Evidence-based Medicine:
What Lesson Can Be Learned for Electrocardiology

Ljuba Bacharova

International Laser Centre, Bratislava, Slovak Republic

Correspondence: L. Bacharova, International Laser Centre, Ilkovicova 3, 812 19 Bratislava, Slovak Republic.
E-mail: bacharova@ilc.sk, phone +421.2.654 21 575, fax +421.2.654 23 244

1.  Introduction

Electrocardiography is a one century old diagnostic method and has the strengths and the weaknesses of its age. On one hand it is a well-established and accepted clinical and experimental method, with a great amount of knowledge and experience accumulated during the century of its existence. On the other hand, there are limitations: the fixed out-of-date views and believes rooted in the accumulated experience with clinical ECG diagnostics, resulting in a gap between the fixed ECG views and the up-to-date non-electrocardiologic knowledge, provided by new diagnostic and imaging techniques. Evidence-based medicine (EBM) provides general principles and a standardized way to seek and evaluate evidence. The aim of this contribution was to apply the principles of EBM to electrocardiology, and to open a discussion on evidence-based electrocardiology. The ECG diagnostics of left ventricular hypertrophy (LVH) based on voltage criteria were used as an exemplar.

2.  Left Ventricular Hypertrophy and ECG Diagnostics

The basic general definition of hypertrophy defines hypertrophy as “increase in size of an organ or tissue without increase in number of its component units. Hypertrophy of the heart may result in several-fold increase of size and functional activity without change in number of the muscle fibres. Often the term is loosely used to mean increase of size without regard to the unit of structure” [Waren, 1953]. In the case of LVH it means, that we have to consider an increase in size, anatomical and electrophysiological remodeling of the left ventricle, as well as the progress and changes over the time. However, the definition of LVH is often reduced to the increase in size or mass, for example: “The most valid definition of hypertrophy is ‘a demonstrable increase in isolated LV muscle mass’” [Davies, 1998].

Electrocardiographic diagnostics of LVH is primarily based on so-called voltage criteria: the increased amplitude of the QRS complex in selected leads [Sokolow and Lyon, 1949; Wolf, 1962]. The current underlying hypothesis expresses the persistent belief that an increased myocardial mass should produce a stronger cardiac electric field reflected in the increased amplitude of QRS complex. For example: ‘The electrocardiographic diagnosis of LVH is based mainly on the increase in QRS voltage generated by the increase in LV mass’ [Liu and Devereux, 1998]. However, using voltage criteria, electrocardiography detects only a small proportion of LVH cases documented by echocardiography or autopsy [Casale et al, 1985; Reichek and Devereux, 1981].

3.  Lesson to be Learned from Evidence-Based Medicine

Sackett et al. [1996] defined evidence-based medicine as the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine (EBM) means integrating individual clinical expertise with the best available external clinical evidence from systematic research, and includes four stages: (1) the formulation of answerable questions, (2) the search for the best evidence, (3) critical appraisal of the evidence, (4) the decision to apply the conclusions to patients’ healthcare.

3.1. Formulation of Answerable Questions

Currently, the continuous effort of electrocardiologists is directed towards the best estimate of left ventricular size or left ventricular mass (LVM). It means that we ask the following questions: “How big is the left ventricle?” or “Is the left ventricle bigger as compared to a normal one?” However, electrocardiography does not provide primarily the information on the size or mass. The magnitude of recorded potentials can, but does not need necessarily reflect the size of the source. In other words, sources of different size can exhibit the same voltage, if they differ in their electrical properties. It follows, that we are asking a question, which is not basically answerable.

3.2. Search of the Best Evidence

Over the years a number of recommended criteria have been published. In spite of the variety of voltage criteria, one theme is common – only values exceeding the upper normal limits are considered to be the evidence. The values within normal limits are earmarked as “false negative” and are neglected in the clinical diagnostic or prognostic decision making.

Another problem is related to the regency of publications. A natural tendency is to read more recent publications, providing latest evidence and opinion, the more, a lot of historical publications is not easily available. However, it can lead to unexpected surprises, as can be demonstrated using an example of quotations of the Brody effect. One interpretation of Brody effect: “This finding would support the Brody effect, namely, an increase in QRS amplitude with a fall in end diastolic volume.” [Fuenamyor et al.,1993], and an opposite interpretation: “Therefore, according to the Brody effect, an increase in left ventricular volume should be accompanied by an increase in surface QRS amplitude, and a decrease in volume, by a reduction in amplitude.” [Vancheri and Barberi, 1989]. Using suitable selected quotations you can explain by the Brody effect both an increase and a decrease in QRS amplitude by a decrease in left ventricular volume.

3.3. Critical Appraisal of the Evidence

Critical Appraisal of the Hypothesis

According to the classical hypothesis we expect, that the increased mass of left ventricle in LVH generates a stronger cardioelectric field. This assumption is rather straightforward: the bigger the mass, the more severe the hypertrophy, the higher should be the amplitude of QRS. Mashima [1976] assigned the hypertrophy causing the enlargement of the QRS amplitude as “ideal” hypertrophy. Ideal hypertrophy refers to a condition where the ventricular muscle increases its volume without any alteration in the activation sequence, and the strength of the double layer and the velocity of the activation wave are the same as normal. In other words, the electrical properties of hypertrophied myocardium are the same as those of healthy tissue.

It follows that the current hypothesis has two implications and therefore could be valid, only if the following two conditions are true:

·        There is no difference between the electrical properties of hypertrophied and healthy myocardium.

·        The electrical properties of hypertrophied myocardium do not change during the evolution and progress of LVH.

However, experimental and clinical cardiology provides enough evidence that these two conditions are not true.

Critical Appraisal of the Application of the Solid Angle Theory

The solid angle theory defines the magnitude of a potential detected at an extracellular site in biophysical terms. However, in the application of the solid angle theory in LVH only spatial determinants are considered. The interplay of non-spatial determinants, such as transmembrane voltage difference, the difference in conductivity or inhomogeneities within cardiac muscle, is not considered at all. Non-spatial determinants are not considered, even when the changes in conductivity are explicitly discussed in relation to the prolongation of QRS duration in the same article [Molloy et al, 1992].

Critical Appraisal of the Design of Studies

In the design of the studies several sources of potential biases can be identified.

Using echocardiography or autopsy as a gold standard can be misleading and a source of potential biases. The increased mass/size is really a dominant characteristic, but only ONE of the characteristics of LVH, not the ONLY characteristic. The endless calculations of specificity and sensitivity, or derived receiver operating characteristics curves, can only repeatedly confirm the well-known fact that the size of an organ and its function are not necessarily proportional.

The simplifications in understanding LVH as an increase in mass/size are often reflected into the used criteria for inclusion of the patients into control/normal and LVH groups, respectively. For example, a variety of cardiovascular pathology is included into both control and LVH groups [Molloy et al, 1992]. Or an unknown proportion of patients with mild hypertension is included into the normal control group, and on the other hand the LVH group contains an unknown proportion of “normotensive patients” [Okin et al, 1995] - are they healthy subjects or hypertensive patients on therapy with well controlled blood pressure?

In most of the studies, the compared groups are not controlled for therapy. This arrangement of the study includes an unstated assumption that therapy has no influence on the recorded QRS voltage.

Similarly, the compared groups are not controlled for known extracardiac factors influencing the physiological variability of QRS amplitude such as age, sex, anthropometric characteristics or race, which are documented to influence the QRS amplitude. But curiously, they are used to explain the false negative results in LVH patients. However, they should influence both normal and LVH population in the same directions, if the studied populations are properly randomized.

The time difference between recorded ECG and the golden standard method measurements can be considerable, especially in studies using autopsy as a reference method. This design of study means that no changes in QRS amplitude are assumed over the time between the recordings of the two methods.

Sources of Flaws in Argumentation and Derived Conclusions

The argumentation used in the ECG diagnostics of LVH is rather monotonous. It assumes that the “electrical dominance” of the left ventricle is enhanced in LVH. So we search for the evidence – the increased QRS amplitude and these results are considered to be TRUE. The QRS amplitude within normal limits is assigned as FALSE negative result. If the proportion of the false negative results is “acceptable”, or the tested criteria “significantly improve” their sensitivity, which could be really of low clinical relevance, the tested ECG criteria are recommended as suitable for ECG diagnostics of LVH. If the proportion of the false negative results is not acceptable, it is concluded that ECG is of limited value for LVH diagnostics or even an obsolete method.

A few weak points can be identified in this sequence of reasoning. One of the possible flaws is generalization: If the increased QRS amplitude is found in a proportion of patients, it does not mean necessarily that it is true for all patients. In reality, the opposite is true: the majority of ECG findings in LVH is within normal limits, what implies for regularity.

And finally, the conclusion that ECG is of limited value or even obsolete for LVH detection is not true. From the fact, that ECG does not estimate the mass we come to a wrong conclusion, that ECG is not suitable for LVH diagnostics. What could be more precisely concluded, it would be the statement that ECG is not suitable for the estimation of left ventricular size/mass. However, the primary information given by electrocardiography is not the information on the size, but on the electrical properties of myocardium. So we are back at the point that we are asking unanswerable question.

3.4. The Decision to Apply the Conclusions to Patient’s Healthcare

The impact of the finding of the increased QRS amplitude on the clinical decision-making is rather limited. In hypertensive patients, the ECG signs of LVH are considered to be an indicator of the ‘target organ damage’. The WHO classification [1978] uses the presence or absence of ECG LVH as a criterion for differentiating between stages 1 and 2 of established hypertension. It is also included in the risk stratification of hypertensive patients recommended by JNC VI [1997]. The practical consequence for an individual patient is the recommendation to start pharmacotherapy without waiting for the effect of non-pharmacological intervention.

In the general population, ECG signs of LVH are rarely included in calculations of the ‘risk score’ in health promotion programmes, in spite of the fact that ECG LVH is an independent risk factor of cardiac morbidity and mortality.

The so-called false negative results are not considered for further diagnostic or prognostic decision making, and have no impact on the decision on therapy. However, the high number of false negative results indicates the necessity to assess the diagnostic and prognostic significance of this phenomenon.

4.  Conclusions

The application of EBM approach to electrocardiology, as demonstrated at the example of LVH, contributed to reveal fixed old habits and inertia in thinking years, as well as gaps in our knowledge:

·        An unanswerable question is asked;

·        The evidence is modified slightly or considerably by re-quotations. The diagnostic validity of ECG is tested only in relation to size, it follows that the traditionally used “gold standard” methods are questionable, the application of the spatial angle theory is only partial and the evidence is biased by selection of patients;

·        There are gaps in our knowledge with respect to the clinical meaning and importance of findings, when the size and the electrical properties are not in accordance and in our knowledge with respect to changes of the relationship between size and electrogenesis during the progress of LVH and under therapy;

·        The dominant findings, the so-called false negative results, are neglected in diagnostics.

Identifying the limitations of the current ECG diagnostics of LVH, the EBM approach has contributed to develop an alternative view on the possibilities of electrocardiography in LVH diagnostics [Bacharova and Kyselovic, 2001, Bacharova 2003]. The alternative view re-defines the false-negative ECG results as true results, attributing the discrepancies between increased mass and normal QRS voltage to changed electrical properties of myocardium due to hypertrophic remodelling. It was demonstrated that the structured and systematic EBM approach to clinical decision making can also contribute to the re-evaluation of old hypothesis and to the shift in paradigm.

Acknowledgements

This study was supported, in part, by the grant 1/0507/03 from The Science Grant Agency (VEGA), Slovak Republic.

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