Thalassaemia & the heart

Transcription

1 Thalassaemia & the heart Dr. Malcolm Walker Consultant Cardiologist University College & the National Heart Hospital London Clinical Director Hatter Cardiovascular Institute UCLH JMW rd Pan American Thalassaemia Conference Buenos Aires

2 Thalassaemia & the heart % Causes of death in TM Heart Infection Liver 40 Thromb 30 Cancer Diabetes Other 0 Cause of Death from Borgna-Pignatti et al

3 The heart is part of an integrated cardiovascular (CV) system 1. In Thalassaemia the CV system is affected as a whole i. Heart function affected by a. Adaptation to anaemia 1. Raised cardiac output 2. Dilatation of ventricles & atria (for BSA) Long term consequences benign?

4 The heart is part of an integrated cardiovascular (CV) system 1. In Thalassaemia the CV system is affected as a whole i. Heart function affected by a. Adaptation to anaemia b. By effects of iron overload

5 Iron accumulates within heart muscle cells

6 Cardiac Complications in Thalassaemia Major Iron overload Heart muscle cells Iron accumulation occurs within myocytes Ventricles > atria LV > RV Epicardial layers may be more affected? Relative absence of fibrosis

7 Iron Toxicity High redox potential Can catalyze conversion of hydrogen peroxide to free-radical ions Fe 3+ + O 2 Fe 2+ + O 2 Fe 2+ + H 2 O 2 Fe 3+ + OH + OH O 2 + H 2 O 2 OH + HO + O 2 Attacks cellular membranes, proteins, and DNA, leading to tissue damage

8 Cardiac Complications in Thalassaemia Major Iron overload within myocytes: Eventual precipitation of heart failure Systolic > diastolic Acute mortality ~50% once grade IV HF Arrhythmia AF, VT as a complication of myocardial iron overload Late arrhythmia not associated with current iron overload ~40% of those >40yr develop AF despite no current iron overload

9 The heart is part of an integrated cardiovascular (CV) system 1. In Thalassaemia the CV system is affected as a whole i. Heart function affected by a. Adaptation to anaemia b. By effects of iron overload c. By changes in the peripheral vasculature

10 Endothelial Function Inflammation Lipid peroxidation Hyperglycemia Oxidative stress Hyperlipidemia Iron overload causes insulin resistance & hyperglycemia. Iron-mediated ROS increases superoxides and COX products. Vitamin C deficiency impairs endothelial NO production. Hemolysis produces NO and arginine dysregulation. Macrophage and T-cell derangements.

11 Types of vascular impairment Impaired flow-mediated dilation (FMD) Correlated with labile iron Increased carotid intimal-medial thickness Decreased arterial compliance Correlated with FMD Also correlated with LDL oxidation. Elastic artery degeneration Histologically similar to vessel changes with scurvy.

12 The heart is part of an integrated cardiovascular (CV) system 1. In Thalassaemia the CV system is affected as a whole i. Heart function affected by a. Adaptation to anaemia b. By effects of iron overload c. By changes in the peripheral vasculature d. By changes in pulmonary circulation Pulmonary arterial hypertension

13 The heart is part of an integrated cardiovascular (CV) system 1. In Thalassaemia the CV system is affected as a whole i. Heart function affected by a. Adaptation to anaemia b. By effects of iron overload c. By changes in the peripheral vasculature d. By changes in pulmonary circulation e. Associated endocrinopathy

14 So how does your doctor know there is iron in the heart? Clinical Features Symptoms of heart failure Breathlessness Tiredness Swelling of feet or abdomen Palpitations BUT these are non-specific, especially in TM

15 So how does your doctor know there is iron in the heart? Clinical Features Signs of cardiac failure Jugular venous pulse elevated New murmurs or heart sounds (S3) Low cardiac output BUT clinical signs of heart failure are late in appearance Always denote serious heart iron overload (in TM) Urgent treatment is life saving at this stage

16 What tests can the doctor use to detect heart iron? Specific heart tests ECG ECHOCARDIOGRAM Cardiac Magnetic Resonance Imaging (CMR T2*)

17 Conclusion ECG Necessary baseline in all patients Minor T wave changes common

18 ECG JMWalker 09 Note non-specific T wave changes

19 Conclusion ECG Necessary baseline in all patients Minor T wave changes common May detect new problems e.g. signs of RV overload due to progressive pulmonary hypertension 24 hr ECG monitors (Holter) for specific instances However a normal ECG does NOT exclude severe cardiac iron overload

20 The ECHOCARDIOGRAM Essential tool for assessing heart function Painless Harmless Widely available bed-side

21 Normal Echo - LV m-mode 2D Sector Image Normal M-mode Echocardiogram

22 Normal Echo - LV m-mode 2D Sector Image Normal M-mode Echocardiogram

23 Normal Echo - LV m-mode 2D Sector Image Normal M-mode Echocardiogram

24 M-mode Echo Parameters : example patient 6 LV size cm 5 LVedd 4 3 LVes LVED LVES

25 M-mode Echo Parameters : example patient LV size cm 6 5 LVedd 4 3 Fractional shortening 35% = normal LVes LVED LVES

26 M-mode Echo Parameters : example patient 6 LV size cm 5 4 LVED LVES 3 2 Routine clinic visit no change in symptoms

27 M-mode Echo Parameters : example patient 6 LV size cm 5 Fractional shortening 17% = abnormal 4 LVED LVES 3 2 Routine clinic visit no change in symptoms

28 M-mode Echo Parameters : example patient 6 LV size cm 5 4 LVED LVES 3 2 Chelation intensified

29 M-mode Echo Parameters : example patient 6 LV size cm 5 4 LVED LVES 3 2 Chelation intensified

30 The ECHOCARDIOGRAM Essential tool for assessing heart function Painless Harmless Widely available bed-side Some cautions Operator dependent Problems with quantification Even simple measurements can be VERY useful for managing individuals

31 Echocardiography It may show unexpected findings

32 The ECHO quantifying function

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34 JMWalker 09

35 The ECHO Ejection Fraction EF why should it be used? We are used to it Widely quoted in the literature We think we understand what it means BUT Dependent on operator & image quality Normal ranges are higher in thalassaemia Normal in our population EF= >64%

36 EF with caution ECHO Parameters Do not accept accept subjective reports that state normal ventricular function Raw data on dimensions May have advantages, especially to follow your patients across time Huge numbers of parameters available M-mode, 2D, Doppler, Tissue Doppler, 3D Echo.. Variable reproducibility & applicability to this patient group To screen for PH, it is the only practical tool in the clinic

37 The ECHO Necessary for complete cardiovascular assessment A relatively simple data set can be useful Dedicated service aware of the issues in TM patients is optimal BUT alone it is not enough IT IS POSSIBLE TO HAVE HIGH HEART IRON WITH NORMAL ECHO

38 Identifying those at risk before the onset of obvious heart failure Until the advent of the CMR T2* technique great difficulty in identifying those at greatest risk Missed many who needed intensive Rx Overtreated some low risk individuals Hence 30% mortality in young adults Joint BHF project with Dudley Pennell investigating use of CMR in iron overload Dr Lisa Anderson

39 Magnetic Resonance Imaging CMR Allows quantification of cardiac iron content T2* measurement for tissue iron load Values over 20ms denote little or no myocardial iron content Liver and heart iron content do not always correlate in individual patients T2* Can be used to follow treatment

40 Prevalence of Cardiac Iron Load % Prevalence Prevalence % Severe Mild-moderate No Fe Tanner et al 2006

41 Results cardiac iron load (CMR T2*) T2* ms P<0.001 P=0.074 DFO + DFP DFO alone Tanner et.al. Circulation 2007

42 T2* Implications for prognosis 652 patients with b-thalassaemia Mean age 27 yr Excluded those with heart failure (HF) at first scan

43 T2* Implications for prognosis: Heart failure 98% of those developing HF had a T2* < 10ms Median time from low T2* to HF =158 days

44 T2* Implications for prognosis: Arrhythmia Threshold for arrhythmia T2*< 20ms 78 AF 14 SVT 5 VT 1 VF

45 So what has been the result of these developments? 1. Capacity to measure tissue specific iron load cmr T2* 2. Protocols of treatment Derived from prospective trial data Local & nationally agreed standards 3. Dedicated multi-specialty clinics Mostly it has been about communication between specialties, between doctors & patients and careful implementation of what we already know!

46 Change in Mortality in UK Thalassaemia Cohort Modell et.al. 2008

47 Conclusions Cardiac disease is treatable & even severe heart muscle impairment is reversible Prevention is preferable Key is better chelation protocols that CAN be complied with Carefully judged combination treatments may be best for many patients

48 Acknowledgements British Heart Foundation TIF & UKTS Colleagues : Dr Beatrix Wonke (Rtd) Prof Dudley Pennell (Royal Brompton) Prof John Porter (UCH) Dr Farrukh Shah, Dr Bernard Davis & Ms Emma Prescott (Whittington) Prof Renzo Galanello (Sardinia) Drs Sunil Nair, Costas O Mahony, Mark Tanner, Paul Kirk, Mark Westwood & Dr Lisa Anderson Conflicts of interest: Educational support from Servier & Aventis Pharma, Schering-Plough within last 2 yr

49 Calibration of T2* What does it measure?

50 Frequency T2* Implications for prognosis Distribution of myocardial T2* values in symptomatic heart failure (n=28) Heart T2* (ms)