Cardiac resynchronization therapy: results, challenges and perspectives for the future

Figures & data

Figure 1. Combined explanatory figure of dyssynchrony and resynchronization in HF. Electrical dyssyncrhony, evident as LBBB on ECG (A), results in an abnormal left ventricular (LV) electrical activation with early- and late-activated regions. Figure 1(b) displays a homogenous electrical activation pattern in the heart with normal intrinsic conduction (left panel). During LBBB activation (middle panel), septum is activated early while the LV lateral wall is activated late. However, these regional differences in electrical activation are ameliorated when CRT is activated (right panel) [3]. Figure 1(c) depicts a CRT-device with one atrial and two ventricular leads. Figure 1(b) is reprinted from ref. [3]. Copyright © (2012), with permission from Elsevier. Figure 1(c) is reproduced with permission of Medtronic, Inc.

Table 1. Effects of dyssynchrony and resynchronization in HF: from cellular to clinical effects.

	Effect of dyssynchrony	Effect of resynchronization
Cellular and molecular – regional LV (late vs. early activated regions)
Ca^2+ handling proteins	Heterogenic expression [4]	Normalized [4]
Connexin-43	Downregulated [4]	Normalized [4]
Stress kinases	Upregulated [4]	Normalized [4]
Action potential duration	Delayed [5]	Partially restored [5]
Cellular and molecular – global LV
Fetal gene program	Activated [6]	Deactivated [6]
β-adrenaline signaling	Depressed [5]	Improved [5]
Ca^2+ sensitivity	Reduced [5]	Improved [5]
Metabolic
Regional differences in  glucose uptake	Present [5]	Normalized [5]
Global MVO2 consumption	Unchanged [7]	Unchanged [7]
Cardiac efficiency	Reduced [7]	Improved [7]
Structural
Later wall hypertrophy	Increased [8]	Decreased [4]
LV volume	Increased [9]	Decreased [10]
Hemodynamic
Mitral valve regurgitation	Increased [11]	Decreased [11]
Systolic function	Depressed [11]	Improved [12]
Diastolic time interval	Shortened [11]	Prolonged [11]
Force frequency relationship	Blunted [13]	Restored [13]
Clinical
Hospitalization rates	Increased [11]	Reduced [14,15]
Mortality	Increased [2]	Reduced [14–16]

Table 2. Clinical trials of CRT in patients with HFrEF.

Study (Reference)	Main inclusion criteria	Study design	Sample size	Follow-up (M)	CRT-effect
CRT in NYHA III–IV
MUSTIC SR [18]	EF ≤35% LVEDD >60mm QRS ≥150 ms	1:1 CRT ON/OFF crossover	67	3/12	Improved 6MWT, QOL, pVO2, Reduced HF-hospitalization
MUSTIC AF [19]	EF ≤35% LVEDD >60mm QRS ≥150 ms	1:1 CRT ON/OFF crossover	37	3/12	Improved 6MWT, QOL, pVO2, reduced HF-hospitalization
PATH-CHF [20]	EF ≤35% QRS ≥120 ms PR ≥150ms	CRT vs. RV pacing vs. epicardial LV pacing crossover	41	12	Improved pVO2 and 6MWT
CONTAK CD [21]	EF ≤35% QRS ≥120 ms	1:1 CRT ON/OFF	290	6	Improved NYHA, VE/CO2, LV volumes, LVEF
MIRACLE [22]	EF ≤35% LVEDD ≥55 mm QRS ≥130 ms	1:1 CRT ON/OFF	453	6	Improved NYHA, pVO2, 6MWT
MIRACLE-ICD [23]	NYHA III and IV EF < =35% QRS ≥130	1:1 CRT ON/OFF	555	6	Improved NYHA, VE/CO2, LV volumes, EF
COMPANION [24]	EF ≤35% QRS ≥120ms	1:2:2 OMT/CRTP/CRTD	1520	15	Reduced primary endpoint (death or hospitalization)
CARE-HF [14]	QRS ≥120 ms EF ≤35%	1:1 OMT vs. CRTP	813	30	Reduced death and CV hospitalization
CRT in NYHA (I)-II
REVERSE [10]	EF ≤40% QRS ≥120ms LVEDD ≥55mm	2:1 CRT ON/OFF	610	12-24	Reversed remodeling and longer time to first hospitalization
MADIT-CRT [25]	EF <30% QRS ≥130ms	3:2 CRT-D vs. ICD	1820	28.8	Reduced combined hospitalization and mortality
MADIT-CRT [16] (extended)	EF <30% QRS ≥130ms	3:2 CRT-D vs. ICD	854	84	Reduced mortality
RAFT [15]	EF ≤30% QRS ≥120ms (>200ms if paced)	1:1 CRTD vs. ICD	1798	40	Reduced mortality and hospitalization

CV: cardiovascular; EF: ejection fraction; LVEDD: left ventricular end diastolic diameter; M: months; ms: milliseconds; NYHA: New York Heart Association Functional Class; OMT: Optimal Medical Therapy; pVO₂: peak oxygen consumption; QOL: quality of life; 6MWT: Distance covered in the 6-minute Walk Test.

Figure 2. Effect of CRT on mortality in patients with (A) NYHA III-IV and mainly (B) NYHA II HFrEF. (A) Effect of CRT on all-cause mortality compared to optimal medical therapy from the CARE-HF trial.(B) Effect of CRT-D vs. ICD alone on all-cause mortality from the RAFT-trial. Figure 2(a) is from Ref. [14]. Copyright ? (2005). Reprinted with permission from Massachusetts Medical Society. Figure 2(b) is from Ref. [15]. Copyright ? (2010). Reprinted with permission from Massachusetts Medical Society.

Figure 3. CRT induces reverse remodeling in both patients with ischemic and nonischemic cardiomyopathy.

Reprinted from Ref. [28], Copyright © (2010), with permission from Elsevier.

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