Data Collection Methods

Invasive methods are the most direct and reliable ways to assess left ventricular diastolic function with measurement of left cavity pressure and simultaneous volume measurements. This requires cardiac catheterization, high fidelity pressure recording, with simultaneous angiography, echocardiography or use of conductance techniques⁷⁰. The rate of relaxation is estimated from the peak negative dp/dt and the time constant of relaxation, tau. The left ventricular distensibility is derived directly from the reconstruction of a pressure-volume loop. The disadvantage is that invasive assessment is cumbersome and impracticable in routine clinical practice⁷¹.

Transmitral flow pulsed-wave Doppler echocardiography is the most conventional method to evaluate diastole. The test, however, shows an important variation in E and A wave indices, and in the ratio between both waves (E/A) in view of changes induced by LV preload. The early transmitral wave E is strongly dependent on loading condition.

A few studies showed the lack of a pattern of normality even with a clear clinical condition of diastolic dysfunction and heart failure. This lack of a pattern began to be designated as “pseudonormal pattern”. Such a pattern results from increased left atrial pressure that becomes higher than the effects of LV relaxation. This dependence on velocity and the isovolumetric relaxation time in relation to LV relaxation, as well as to left atrial pressure, was noticed long ago, and these variables set a framework that conveys the limitations of the methods based on transmitral flow assessment.

Although the mitral inflow velocity curves are predictive offilling pressures and can determine prognosis in subgroups ofpatients, there are major pitfalls that can limit the utilityof mitral inflow in the general assessment of diastolic function.First, prediction of left ventricular filling pressures by mitralvalve inflow velocities appears to be accurate only in thosepatients with systolic dysfunction, as patients with normalsystolic function show wide scatter of filling pressures.This is related to the progression of disease that occurs, so that in an advanced state of diastolic dysfunction the mitral inflow pattern looks identical to the normal state. The reasonfor the confusing similarity is that normal hearts have rapid relaxation and fall in left ventricular pressure such that blood is

"sucked" across the mitral valve. Those with grade II diastolic dysfunction display a

"pseudonormal" mitral inflow from theraised left atrial pressure where blood is "pushed"

across thevalve. There also are data that demonstrate that patients withan E/A ratio < 1 can have raised left ventricular fillingpressures as they transition to higher degrees of

diastolic abnormality.The distinction of normal versus pseudonormal filling is difficult using the mitral inflow alone and in mostpatients other parameters will be necessary to complete theassessment.

Pulmonary venous flow velocities: Pulmonary venous flow velocities may be obtained from either the transthoracic or tranesophageal imaging windows. This tracing is obtained in the apical four chamber view by placing the sample volume 0.5-1.0cm in the pulmonary vein. Four velocities components are obtained during the cardiac cycle: two systolic forward flow(S1 and S2 waves due to atrial relaxation with lowering of atrial pressure with consequent pulmonary vein flow to the left atrium and due to increase in pulmonary venous pressure following right ventricular contraction respectively), a diastolic forward flow velocity (D-wave due to forward flow which occur in diastole as a result of the drop in left atrial pressure resulting from mitral valve opening), and an atrial reversal wave during atrial contraction (Ar-wave).

Pulmonary venous flow is used as an adjunct to mitral inflow.Pulmonary venous flow pattern has also been well characterised and provides additive insight to diastolic filling of the leftventricle⁷². The pattern of flow (systolic versus diastolicpredominance) has been proposed as a predictor of left atrialpressure but is not applicable in unselected patients because of the multiple contributions to these velocities. Comparison of the duration of flow at atrial contraction across the mitralvalve and the durationof reversal flow back into the pulmonary veins has been repeatedly demonstrated toreflect the left ventricular end diastolic pressure. As fillingpressures and therefore operating chamber characteristics worsen, a worsening relative compliance of the left ventricle compared with the pulmonary venous circuit is observed. Transmitral flowat atrial contraction is shortened while retrograde flow at atrial contraction into the low resistance pulmonary

venouscircuit continues for a longer duration. If the duration ofatrial reversal flow in the pulmonary vein exceeds by more than30 ms the duration of flow across the mitral valve, raised leftventricular end diastolic pressure can be diagnosed with high specificity. The major limitations to the use of the pulmonary venous signals are that these signals are difficultto obtain and interpret⁷³. The technical feasibility of obtainingadequate signals has been reported at less than 80% of unselectedpatients⁷⁴.

Colour M-mode colour flow: This method aims to define the propagation of flow from the atrium to the ventricle during diastole. This is achieved by positioning the M-mode cursor through the centre of the mitral annulus in the apical four chamber view and aligned to approximate the vector through the mitral valve. Two waves of flow propagation are seen, the first corresponding to the early filling(E-wave) and the second with atrial contraction (A-wave)⁷². The velocity of propagation of flow through the left ventricle represented by the slope of the colour waveform is an index of diastolic function.

Similar to the tissue Doppler velocities, colour M mode flowpropagation has been combined in a ratio with the mitral E velocityto provide an "adjusted" parameter (E/Vp) with strong correlationto filling pressures and prognosis.The chieflimitations of this tool are lack of consensus on techniqueand theoretical concerns that this will be invalid in smallleft ventricular cavities⁷⁴.

Tissue Doppler echocardiography: This is based on the application of the principle of Doppler to measure tissue velocities. Tissue motion when compared to blood motion has a lower velocity. Consequently by rearranging the filter and amplification, bypassing the

high pass filter and lowering gain amplification, the Doppler signal reflected by the ventricular wall are displayed. Three basic tissue motions are displayed. The first occur during systole (Sⁱ). Two diastolic motion velocities (Eⁱ)and Aⁱ in late diastole are seen.

Tissue Doppler imaging has been shown to be more reliable and an easy method to evaluate diastolic function⁷³. Patients who have been classified as having normal diastolic function based on transmitral in-flow velocities have been shown from tissue Doppler imaging to actually have diastolic dysfunction. Transmitral parameters alone do not correlate with LV filling pressure in patients with preserved systolic function⁷⁵. The use of tissue Doppler helps to differentiate pseudonormal from impaired relaxation and it has been shown to be a preload independent index of left ventricular diastolic function⁷⁶.

Tissue Doppler (TD) assesses high-amplitude and low-velocity signals from the myocardium. This resource has been useful as a quantitative index of LV segmental function for analysis of both diastole and systole. Diastolic dysfunction studies have shown that this is relatively independent of preload and it has been documented that probability of the same “pseudonormalizaton” seen appearing is low with TDI assessment of the diastolic function, and may even be used to yield a highly accurate diastolic segmental analysis, as shown in a recent study⁷⁶, in which interrogation of multiple sites with this technique was possible using color tissue Doppler data and processing signals from all LV segments.

Tissue Doppler is the method that assesses segmental myocardial velocity at both diastole and systole. In a study comparing the interventricular septum on TDI⁷⁷ with that of transmitral flow in twenty patients with standard relaxation deficit (E/A wave ratio

<1), who received an infusion of 700 ml of physiological saline, a significant change was observed in the E/A velocity ratio measured by transmitral flow (E/A=0.7 ± 0.1 vs. 0.9 ±

0.1 p < 0.01), which was not observed in the TDI measurements (E’/A’=0.5 ± 0.1 vs. 0.5

± 0.1. p=NS) . These results point to the fact that assessment of segmental ventricular wall motion by TDI is relatively independent from ventricular preload.

The velocity of the mitral annulus, representing velocity of changes in left ventricular long axis dimensions, has been relatedto measures of systolic and diastolic left ventricular performance. The diastolic velocity has been proposed as representing the intrinsic speed of myocardial relaxation. This may then be used to determine the difference between the effect of "suction"(normal E wave and rapid early mitral annular velocity) versus"pushing" with high left atrial pressure causing an increasein transmitral flow (normal E wave with reduced early mitralannular velocity)⁷⁶.

The ventricle elongates in two distinct phases. The annular velocities recorded during these two phases are called E' and A', which correspond temporally with the mitral E and A waves.The velocity of E' has been modestly correlated to the timeconstant of relaxation. A pattern of progression of diastolic dysfunction of the Doppler tissue velocities can be seen. In the initial stages of diastolic dysfunction, the relaxationvelocity (E') decreases and remains reduced throughout the remainingstages of impaired diastole.

Investigations have shown that combining the mitral inflow with the mitral annular velocity into a ratio (E/E') can predict left ventricular filling pressure⁷⁶. The ability of this ratio to predict filling pressure has been demonstrated in patients with normal sinus rhythm, sinus tachycardia,preserved systolic function, atrial fibrillation, and in patientswith hypertrophic cardiomyopathy⁷⁸. This combination may resolvethe issue of discriminating normal from pseudonormal filling.Patients with diastolic dysfunction and a normal appearing mitral inflow pattern will also have a reduced mitral annular

velocity(E') and an elevated E/E' ratio. Again, cut off values can easilybe selected from published data. If E/E' is > 15, left ventricularfilling pressure is raised, and when E/E' is

< 8 filling pressure is low. However, between 8–15 there isconsiderable variability in filling pressure.⁷⁶

Figure 2 showing the indices of tissue Doppler imaging.

Reproduced from: Dokainish H. Tissue Doppler imaging in the evaluation of left ventricular diastolic function. Curr Opin Cardiol 2004;19:437-41.

Table 1 : Classification of diastolic dysfunction by pulsed wave Doppler and tissue Doppler imaging⁷².

Transmitral flow TDI

Grade E/A DT(ms) IVRT(ms) Ei/Ai

Normal 1-2 150-200 50-100 1-2

Mild <1 >200 >100 <1

Moderate 1-2 150-200 <50 <1

Severe >2 <150 <50 <1

Just as systolic functions in SCA subjects have resulted in conflicting conclusions, there is also conflicting conclusions in the diastolic function in SCA subjects. Doppler assessment of left ventricular function of some SCA patients has demonstrated diastolic dysfunction⁷⁹.

Lewis et. al.⁸⁰ observed that 17% of 30 SCA patients studied had evidence of abnormal diastolic filling while others had normal diastolic function. They also reported that left ventricular filling abnormalities were evident in Doppler echocardiography in many patients with SCA even in the absence of symptoms of heart failure or left ventricular systolic dysfunction. Balfour and colleagues ²⁷ observed that diastolic dysfunction is an important factor in limiting the exercise capacity of patients with SCA.

In a study by Adebayo and Balogun¹⁰, Doppler assessment of the transmitral flow velocity curve of 41 SCA patients suggested that LV diastolic abnormalities were present in patients with SCA despite normal systolic function. The mitral E/A ratio was higher among the SCA subjects than the controls, but it was not statistically significant. This was attributed to the apparent normalization of the very high mitral E/A ratio in some of the SCA subjects and those with very low values.

San et. al⁸¹. also noted evidence of diastolic dysfunction in SCA subjects compared with controls. They used transmitral flow parameters to assess the diastolic function. The abnormal diastolic function found in SCA subjects was concluded to be likely caused by left ventricular hypertrophy and increased LV mass among SCA subjects. Similarly, Kingue et. al.⁸² noted evidence of diastolic dysfunction in 50 SCA subjects as assessed by transmitral flow indices. When compared with the controls, the SCA subjects had higher frequency of diastolic dysfunction.

On the other hand, in a study by Betra et. al.⁸³ of 122 adolescents with SCD, diastolic dysfunction was found among the SCD subjects, but there was no difference in the prevalence of diastolic dysfunction among sickle cell subjects and normal controls.

The indices used in the assessment included transmitral flow and tissue Doppler imaging.

Similarly, Kanadasi et. al.⁸⁴ studied 31 SCA subjects with a mean age of 26.4years, using tissue Doppler imaging. They observed that left ventricular diastolic dysfunction is uncommon in SCA subjects who do not have congestive heart failure. He also noted that tissue Doppler imaging was a reliable and easy method to evaluate diastolic function.

The early diastolic mitral annular velocity Eⁱ has been shown to be a relatively load independent measure of myocardial relaxation in patients with cardiac disease⁷⁶. The TDI may be combined with pulsed Doppler transmitral flow in early diastole (E), and the resultant ratio (E / Eⁱ ratio) has been correlated with left ventricular filling pressures measured invasively^75,76. Increased E/ Eⁱ ratio has been shown to suggest increased myocardial stiffness⁸⁵. Values less than 8 has been associated with normal left ventricular filling pressures, 8-15 is intermediate, which means that they are variable, but values higher than 15 have been associated with high left ventricular filling pressure.

Zilberman et. al.⁸⁵ studied diastolic function in SCA children and adolescents using the the combination of TDI and transmitral flow indices. They suggested that there may be increased LV myocardial stiffness in SCA based on the increase in the ratio of the E/E^i..They suggested that there may be evidence of diastolic dysfunction in SCA subjects as they increase in age as a result of the possible progression of LV stiffness with age.

54% of the subjects studied were 12 years and he found higher values of E/Ei ratio among the older age group.

Left Ventricular geometry in sickle cell anaemia.

When the heart faces a haemodynamic burden, it can do the following to compensate:

1. Use the Frank-Starling mechanism to increase the cross bridge formation.

2. Augment muscle mass to bear the extra load.

3. Recruit neurohormonal mechanisms to increase contractility.

The first mechanism is limited in its scope and the third is deleterious as a chronic adjustment. Thus, increasing mass assumes a key role in the compensation for haemodynamic overload. This increase in mass is due to the hypertrophy of existing myocytes rather than hyperplasia, because cardiomyocytes become terminally differentiated soon after birth.

There is a parallel addition of sarcomeres, which result in increase in myocyte width with subsequent increase in thickness. This in turn leads to an increased ratio of wall thickness to chamber dimension, which is concentric hypertrophy.

According to Laplace’s law, the load on any region of the myocardium is given as follows:

(Pressure × radius) / 2 × wall thickness)

Thus an increase in pressure can be offset by an increase in wall thickness. Because systolic stress is a major determinant of ejection performance, the normalization of systolic stress helps maintain a normal ejection fraction even when there is a need to generate high levels of systolic pressure^.86

In volume overload as in subjects with SCA, there is myocyte elongation or lengthening by sarcomere replication in series with an increase in ventricular volume.

They often have an eccentric pattern of LV hypertrophy. Chronic volume overload is one of the leading causes of ventricular remodelling and heart failure among patients with valvular regurgitation, congenital heart disease and arteriovenous shunt. This pattern of hypertrophy which is eccentric is initially compensatory, such that the heart can meet the demand to sustain a high stroke volume. However, chronic hypertrophy may be deleterious because it increases the risk for the development of heart failure and death.

With increased hemodynamic stress, the heart must adjust to meet the greater demands placed upon it. This adjustment frequently involves an alteration or remodeling in its structure or geometry, which augments its performance and helps to maintain adequate function under changing conditions⁸⁷. One of the most important forms of remodeling that the heart may undergo is an increase in muscle mass in response to a pressure or volume overload or myocardial injury. This increase in muscle mass is known as left ventricular hypertrophy (LVH). LVH is of great importance from a risk selection perspective for two reasons: it is common, and it is associated with a significant increase in both morbidity and mortality risk.

The LV geometric pattern characterisation among SCA subjects has been less studied.

Studies have shown evidence of eccentric LV hypertrophy among SCA subjects and this

is similar to other conditions of volume overload such as aortic regurgitation⁸⁸. A recent study by Sachdev et. al.⁸⁹ showed that LV concentric remodelling was a prevalent geometric pattern among the SCA subjects that were studied. They found 14.9% of their SCD subjects with concentric LV remodelling, 3.8% with concentric LV hypertrophy and while only 3% had eccentric hypertrophy.

There is need for more studies in this environment to characterize the LV geometry in SCA subjects.

RATIONALE FOR THE STUDY

It would be seen from the foregoing that the heart is not spared in sickle cell anaemia though the precise effect of the disease on the heart has not been conclusively described.

The probable causes of the cardiovascular abnormalities seen in sickle cell anaemia would include the effect of the chronic anaemia on the heart, the effects of intracoronary sludging and sickling resulting in myocardial ischaemia and/or infarction, and the consequences of the pulmonary involvement by the disease.

Although Nigeria has a high prevalence of the disease, few works had been done to evaluate the cardiac function in patients with SCA. Most of the previous studies on SCA and the heart had come from North America and virtually little had emerged from Africa.

Studies that have been done in Nigeria showed evidence of normal systolic function in SCA subjects^9,10. This study in particular becomes necessary since as it would provide much needed information on whether a depressed cardiac function does indeed occur in Nigerians with SCA and contribute to their morbidity and mortality, assess if there is diastolic dysfunction among SCA subjects and also characterize their LV geometry.

CHAPTER THREE

AIMS AND OBJECTIVES

GENERAL AIM

To assess the left ventricular structure and functions in patients with sickle cell anaemia seen at the University College Hospital, Ibadan.

SPECIFIC OBJECTIVES

(1). To assess the left ventricular diastolic and systolic functions in SCA patients.

(2) To compare the left ventricular diastolic and systolic functions in sickle cell anaemia patients with comparable age and sex matched controls.

(3). To characterize the left ventricular geometric patterns in sickle cell anaemia patients seen at UCH, Ibadan.

(4). To compare the left ventricular geometry in SCA with comparable age and sex matched controls.