI tissue Doppler image
TMD transmitral Doppler
VAT ventricular activation time
Hypertension and diastolic dysfunction: the scope of the problem
Hypertension is one of the major risk factors associated with cardiovascular events. The disease burden is estimated to be as high as to 30% amongst the general population in the United States .
Among the asymptomatic hypertensive population, diastolic dysfunction echocardiography parameters have shown a significant correlation with the increase in systolic and diastolic blood pressure. The severity of diastolic dysfunction also progressed (from grade I to grade III) with the rise in blood pressure readings. The process of myocardial remodeling starts before the onset of symptoms, hence diastolic dysfunction echo parameters are sensitive to the earliest myocardial pathophysiologic changes .
Diastolic heart failure may result in clinical manifestations and exercise limitations. Approximately 20 million patients in 51 European countries have echocardiographic evidence of diastolic dysfunction. Fifty percent of patients with overt congestive heart failure (CHF) have diastolic dysfunction without reduced ejection fraction (EF). Redfield et al demonstrated that the mortality rate secondary to mild diastolic impairment was 10% in a 5-year period compared to 25% in moderate to severe diastolic dysfunction (grade II and III) .
ECG voltage criteria in left ventricular hypertrophy
An electrocardiogram (ECG) is of limited use for left ventricular hypertrophy (LVH) risk stratification in asymptomatic patients with elevated blood pressure. The sensitivity and specificity of standard ECG criteria were relatively poor for the diagnosis of LVH on echocardiography. Among all ECG criteria, the Cornell voltage product is the most sensitive (50%), followed by Sokolow-Lyon (29%) and Romhilt-Estes (22%). However, there is no correlation between QRS duration and left ventricular mass index (LVMI) .
In the hypertensive population, the 12-lead ECG proved to have limited sensitivity and specificity for the detection of LVH in asymptomatic patients. Cornell product, as a surrogate for the most sensitive voltage criteria, sensitivity is 25.4% (95% CI: 15.3% to 37.9%) and specificity of 75.0% (95% CI: 19.4% to 99.4%). Bacharova et al have extended investigation for more sensitive markers. They employed a computer model to evaluate the effect of changes in the anatomy and conduction velocity of the left ventricle on QRS complex durations. This proved that LVM is not the only determinant of the QRS complex changes in LVH, but it is rather a combination of anatomic and electric remodeling that creates the whole spectrum of the QRS complex duration prolongation seen in LVH patients .
Furthermore, the relationship between QRS amplitude and left ventricular mass (LVM) in the early stages of LVH was also investigated and revealed a lower QRSmax voltage when compared to normal. This is attributed to the changes in the electrogenetic properties of the myocardium in the early stage of developing LVH, enforcing the theory that electrical remodeling plays a key role and may precede detectable anatomical remodeling .
Classic ECG criteria alone may lack the ability to detect the changes in LVH patients and they have shown a low sensitivity. However, early changes in QRS duration and maximum amplitude provide a potential novel marker for early changes.
Ventricular activation time and hypertensive diastolic dysfunction
Activation starts on the left side of the interventricular septum about 0.01 to 0.015 seconds earlier than the right side. However, since the left side branch of the bundle of His enters the septum higher than the right side branch, the greater myocardial thickness of the left-sided septum and the earliest output on the right side are in the mid RV cavity; this facilitates faster activation on the right septum, and the earliest output direction of the vector is essentially to the right mid cavity. This first wave of electric movement is a rather important fact as it the normal septal Q-wave in leads I, aVL, V5 and V6. The cardiac apex depolarises immediately after the right ventricle (RV) septum which reflects the R-wave on surface ECG in leads I, II and III. Right ventricular depolarisation occurs quickly and completes earlier than the left ventricle owing to the thinness of the RV muscle structure compared to that of the left ventricle (LV). The third wave is the spread of the depolarisation towards the lateral wall of the LV and coincides with R-wave amplitude in II and I and an S-wave in III.
Ventricular activation time (VAT) or intrinsicoid deflection is measured in milliseconds on the surface electrocardiogram from the onset of the QRS complex to the peak of the R-wave (QR interval).
VAT had various clinical values in previous literature. Early reports by Romhilt- Estes developed scoring criteria for left ventricular hypertrophy. This employed a VAT duration of more than 0.05 sec in V5 or V6 as a valid scoring point . Later, Berruezo et al investigated the role of the intrinsicoid deflection VAT in identifying the epicardial origin of ventricular tachycardia of >85 ms . However, the use of VAT as a marker in the hypertensive population without LVH was not fully established.
A recent prospective study in patients with newly diagnosed and untreated hypertension was designed to investigate the role of VAT and P-wave morphology/duration for the detection of diastolic dysfunction. All patients had a high-resolution ECG and echocardiographic assessment equipped with tissue Doppler imaging (TDI) capabilities. Baseline echocardiography examinations were done to rule out LV hypertrophy, defined, according to the American Society of Echocardiography, as an LV mass index (LVMI) >115 g/m2 (male) or 95 g/m2 (female) . LV diastolic dysfunction was assessed according to the AHA/ESC Consensus Guidelines .
VAT was prolonged in subjects with diastolic dysfunction (46.3±0.4 vs. 39.6±0.3 ms; p<0.01); this prolongation was statistically significant and proportional to TDI indices of diastolic dysfunction such as early diastolic velocity (e') (r=-0.53; p<0.0001), ratio of early and late diastolic Doppler velocities (e'/a') (r=-0.53; p<0.0001), ratio of early peak filling rate and early deceleration peak (E/A) (r=-0.32; p=0.001), and ratio of early diastolic mitral inflow and early diastolic velocities (E/e') (r=0.44; p<0.0001). A multivariate stepwise regression model showed that tissue Doppler e′/a′ and E/e′ were independent determinants of VAT in assessing diastolic dysfunction without contribution from age, gender, left atrial (LA) dimension, LVMI and interventricular septal diameter as covariates (r2=0.40; p<0.0001). The best VAT correlations between mean VAT readings and all 12-lead readings were found in V6 .
Almuntaser et al compared ECG voltage criteria against LV stiffness index (LV stiffness measured by dividing the E/E’ Doppler parameters by the LV end-diastolic dimension) in a meta-analysis study . The latter represents the pressure-volume relationship in diastolic dysfunction. The study showed progressive VAT prolongation from grade I to grade III of diastolic dysfunction. Additionally, this study validated the superiority of VAT, in a group with LVH and interventricular septum more than 1.2 cm, over Sokolow, Cornell product and the five other known ECG voltage criteria. The classic ECG voltage criteria have failed to correlate with LVH (2-17% depending on which voltage criteria are used); on the other hand, VAT was a more sensitive indicator up to 90% sensitivity with LVH (i.e., an increase of more than 1.2 cm of the end-diastolic thickness of the interventricular septum [IVSd]).
These results have validated VAT delay in apparently structurally normal myocardium (i.e., normal LVMI) as the only ECG marker to indicate the degree of left ventricular stiffness in diastolic dysfunction.
P-wave terminal force in V1 and hypertensive diastolic dysfunction
P-wave terminal force in V1 (PTFV1) has emerged as a novel ECG marker with a strong prognostic value in cardiovascular events . PTFV1 is defined as the product of the amplitude of the terminal negative component of the P-wave in V1 (i.e., each small square measured equally in mm or 0.1 mv) and the duration (ms). A negative cut-off value of P-wave terminal forces more than and/or equal to 40 mm/ms was considered positive and was a predictor of cardiac death or hospitalization for heart failure. PTFV1 (duration x amplitude) was superior to P-wave duration only as a prognostic marker . In another study, PTFV1 was found to be associated with an increased risk of atrial fibrillation . Moreover, Kohsaka et al found a proportional relationship between a PTFV1 ≥40 mm/ms and ischemic cerebrovascular events . Another large population-based study identified PTFV1 as an ECG marker associated with an increased risk of all-cause, cerebrovascular disease and ischemic heart disease mortality .
The pathophysiologic explanation of hypertension effect links the diastolic dysfunction occurrence with left atrial pressure changes resulting from elevated left ventricular end-diastolic pressures. These changes, in turn, are transmitted to the left atrium (LA), leading to continuous stretching and scar formation. In another explanation, atrial changes mainly occur secondary to pressure tension transmitted to the atrial walls from increased resistance in the early diastolic filling phase. Subsequently the remodelled and geometrically changed LA may impede the propagation of the electrical impulse, leading to voltage and conduction time augmentation.
A PTFV1 of more than minus 40 mm/ms would theoretically reflect LA geometric changes in diastolic dysfunction due to delayed electrical propagation in the atrial tissue. P-wave amplitude and duration together (in PTFV1) have superior diagnostic value in assessing LV end-diastolic pressure and hence diastolic dysfunction than P-wave duration only .
Hence PTFV1, as an ECG marker, was studied with diastolic parameters assessed by echocardiography. The patient cohort included previously undiagnosed hypertensives who were screened by echocardiography for diastolic dysfunction. Those who had diastolic dysfunction were investigated further using PTFV1 on the surface ECG. Echo parameters for diastolic dysfunction were statistically significant with PTFV1 ≥40 mm/ms with a sensitivity of 62% and specificity of 75%. This study highlights the potential role of PTFV1 in diagnosing hypertension in the early phases .
P-wave dispersion in hypertensive diastolic dysfunction
P-wave dispersion (PWD) is defined as the difference in milliseconds between the longest and shortest P-wave duration on the 12-lead ECG. PWD has been extensively studied in various cardiovascular and non-cardiac conditions. At present, PWD is an established non-invasive marker for risk of developing atrial fibrillation .
In diastolic dysfunction, Dogan et al emphasized the heterogeneous pattern of propagation of electrical activity through the atria in hypertensive patients because of “scar tissue” accumulation. In this study, longer PWD duration correlated significantly with the parameters of impaired diastolic function .
When PWD was investigated in early hypertensive diastolic dysfunction, a significant correlation was also shown with echo diastolic parameters such as TDI E’/A’ (r=-0.37; p<0.0002) and TMD E/A (r=-0.23; p<0.002) .
Electrical remodeling in hypertensive diastolic dysfunction
Ventricular diastolic dysfunction is an earlier cardiac manifestation of hypertension that preceded the detection of LVH on the ECG [21,22].
Previous studies in animal models confirmed the role of electrical remodelling on conduction velocity and pulse propagation in QRS duration and maximum voltage [5,6].
Remarkably, well-known LVH ECG voltage criteria induced by longstanding high blood pressure cannot independently identify diastolic abnormalities [12,23]. However, careful examination of ECG VAT and atrial parameters, without LVH criteria, may predict diastolic dysfunction, providing novel diagnostic markers of this common disease.
Electrical cardiac remodelling may be associated with early diastolic heart dysfunction (i.e., velocity delays): it can precede any increase in the LV mass and the development of LVH in undiagnosed hypertension. Previous studies support the fact that diastolic dysfunction occurs early in the course of hypertension and precedes measurable LVH . A VAT increase secondary to electrical remodelling is proved, even if LV geometry remains unchanged.
The importance of the diagnosis of diastolic heart dysfunction in the community is linked to the wide prevalence of hypertension. Since hypertension is an asymptomatic and insidious disease, early ECG signs for cardiac electrical remodelling provide a wealth of information for disease stratification.