Δημήτριος M. Κωνσταντίνου

Ειδικός Καρδιολόγος, MD, MSc, PhD, CCDS

Πανεπιστημιακός Υπότροφος

ECG in CRT patients & novel HF therapies

Dr. Konstantinou has received grants from Medtronic®

Is identification of LV pacing site feasible from

surface ECG analysis?

J Electrocardiol 2014;47(2):202-11

Baseline ECG

AF, LBBB, QRSd=160ms

2013 ESC guideline

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

Post-CRT

Quadripolar LV leads introduce additional layers of complexity…

BiV pacing

Baseline ECG

Cardiol J 2011;18(6):610-24

LV only pacing

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)

A very basal LV lead position can produce a prominent R wave in I lead

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

Baseline ECG

Post-CRT

BiV paced beats Pseudofusion beats

Post AVJ ablation

Baseline ECG

Pseudofusion BiV PVC

PVCFusion

Post-CRT

Baseline ECG Post-CRT

Which of the QRS complexes represent biV pacing and which are the result from fusion?

“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

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

Baseline ECG

Paced QRSd=160msQRS morphology

Lead I: rsLeads II, III, avF: QS

Lead V1: Rsr’

Why QRS doesn’t get narrower?

Post-CRT

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

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

Emerging Heart Failure Therapies

Novel Targets in Heart Failure

SNS

RAAS

VasoconstrictionBlood pressure

Sympathetic toneAldosteroneHypertrophy

Fibrosis

Ang II AT1R

HFrEFSYMPTOMS & PROGRESSION

Epinephrine

Norepinephrineα1, β1, β2

receptors

VasoconstrictionRAAS activity

VasopressinHeart rate

Contractility

RAAS inhibitors

(ACEI, ARB, MRA)

β-blockers

Natriuretic peptide

system

VasodilationBlood pressureSympathetic toneNatriuresis/diuresisVasopressinAldosteroneFibrosisHypertrophy

NPRs NPs

1. McMurray et al. Eur Heart J 2012;33:1787–847Figure references: Levin et al. N Engl J Med 1998;339:321–8; Nathisuwan & Talbert. Pharmacotherapy 2002;22:27–42; Kemp & Conte.

Cardiovascular Pathology 2012;365–371; Schrier & Abraham. N Engl J Med 1999;341:577–85

The crucial importance of the RAAS is supported by the beneficial effects of ACEIs, ARBs and MRAs1

Benefits of β-blockers indicate that the SNS also plays a key role1

Vasorelaxation

Blood pressure

Sympathetic tone

Aldosterone levels

Fibrosis

Hypertrophy

Natriuresis/diuresis

Inactive

fragments

ANP, BNP, CNP, othervasoactive peptides*

AT1 Receptor

Vasoconstriction

Blood pressure

Sympathetic tone

Aldosterone

Fibrosis

Hypertrophy

Angiotensinogen(liver secretion)

Ang I

Ang II

RAAS

LCZ696 simultaneously inhibits NEP (via LBQ657) and blocks AT1 receptors (via valsartan)

LCZ696

Sacubitril (AHU377; pro-drug)

InhibitingEnhancing

LBQ657(NEP inhibitor)

OH

OHN

O

HO

O

Valsartan

N

NHN

N

N

O

OH

O

*Neprilysin substrates listed in order of relative affinity for NEP: ANP, CNP, Ang II, Ang I, adrenomedullin, substance P, bradykinin, endothelin-1, BNPLevin 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

PARADIGM-HF: The most geographically diverse trial in patients with HFrEF

1. McMurray et al. Eur J Heart Fail. 2014;16:817–25; 2. McMurray et al. Eur J Heart Fail 2013;15:1062–73

8442 patients were randomized at 985 sites in 47 countries

Characteristic*LCZ696 (n=4187)

Enalapril (n=4212)

Age, years 63.8 ± 11.5 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 ± 6.1 29.4 ± 6.3

NYHA functional class, n (%)II III

2998 (71.6)969 (23.1)

2921 (69.3)1049 (24.9)

SBP, mmHg 122 ± 15 121 ± 15

Heart rate, beats/min 72 ± 12 73 ± 12

NT pro-BNP, pg/mL (IQR) 1631 (885–3154) 1594 (886–3305)

BNP, pg/mL (IQR) 255 (155–474) 251 (153–465)

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)

PARADIGM-HF: baseline characteristics

*mean ± standard deviation, unless statedMcMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Primary endpoint:

Death from CV causes or first hospitalization for HF

McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Hazard ratio = 0.80 (95% CI: 0.73–0.87)P=0.0000004

Days since randomizationNo at riskLCZ696 4187 3922 3663 3018 2257 1544 896 249Enalapril 4212 3883 3579 2922 2123 1488 853 236

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1.0

0.6

0.4

0.2

0

0 180 360 540 720 900 1080 1260

Enalapril

LCZ696

In the PARADIGM-HF trial, CV causes accounted for 81% of all deaths

Sudden death, 36%

Presumed sudden death, 3%

Worsening HF; 21%

Fatal MI; 4%

Fatal stroke, 4%

Presumed CV death, 10%

Other CV death, 2%

Unknown; 4%Non-CV death,

15%

45% of CV deaths

26% of CV deaths

Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186

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

• Resuscitated sudden deaths* occurred in 16 patients receiving LCZ696 versus 28 patients receiving enalapril (HR 0.57, 95% CI: 0.31–1.04, 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: 0.66–0.92, p=0.002)

LCZ696 significantly reduced the number of sudden cardiac deaths compared with enalapril

Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186;

Data on file. Clinical Study Protocol CLCZ696B2314

Hazard ratio = 0.80 (95% CI: 0.68–0.94) p=0.008

Enalapril

LCZ696

0 180 360 540 720 900 1,080 1,260

0

0.02

0.04

0.06

0.08

0.10

Days since randomizationNo. at riskLCZ696 4,187 3,891 2,478 1,005Enalapril 4,212 3,860 2,410 994

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*Resuscitated sudden deaths were defined as successful resuscitation following cardiac arrest

CI=confidence interval; HR=hazard ratio

The LCZ696 treatment effect for sudden cardiac death was not influenced by the presence of implantable defibrillator devices

Desai et al. Eur Heart J 2015; epub ahead of print: DOI:10.1093/eurheartj/ehv186

Sudden cardiac death n (%)

Hazard ratio, LCZ696 vs enalapril(95% CI)

p-value for interaction

ICD 525 (93.6%) 0.82 (0.69–0.98)

0.17+ICD 36 (6.4%) 0.49 (0.25–0.98)

CI=confidence interval; ICD=implantable cardioverter defibrillator; vs=versus

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