Dear Editor,

I read with great interest the article presenting tissue Doppler techniques as technological advances.[1] The authors conclude with the “limitations” of tissue Doppler stating “There is still a significant variability in TDI (tissue Doppler imaging) derived parameters because of differences in machine characteristics and lack of guidelines for standardization of sample positions and machine settings. Therefore it is still difficult to provide firm recommendations for clinical practice. More clinical trials are needed for establishing sensitive and effective parameters for diagnosing specific conditions or detecting abnormalities”. In which case is it technological advances?

There are philosophical, methodical and application flaws in tissue Doppler.[2] The basic principles of measurement and Doppler are compromised in this technique. After you make a measurement as per established methods you could have “limitations”. But if you make a measurement paying scant regard to established norms it’s a “blunder”. So you cannot blame “differences in machine characteristics” nor “lack of guidelines for standardization of sample positions and machine settings”. It is like measuring the height of a patient without knowing the required alignment, making random measurements and calling the erroneous measurements as “limitations” of the scale (see figure)! This would be a case of right tool, wrongly used. You cannot sweep the basic flaws under the carpet by labeling them as “limitations”.

The authors state “In practice, from the apical window, only longitudinal shortening can be obtained from every segment of the left and right ventricle. These longitudinal velocities reflect both active and passive myocardial motion, which forms the major limitation of the technique”. The problem here is much more than “active and passive myocardial motion”. Doppler will give consistent results only if there is a unique velocity or if the other conflicting velocity vectors are constant. In tissue motion there are several velocity vectors affecting the resultant longitudinal vector. Since we do not know the influence of these conflicting vectors we will consistently get variable results. Compare flow motion and tissue motion to understand this better.

The authors also state that “The sample volume should be positioned in the centre of the region of interest. It is recommended to check the sample volume position before acquiring the still frames since the motion of the atrioventricular ring may differ around the basal myocardial segment”. Pray, where are the regions of interest and the points of interrogation? In case of flow Doppler these are unique points - the normal and abnormal orifices. Can we ever define a proper point of interrogation on tissue Doppler? That is also why the authors correctly state “normal values for longitudinal velocities depend on the position of the sample area within the wall”. This is also why, as the authors mention, there are “lack of guidelines for standardization of sample positions”.

Doppler strain and E/E’ are incorrect because the foundation is wrong. Besides in the formula for strain calculation, the modulus of a vector quantity (velocity) is incorrectly substituted for a scalar quantity (length) in the original equation. E/E’ also goes against the scientific “principle of parsimony”.[3]

When cardiac uses of Doppler were first studied, Doppler recordings were thought to come from the heart tissues and no signals were attributed to blood flow. Consequently the Doppler technique did not interest the cardiologists then! When considering developments in echocardiography, the developments should incrementally add to our knowledge and refine the data collection. In tissue Doppler it is a retrograde development. We use Doppler to study flow because we cannot image flow. When imaging flow becomes a reality, Doppler would be relegated to the background. When we can “see” the tissue there is no need for an indirect Doppler methodology. In this context the authors mention about 2D speckle tracking. They state “Local 2-dimensional tissue velocity vectors are derived from the spatial and temporal data of each speckle” This would be advancement in the right direction.

Another problem is the high sensitivity of tissue Doppler compromising on the specificity. An akinetic segment correctly displayed on M-mode is never displayed as 0 velocity on tissue Doppler. This will also affect the temporal data. The authors correctly mention this albeit with a wrong explanation. “However, in patients with ischemic cardiomyopathy, TDI and realtime three-dimensional echocardiography show poor agreement for evaluating the magnitude of intraventricular dyssynchrony and the site of maximal mechanical delay. This may be explained by their respective assessment of longitudinal versus radial timing”.

Tissue Doppler can never be a technological advancement. All advancements are built on strong foundations in basic sciences. Here the basic principles of measurement and Doppler are compromised. Making clinical judgments based on this faulty modality would be unacceptable to the scientific cardiologist.

Figure 1
Principles of measurement. We should know the alignment before we apply the measurement tool. In the case of measurement of height, the person has to be standing erect and the scale has to be applied in the AB direction. Any other measurement like XY would be invalid. Similarly you cannot measure the height correctly in a non-erect position. In tissue Doppler measurements we do not know the alignment of the significant velocity vector to apply the Doppler tool. Besides, myocardial motion is complex and cannot be studied with "line of sight" measurement tool like Doppler.

References

1. Van de Veire N, De Sutter J, Bax JJ, and Roelandt JR.
Technological advances tissue doppler imaging echocardiography
Heart Online First. January 29, 2008

2. Thomas G.
Tissue Doppler echocardiography – A case of right tool, wrong use.
Cardiovascular Ultrasound 2004;2:12.
Available at http://www.cardiovascularultrasound.com/content/2/1/12

3. Thomas G.
Is E/E’ really reliable? Comment on
Cardiovascular Ultrasound 2007; 5:16.
Available at http://www.cardiovascularultrasound.com/content/5/1/16/comments

Dear Editor,

It is with great interest that we read the contribution by Kayvan and colleagues (1) on the long-term effects of cardiac resynchronization therapy (CRT) in patients with atrial fibrillation (AF), not treated with atrio-ventricular junction (AVJ) ablation. Somewhat surprising is the extremely high proportion of AF patients in this cohort : 86/295 patients (29%), probably the highest incidence ever reported in CRT. At a more careful analysis, it can be noted that 20/86 (23%) of AF patients presented only paroxysmal AF (PAF). PAF patients, even before CRT, spend more than 90% of the time in sinus rhythm (SR), and it is well known that CRT significantly reduces AF burden during follow-up (2). This means that PAF patients, after CRT, are paced in DDD modality for about 90-95% of the time. Would these 20 PAF patients be considered in the SR group, then the proportion of AF patients would approach that of other larger series (3, 4). Placing PAF patients as part of the AF group may have introduced 2 important biases in the Kayvan study: 1) patients with PAF, usually present higher mean biventricular pacing percentages (BVP%) compared to patients with permanent AF (explaining the 87% BVP% in this AF group); 2) PAF behave “clinically” like SR patients, and drag, within the AF group, the positive effects conferred by CRT in SR. Mixing these 20 “clinically”, SR-like patients into the AF group, may confound any outcome result. The high BVP% reported into the AF group is even more astonishing considering the low use of chronotropic-negative drugs and the lack of use of ventricular rate regularization (VRR) feature, extremely important to ensure biventricular capture in case of fast irregular rhythm. Conversely, in our experience (3), after 2 months of CRT, only 30% (48/162) of AF patients presented BVP% >85% despite implementation of a rigorous rate-control protocol (rate-lowering drugs plus VRR and trigger mode). Another explanation accounting for the high BVP% in the Kayvan series may be that several AF patients presented very low-rate AF at baseline, with a possible coexisting pacing indication, thus rendering futile recourse to AVJ ablation: unfortunately this hypothesis cannot be ruled out as mean baseline heart rate was not presented.

References

1) Kayvan K, Foley PW, Chalil S et al.
Long-term effects of cardiac resynchronization therapy in patients with atrial fibrillation.
Heart Online First, January 2008.

2) Hugl B, Bruns HJ, Unterberger-Buchwald C et al.
Atrial fibrillation burden during the post-implant period period after crt using device-based diagnostics.
J Cardiovasc Electrophysiol 2006; 17: 813-7.

3) Gasparini M, Auricchio A, Regoli F et al.
Four-year efficacy of cardiac resynchronisation therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation.
J Am Coll Cardiol. 2006 Aug 15;48(4):734-43.

4) Auricchio A, Metra M, Gasparini M et al.
Long-term survival of patients with heart failure and ventricular conduction delay treated with cardiac resynchronization therapy.
Am J Cardiol. 2007;99:232-8.

Dear Editor,

I would like to thank Mr Munsch for his enjoyable and informative article(1) in February’s journal, and think that it highlights an important issue.

Multidisciplinary meetings are an integral part of cardiovascular practice and cardiologists and cardiac surgeons have long worked closely together, perhaps more so than other medical specialties with their respective surgical colleagues. This is primarily because of the overlap in care, particularly with regards to patients in need of coronary revascularisation.

This collaboration appears to be set to continue, if not become even more pronounced. The advent of the percutaneous aortic valve replacement (trans- femoral and trans-apical) means cardiologist and cardiac surgeon work more closely than ever before, and it is important that the patients involved are not part of a turf war, but a combined discipline that puts them first, to ensure the best possible care.

These types of combined procedure will surely become more common and may well appear in other specialties, and as a field cardiac care has the opportunity to set the standards for such practice. Teamwork is essential with a necessity for experienced practitioners in imaging, catheter intervention and surgery.

Mr Munsch states that cardiology trainees would be welcomed with open arms into theatre and I believe many trainees would be very grateful for this opportunity, knowing that it would be a tremendous learning experience. However, it has to be said that this is difficult to incorporate into daily practice.

It is also true that surgical trainees could learn from their medical colleagues, maybe spending some time in the catheter or echo labs. Trainees in each field surely have a lot to learn from the other discipline and perhaps some structured exposure to the complementary specialty during specialist training would help to build on current collaborations and facilitate effective ones in the future.

References

1. Munsch C.
What cardiology trainees should know about coronary artery surgery--and coronary artery surgeons: ischaemic heart disease.
Heart. 2008 Feb;94(2):230-6.

Dear Editor,

We have carefully read the article by Gjesdal et al [1] showing the result of an exploratory analysis pooling data from the SPORTIF III and V trials [2,3]. By means of a Cox proportional hazard analysis the authors concluded that the use of digitalis may increase mortality.
Although we acknowledge the merit of this manuscript, in our opinion some points deserve further elucidation.
In a previous publication [4] we showed that anticoagulation therapy was inversely associated while digoxin (digitalis) and antiarrhythmic drugs were directly associated with increased mortality after adjustment for other covariates in patients treated with a “rate control� approach compared to patients treated with a “rhythm control� approach. That conclusion did not apply to patients with advanced heart failure (HF) as the studies available for the meta-analysis did not include patients with NYHA class IV HF.
Gjesdal et al suggested that the possible ominous effect of the digitalis may be concealed in patients with HF. However, no data are available about the possible progression to the end stage disease nor any mention about concomitant drug therapy, severity of symptoms, mechanism of HF and indication for digitalis use. They also reported a percentage of digoxin users up to 10% with levels in the range of toxicity, but they conclude that “there is little reason� to think that this is a serious problem as it was not clinically relevant.
Moreover, in a previous independent non–funded publication we showed that long-term ximelgatran therapy was associated with a significantly reduced risk of major life-threatening bleeding in the prevention of atrial fibrillation-related stroke (OR 0.71 [0.55-0.92], p=0.009, p for H=0.83, I2 0%) [5].
How did the authors address this point?
Of note, the authors did not mention the hepatotoxicity related to ximelagatran prolonged administration but they include ximelagatran therapy in the multivariate analysis. We showed that ximelagratan treatment > 3 months was associated with an odds ratio for hepatotoxicity of 6.73 (95% confidence interval: 5.01-9.05) compared to warfarin (p<0.001). In absolute terms, for prolonged treatments, the incidence of hepatotoxicity rose from 1.1% to 7.1%, with a number needed to harm of 17 [5-7]. This risk led the U.S. Food and Drug Administration to deny approval for ximelagratan in the USA, the European Agency for the Evaluation of Medicinal Products (EMEA) to allow only short term administration and the manufacturer (Astrazeneca), after a further fatality in a post-marketing study, to withdraw the drug [8-10]
We wonder if this point has been adequately addressed.
Although hepatic damage was clinically silent in most cases (even without discontinuation of therapy), 2 fatal cases of hepatic injury have been reported in the SPORTIF trials and no data are available about the long term hepatic function of enrolled patients. Although a possible pharmacodinamic/pharmacokynetic interaction between digoxin and ximelgatran has been not demonstrated as both metabolisms do not involve the liver cytochrome P-450 system [11], the “clinical interaction�, i.e. the impact of hepatotoxicity on mortality cannot be excluded. Thus, the “background noise� of hepatotoxicity should have been included in the analysis.
In conclusion, we wonder if a multi-drug context in which one of the two “study drugs� has been definitely withdrawn because of its potential fatal effect is really the appropriate context to assess the potentially fatal effect of a third drug.

Reference

1. K Gjesdal, J Feyzi and S B Olsson.
Digitalis: a dangerous drug in atrial fibrillation? An analysis of the SPORTIF III and V data.
Heart 2008:94;191-196.

2. Olsson SB, The Executive Steering Committee on behalf of the SPORTIF III Investigators.
Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non- valvular atrial fibrillation (SPORTIF III): randomised controlled trial.
Lancet 2003;362:1691–8.

3. Albers GW, Diener HC, Frison L, et al.
Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial.
JAMA 2005;293:690–8.

4. Testa L, Biondi-Zoccai GG, Dello Russo A, Bellocci F, Andreotti F, Crea F.
Rate-control vs. rhythm-control in patients with atrial fibrillation: a meta-analysis.
Eur Heart J. 2005;26:2000-6.

5. Testa L, Andreotti F, Trotta G, Biondi Zoccai GGL, Burzotta F, Bellocci F, Crea F.
Ximelagatran/melagatran versus conventional anticoagulant therapy: meta-analysis of 13 randomised controlled trials enrolling 22639 patients. European Society of Cardiology/World congress of Cardiology 2007. Oral Presentation for the Young Investigator Award in Thrombosis.
Published in Int J Cardiol. 2007 Nov 15;122(2):117-24.

6. Testa L, Bhindi R, Agostoni P, Abbate A, Zoccai GG, van Gaal WJ.
The direct thrombin inhibitor Ximelagatran/melagatran: a systematic review on clinical applications and an evidence based assessment of risk benefit profile.
Expert Opin Drug Saf. 2007;6:397-406.

7. Testa L, Van Gaal W, Agostoni P, Abbate A, Trotta G, Biondi-Zoccai GG.
Ximelagatran versus warfarin in the prevention of atrial fibrillation- related stroke: both sides of the story.
Stroke. 2007 ;38(7):e57.

8. AstraZeneca receives action letter from FDA for Exantaâ„¢ (ximelagatran).
Available at http://fdaadvisorycommittee.com

9. Successful outcome of the mutual recognition procedure for Exantaâ„¢ (ximelagatran) in Europe.
Press release from European Agency for the Evaluation of Medicinal Products (EMEA).
Available at http://www.emea.eu.int

10. AstraZeneca Decides to Withdraw Exantaâ„¢ (ximelagatran).
Press release from AstraZeneca international, February 14, 2006.
(Accessed February 15, 2006, at http://www.astrazeneca.com/pressrelease).

11. Gheorghiade M, Adams KF Jr, Colucci WS.
Digoxin in the management of cardiovascular disorders.
Circulation. 2004;109:2959-64.