ECG in CRT patients & novel HF therapies. Δημήτριος M. Κωνσταντίνου Ειδικός Καρδιολόγος, MD, MSc, PhD, CCDS Πανεπιστημιακός Υπότροφος

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1 ECG in CRT patients & novel HF therapies Δημήτριος M. Κωνσταντίνου Ειδικός Καρδιολόγος, MD, MSc, PhD, CCDS Πανεπιστημιακός Υπότροφος

2 Dr. Konstantinou has received grants from Medtronic

3 Is identification of LV pacing site feasible from surface ECG analysis? J Electrocardiol 2014;47(2):202-11

4 Baseline ECG AF, LBBB, QRSd=160ms 2013 ESC guideline

5 Post-CRT Dominant R in lead V1 corresponds to a LV lead position towards the free wall Predominately -ve QRS complex in lead avf (i.e. superior axis) indicates an inferolateral position Early transition to a predominately -ve QRS complex in chest leads is suggestive of an apical position

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7 Quadripolar LV leads introduce additional layers of complexity

8 Baseline ECG BiV pacing

9 Cardiol J 2011;18(6): LV only pacing

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11 A very basal LV lead position can produce a prominent R wave in I lead LV pacing does not necessarily results in a -ve QRS in lead I When LV pacing is performed from the basis of the LV, especially in dilated and leftward displaced hearts, the activation spreads from basis to apex and from right to left, resulting a +ve QRS in lead I Journal of Atrial Fibrillation 2015;7(6)

12 Suboptimal (i.e. <98%) biventricular pacing % The most frequent causes of pacing loss include: an inappropriately long programmed AV delay frequent episodes of atrial tachycardia/af a high burden of PVCs 2013 ESC guideline

13 Baseline ECG

14 Post-CRT BiV paced beats Pseudofusion beats

15 Post AVJ ablation

16 Baseline ECG

17 Post-CRT Pseudofusion BiV PVC Fusion PVC

18 Baseline ECG Post-CRT Which of the QRS complexes represent biv pacing and which are the result from fusion?

19 The marked narrowing of the QRS complex in lead V1 strongly suggests ventricular fusion with the intrinsic QRS complex rather than QRS narrowing from satisfactory BiV pacing... Ann Noninvasive Electrocardiol 2005;10:231-55

20 Baseline ECG SR, 1 st degree AV block (PR=220ms) LBBB (QRSd=140ms)

21 Post-CRT Why QRS doesn t get narrower? Paced QRSd=160ms QRS morphology Lead I: rs Leads II, III, avf: QS Lead V1: Rsr

22 Some fusion may not be detrimental after all The effect of the underlying PR interval duration may be explained in terms of concealed resynchronization Ventricular activation in patients with a normal PR interval may have resulted from fusion of electrical wave fronts coming from the right bundle branch and the impulse from the LV electrode Hemodynamic response may thereby be superior as detrimental effects of RV apical stimulation are avoided The wider QRS width during BiV pacing in patients with a long PR interval supports this hypothesis Pacing Clin Electrophysiol 2005;28:754-61

23 Please note that devices work better in medically optimized patients! Device based therapy is only the fifth step in HF treatment algorithm!!! 2012 ESC guideline

24 Emerging Heart Failure Therapies

25 Novel Targets in Heart Failure SNS β-blockers Natriuretic peptide system NPRs NPs Vasodilation Blood pressure Sympathetic tone Natriuresis/diuresis Vasopressin Aldosterone Fibrosis Hypertrophy HFrEF SYMPTOMS & PROGRESSION Epinephrine Norepinephrine RAAS Ang II α 1, β 1, β 2 receptors Vasoconstriction RAAS activity Vasopressin Heart rate Contractility AT 1 R Vasoconstriction Blood pressure Sympathetic tone Aldosterone Hypertrophy Fibrosis RAAS inhibitors (ACEI, ARB, MRA) The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs 1 Benefits of β-blockers indicate that the SNS also plays a key role 1 1. McMurray et al. Eur Heart J 2012;33: Figure references: Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Kemp & Conte. Cardiovascular Pathology 2012; ; Schrier & Abraham. N Engl J Med 1999;341:577 85

26 LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks AT 1 receptors (via valsartan) LCZ696 ANP, BNP, CNP, other vasoactive peptides* RAAS Sacubitril (AHU377; pro-drug) Angiotensinogen (liver secretion) Ang I Inactive fragments LBQ657 (NEP inhibitor) Valsartan Ang II Enhancing Vasorelaxation Blood pressure Sympathetic tone Aldosterone levels Fibrosis Hypertrophy Natriuresis/diuresis HN O HO O OH O O N O OH N N N NH Vasoconstriction AT 1 Receptor Inhibiting Blood pressure Sympathetic tone Aldosterone Fibrosis Hypertrophy *Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNP Levin et al. N Engl J Med 1998;339:321 8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27 42; Schrier & Abraham N Engl J Med 1999;341:577 85; Langenickel & Dole. Drug Discov Today: Ther Strateg 2012;9:e131 9; Feng et al. Tetrahedron Letters 2012;53:275 6

27 PARADIGM-HF: The most geographically diverse trial in patients with HFrEF 8442 patients were randomized at 985 sites in 47 countries 1. McMurray et al. Eur J Heart Fail. 2014;16:817 25; 2. McMurray et al. Eur J Heart Fail 2013;15:

28 PARADIGM-HF: baseline characteristics Characteristic* LCZ696 Enalapril (n=4187) (n=4212) Age, years 63.8 ± ± 11.3 Women, n (%) 879 (21.0) 953 (22.6) Ischemic cardiomyopathy, n (%) 2506 (59.9) 2530 (60.1) LV ejection fraction, % 29.6 ± ± 6.3 NYHA functional class, n (%) II III 2998 (71.6) 969 (23.1) 2921 (69.3) 1049 (24.9) SBP, mmhg 122 ± ± 15 Heart rate, beats/min 72 ± ± 12 NT pro-bnp, pg/ml (IQR) 1631 ( ) 1594 ( ) BNP, pg/ml (IQR) 255 ( ) 251 ( ) History of diabetes, n (%) 1451 (34.7) 1456 (34.6) Treatments at randomization, n (%) Diuretics 3363 (80.3) 3375 (80.1) Digitalis 1223 (29.2) 1316 (31.2) β-blockers 3899 (93.1) 3912 (92.9) Mineralocorticoid antagonists 2271 (54.2) 2400 (57.0) ICD 623 (14.9) 620 (14.7) CRT 292 (7.0) 282 (6.7) *mean ± standard deviation, unless stated McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

29 Cumulative probability Primary endpoint: Death from CV causes or first hospitalization for HF Enalapril LCZ Hazard ratio = 0.80 (95% CI: ) P= Days since randomization No at risk LCZ Enalapril McMurray, et al. N Engl J Med 2014; epub ahead of print: DOI: /NEJMoa

30 In the PARADIGM-HF trial, CV causes accounted for 81% of all deaths Unknown; 4% Other CV death, 2% Presumed CV death, 10% Non-CV death, 15% Sudden death, 36% 45% of CV deaths 26% of CV deaths Fatal stroke, 4% Fatal MI; 4% Worsening HF; 21% Presumed sudden death, 3% ACEI=angiotensin-converting-enzyme inhibitor; ARNI=angiotensin receptor neprilysin inhibitor; CV=cardiovascular; HF=heart failure; MI=myocardial infarction; PARADIGM-HF=Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186

31 Cumulative probability of event LCZ696 significantly reduced the number of sudden cardiac deaths compared with enalapril Enalapril LCZ Hazard ratio = ) p=0.008 (95% CI: ,080 1,260 Days since randomization No. at risk LCZ696 4,187 3,891 2,478 1,005 Enalapril 4,212 3,860 2, Resuscitated sudden deaths* occurred in 16 patients receiving LCZ696 versus 28 patients receiving enalapril (HR 0.57, 95% CI: , p=0.07). Further, LCZ696 significantly reduced the risk of combined resuscitated and non-resuscitated sudden deaths by 22% when compared with enalapril (HR 0.78, 95% CI: , p=0.002) *Resuscitated sudden deaths were defined as successful resuscitation following cardiac arrest CI=confidence interval; HR=hazard ratio Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186; Data on file. Clinical Study Protocol CLCZ696B2314

32 The LCZ696 treatment effect for sudden cardiac death was not influenced by the presence of implantable defibrillator devices Sudden cardiac death n (%) Hazard ratio, LCZ696 vs enalapril (95% CI) p-value for interaction ICD 525 (93.6%) 0.82 ( ) +ICD 36 (6.4%) 0.49 ( ) 0.17 CI=confidence interval; ICD=implantable cardioverter defibrillator; vs=versus Desai et al. Eur Heart J 2015; epub ahead of print: DOI: /eurheartj/ehv186

33 Ευχαριστώ πολύ για την προσοχή σας!