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Very Late Continued Reverse Remodelling After Cardiac Resynchronization Therapy in Patients With Extreme Left Ventricular Dilatation
Accepted Manuscript Very late continued reverse remodeling after cardiac resynchronization therapy in patients with extreme left ventricular dilatation Samuel Larue-Grondin, MD, François Philippon, MD, Jean-François Sarrazin, MD, Sacha-Michelle Dubois-Sénéchal, Michelle Dubois, RN, BSc, Mario Sénéchal, MD PII:
S0828-282X(17)30108-3
DOI:
10.1016/j.cjca.2017.02.016
Reference:
CJCA 2387
To appear in:
Canadian Journal of Cardiology
Received Date: 15 August 2016 Revised Date:
6 February 2017
Accepted Date: 18 February 2017
Please cite this article as: Larue-Grondin S, Philippon F, Sarrazin J-F, Dubois-Sénéchal S-M, Dubois M, Sénéchal M, Very late continued reverse remodeling after cardiac resynchronization therapy in patients with extreme left ventricular dilatation, Canadian Journal of Cardiology (2017), doi: 10.1016/ j.cjca.2017.02.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Very late continued reverse remodeling after cardiac resynchronization therapy in patients with extreme left ventricular dilatation Samuel Larue-Grondin 1, MD, François Philippon 1, MD, Jean-François Sarrazin 1, MD, Sacha-
1
RI PT
Michelle Dubois-Sénéchal 2, Michelle Dubois 2, RN, BSc, Mario Sénéchal 1, MD
Department of cardiology, 2 Research Center, Institut universitaire de cardiologie et de
M AN U
Short title : Late Reverse Remodeling After CRT
EP
Mario Sénéchal, MD
TE D
Work Count: 1443
Corresponding Author
SC
pneumologie de Québec, Laval University, Quebec City, Quebec, Canada
Associate Professor, Faculty of Medicine, Laval University
AC C
Institut universitaire de cardiologie et de pneumologie de Québec 2525 chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada Phone: 418-656-8711 Fax: 418-656-8157 [email protected]
ACCEPTED MANUSCRIPT
Brief summary Severe LV dilatation, ambulatory NYHA class IV and severe MR have been associated with
RI PT
worse outcomes after CRT. The present report describes two patients with long-lasting evolution of cardiac heart failure symptoms with extreme initial LV dilatation and severe MR who
experienced after CRT, continuous increase of LVEF and reduction of LV dimensions over 4
AC C
EP
TE D
M AN U
SC
years’ follow-up.
ACCEPTED MANUSCRIPT
Abstract Response to cardiac resynchronization therapy (CRT) varies greatly amongst patients. We
RI PT
present two patients with severe HF symptoms (NYHA IV) with extreme initial LV dilatation (LV end-diastolic diameter of 92 mm and 80 mm respectively) and severe functional MR who underwent CRT implantation. Long-term follow-up showed late (≥4 years) normalization of LV ejection fraction (LVEF), LV dimensions and functional status. In a subgroup of patients with
SC
non-ischemic dilated cardiomyopathy (NIDCM) and complete LBBB, late continued LV reverse
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remodeling may lead to normalization of LV volumes and LVEF and significative improvement
AC C
EP
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in functional class.
ACCEPTED MANUSCRIPT
Introduction Unfortunately, the degree of response to cardiac resynchronization therapy (CRT) varies amongst patients. Severe left ventricular (LV) dilatation, ambulatory NYHA class IV heart failure (HF)
RI PT
and severe mitral regurgitation (MR) have been associated with worse outcomes after CRT.1-3 In contrast, CRT responders and super-responders have been found to have a better outcome and survival benefit. Recent studies have identified patient characteristics associated with super-
SC
response to CRT such as a non-ischemic origin, left bundle branch block (LBBB), smaller LV and shorter duration of HF symptoms.1-2 However, these relatively small studies conducted
M AN U
follow-up echocardiographic assessment of LV ejection fraction (LVEF) response mainly 6 months post-implantation.1-2 The present report describes two patients with severe HF symptoms (NYHA IV) with extreme initial LV dilatation (LV end-diastolic diameter of 92 mm and 80 mm respectively) and severe functional MR who experienced after CRT a continuous increase of their
Cases Presentation
EP
Case 1
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LVEF and reduction of LV dimensions over a long period of time (≥ 4 years).
A 49-year-old man first came to the emergency department in 2006 with complaints of dyspnea
AC C
and diminished exercise tolerance lasting for more than 6 months. When admitted, the patient was complaining of shortness of breath at rest (ambulatory NYHA class IV). The patient did not have any consumption of alcohol. The resting ECG showed sinus rhythm and complete LBBB with a QRS width of 150 ms. Heart catheterization showed normal coronary arteries. An endomyocardial biopsy was performed and showed normal myocytes. A cardiac MRI was also performed and demonstrated viability in all segments without oedema or necrosis. A transthoracic echocardiography showed a depressed LVEF at 15% with extreme LV dilatation
ACCEPTED MANUSCRIPT
(LV end-diastolic diameter of 92 mm, LV end-diastolic volume of 259 ml/m2) and severe functional MR (Figures 1A, 1B and 1C). Heart failure medications were started and up titrated as tolerated for more than 3 months without significant symptoms relief (bisoprolol 5 mg die,
RI PT
ramipril 5mg die, furosemide 40mg die and aldactone 25 mg die). He was then referred for a CRT defibrillator implantation. During follow-up, reverse remodeling of the LV was progressive and continued for a period of ≥4 years. Two thirds of the reverse remodeling occurred during the
SC
first 2 years. Nonetheless, one third of the LV reverse remodeling occurred more than 2 years after CRT implantation. Approximately 1 year after CRT implantation the functional class of the
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patient improved to class II. The LVEF was near normal (≥50%) more than 4 years after CRT implantation and the patient’s symptoms improved progressively to NYHA class I. Furosemide was stopped and the rest of the medications was not modified. Case 2
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A 47-year-old man first came to the emergency department in 2002 with complaints of dyspnea and diminished exercise tolerance lasting for more than 6 months. The patient did not have any
EP
consumption of alcohol. At the time of consultation, the patient complained of shortness of breath at rest (ambulatory NYHA class IV). The resting ECG showed sinus rhythm and complete LBBB
AC C
with a QRS width of 160 ms. Heart catheterization showed normal coronary arteries. A transthoracic echocardiography showed a depressed LVEF of 18% with extreme LV dilatation (LV end-diastolic diameter of 80 mm, LV end-diastolic volume of 169 ml/m2) and severe functional MR (Figures 1A, 1B and 1C). Heart failure medications were started and up titrated as tolerated for more than 3 months without significant symptoms relief (bisoprolol 7,5 mg die , ramipril 5mg bid, furosemide 40mg die and aldactone 25 mg die). He was then implanted with a CRT defibrillator. Similarly to the first patient, impressive LV reverse remodeling occurred
ACCEPTED MANUSCRIPT
during the first 3 years (2/3 of the entire reverse remodeling) with progressive continued late reverse remodeling thereafter. Approximately 1 year after CRT implantation the functional class
was stopped and the rest of the medications was not modified. Discussion
RI PT
of the patient improved to class II and later improved progressively to NYHA class I. Furosemide
SC
In some sub-groups of patients with non-ischemic dilated cardiomyopathy (NIDCM), LBBB, and severe cardiac HF, CRT has been shown to improve LV function to near normal.2 Prior clinical
M AN U
studies in patients with symptomatic HF have reported an incidence of 10-29% of CRT hyperresponders (commonly defined as improvement of LVEF ≥50% with functional recovery (NYHA class I or II)). In prior reports, the time to recovery in super-responders to CRT has been variable among patients and usually between 3 and 6 months. Few studies have assessed LV reverse remodeling over a very long period of time (≥12 months).1-2 Moreover, in most studies a shorter
TE D
duration of HF symptoms and smaller LV dimensions were predictors of CRT response.1-2 We present two patients with long-lasting (≥6 months) HF symptoms and extreme LV dilatation who experienced very late continued and sustained LV reverse remodeling over a very long period of
EP
time (≥4 years).3 In accordance with our results, Gaspirini et al have demonstrated in a population
AC C
of 48 patients with CRT that the greatest changes in LVEF and reverse remodeling usually occurred within the first 6 months but can continue ≥ 2 years. In that study, LV end-systolic diameter decreased by approximately 35% at 12 months, but continued LV reverse remodeling occurred after 12 months allowing the LV end-systolic diameter to decrease by ≥50% of the initial volume.4 In our patients, more than 2 years after CRT implantation LV end-diastolic diameter/volume decreased by ≥1/3 of the initial volume suggesting that significant late continue reverse remodeling is possible in a sub-group of patients. In our cases, significant MR reduction
ACCEPTED MANUSCRIPT
mainly appears in the first year after CRT implantation. In accordance with our results, previous studies have shown that CRT may improve the degree of MR, both immediately (by resynchronization of the papillary muscles from short-term increase in LV closing force) and in
RI PT
the longer-term as a consequence of reverse remodeling (resulting in a reduction of mitral valve tethering forces).5
In patients with LBBB, it could be suggested that LBBB-induced dyssynchrony can leads to
SC
reduce LV contractility which may increase intraventricular conduction leading to larger QRS duration. Per se this phenomenon may be the cause of our 2 patients severe NIDCM that
M AN U
eventually regressed and even completely recovered with medical treatment and CRT.1-2-3 Conflict of Interest None
EP AC C
None
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Financial support
ACCEPTED MANUSCRIPT
References 1. Cappola TP, Harsh MR, Jessup M, et al. Predictors of remodeling in the CRT era:
RI PT
influence of mitral regurgitation, BNP, and gender. J Card Fail 2006;12:182-8. 2. Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy
and
hyper-responders
to
cardiac
resynchronization
therapy:
characteristics and long-term evolution. Europace 2009;11:350-5.
M AN U
heart failure. Curr Cardiol Rep 2009;11:175-83.
SC
3. Khoo M, Kelly PA, Lindenfeld J. Cardiac resynchronization therapy in NYHA class IV
4. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734-43.
TE D
5. Verhaert D, Popović ZB, De S, et al. Impact of mitral regurgitation on reverse remodeling and outcome in patients undergoing cardiac resynchronization therapy. Circ Cardiovasc
AC C
EP
Imaging 2012;5:21-6.
ACCEPTED MANUSCRIPT
Figure legends Figure 1 (A) Modification of LV end-diastolic diameter after CRT; (B) Modification of indexed
RI PT
LV end-diastolic volume after CRT; (C) Modification of orifice regurgitant area after CRT. Abbreviations; CRT (cardiac resynchronization therapy), LVEDD (left ventricle end-diastolic diameter), LVEDV (left ventricle end-diastolic volume), MR (mitral regurgitation), ORA (orifice
SC
regurgitant area).
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EP
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Figure 2 Modification of LVEF after CRT. Abbreviations; LVEF (left ventricular ejection fraction).
AC C
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ACCEPTED MANUSCRIPT
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S0828-282X(17)30108-3
DOI:
10.1016/j.cjca.2017.02.016
Reference:
CJCA 2387
To appear in:
Canadian Journal of Cardiology
Received Date: 15 August 2016 Revised Date:
6 February 2017
Accepted Date: 18 February 2017
Please cite this article as: Larue-Grondin S, Philippon F, Sarrazin J-F, Dubois-Sénéchal S-M, Dubois M, Sénéchal M, Very late continued reverse remodeling after cardiac resynchronization therapy in patients with extreme left ventricular dilatation, Canadian Journal of Cardiology (2017), doi: 10.1016/ j.cjca.2017.02.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Very late continued reverse remodeling after cardiac resynchronization therapy in patients with extreme left ventricular dilatation Samuel Larue-Grondin 1, MD, François Philippon 1, MD, Jean-François Sarrazin 1, MD, Sacha-
1
RI PT
Michelle Dubois-Sénéchal 2, Michelle Dubois 2, RN, BSc, Mario Sénéchal 1, MD
Department of cardiology, 2 Research Center, Institut universitaire de cardiologie et de
M AN U
Short title : Late Reverse Remodeling After CRT
EP
Mario Sénéchal, MD
TE D
Work Count: 1443
Corresponding Author
SC
pneumologie de Québec, Laval University, Quebec City, Quebec, Canada
Associate Professor, Faculty of Medicine, Laval University
AC C
Institut universitaire de cardiologie et de pneumologie de Québec 2525 chemin Sainte-Foy, Quebec, Qc, G1V 4G5, Canada Phone: 418-656-8711 Fax: 418-656-8157 [email protected]
ACCEPTED MANUSCRIPT
Brief summary Severe LV dilatation, ambulatory NYHA class IV and severe MR have been associated with
RI PT
worse outcomes after CRT. The present report describes two patients with long-lasting evolution of cardiac heart failure symptoms with extreme initial LV dilatation and severe MR who
experienced after CRT, continuous increase of LVEF and reduction of LV dimensions over 4
AC C
EP
TE D
M AN U
SC
years’ follow-up.
ACCEPTED MANUSCRIPT
Abstract Response to cardiac resynchronization therapy (CRT) varies greatly amongst patients. We
RI PT
present two patients with severe HF symptoms (NYHA IV) with extreme initial LV dilatation (LV end-diastolic diameter of 92 mm and 80 mm respectively) and severe functional MR who underwent CRT implantation. Long-term follow-up showed late (≥4 years) normalization of LV ejection fraction (LVEF), LV dimensions and functional status. In a subgroup of patients with
SC
non-ischemic dilated cardiomyopathy (NIDCM) and complete LBBB, late continued LV reverse
M AN U
remodeling may lead to normalization of LV volumes and LVEF and significative improvement
AC C
EP
TE D
in functional class.
ACCEPTED MANUSCRIPT
Introduction Unfortunately, the degree of response to cardiac resynchronization therapy (CRT) varies amongst patients. Severe left ventricular (LV) dilatation, ambulatory NYHA class IV heart failure (HF)
RI PT
and severe mitral regurgitation (MR) have been associated with worse outcomes after CRT.1-3 In contrast, CRT responders and super-responders have been found to have a better outcome and survival benefit. Recent studies have identified patient characteristics associated with super-
SC
response to CRT such as a non-ischemic origin, left bundle branch block (LBBB), smaller LV and shorter duration of HF symptoms.1-2 However, these relatively small studies conducted
M AN U
follow-up echocardiographic assessment of LV ejection fraction (LVEF) response mainly 6 months post-implantation.1-2 The present report describes two patients with severe HF symptoms (NYHA IV) with extreme initial LV dilatation (LV end-diastolic diameter of 92 mm and 80 mm respectively) and severe functional MR who experienced after CRT a continuous increase of their
Cases Presentation
EP
Case 1
TE D
LVEF and reduction of LV dimensions over a long period of time (≥ 4 years).
A 49-year-old man first came to the emergency department in 2006 with complaints of dyspnea
AC C
and diminished exercise tolerance lasting for more than 6 months. When admitted, the patient was complaining of shortness of breath at rest (ambulatory NYHA class IV). The patient did not have any consumption of alcohol. The resting ECG showed sinus rhythm and complete LBBB with a QRS width of 150 ms. Heart catheterization showed normal coronary arteries. An endomyocardial biopsy was performed and showed normal myocytes. A cardiac MRI was also performed and demonstrated viability in all segments without oedema or necrosis. A transthoracic echocardiography showed a depressed LVEF at 15% with extreme LV dilatation
ACCEPTED MANUSCRIPT
(LV end-diastolic diameter of 92 mm, LV end-diastolic volume of 259 ml/m2) and severe functional MR (Figures 1A, 1B and 1C). Heart failure medications were started and up titrated as tolerated for more than 3 months without significant symptoms relief (bisoprolol 5 mg die,
RI PT
ramipril 5mg die, furosemide 40mg die and aldactone 25 mg die). He was then referred for a CRT defibrillator implantation. During follow-up, reverse remodeling of the LV was progressive and continued for a period of ≥4 years. Two thirds of the reverse remodeling occurred during the
SC
first 2 years. Nonetheless, one third of the LV reverse remodeling occurred more than 2 years after CRT implantation. Approximately 1 year after CRT implantation the functional class of the
M AN U
patient improved to class II. The LVEF was near normal (≥50%) more than 4 years after CRT implantation and the patient’s symptoms improved progressively to NYHA class I. Furosemide was stopped and the rest of the medications was not modified. Case 2
TE D
A 47-year-old man first came to the emergency department in 2002 with complaints of dyspnea and diminished exercise tolerance lasting for more than 6 months. The patient did not have any
EP
consumption of alcohol. At the time of consultation, the patient complained of shortness of breath at rest (ambulatory NYHA class IV). The resting ECG showed sinus rhythm and complete LBBB
AC C
with a QRS width of 160 ms. Heart catheterization showed normal coronary arteries. A transthoracic echocardiography showed a depressed LVEF of 18% with extreme LV dilatation (LV end-diastolic diameter of 80 mm, LV end-diastolic volume of 169 ml/m2) and severe functional MR (Figures 1A, 1B and 1C). Heart failure medications were started and up titrated as tolerated for more than 3 months without significant symptoms relief (bisoprolol 7,5 mg die , ramipril 5mg bid, furosemide 40mg die and aldactone 25 mg die). He was then implanted with a CRT defibrillator. Similarly to the first patient, impressive LV reverse remodeling occurred
ACCEPTED MANUSCRIPT
during the first 3 years (2/3 of the entire reverse remodeling) with progressive continued late reverse remodeling thereafter. Approximately 1 year after CRT implantation the functional class
was stopped and the rest of the medications was not modified. Discussion
RI PT
of the patient improved to class II and later improved progressively to NYHA class I. Furosemide
SC
In some sub-groups of patients with non-ischemic dilated cardiomyopathy (NIDCM), LBBB, and severe cardiac HF, CRT has been shown to improve LV function to near normal.2 Prior clinical
M AN U
studies in patients with symptomatic HF have reported an incidence of 10-29% of CRT hyperresponders (commonly defined as improvement of LVEF ≥50% with functional recovery (NYHA class I or II)). In prior reports, the time to recovery in super-responders to CRT has been variable among patients and usually between 3 and 6 months. Few studies have assessed LV reverse remodeling over a very long period of time (≥12 months).1-2 Moreover, in most studies a shorter
TE D
duration of HF symptoms and smaller LV dimensions were predictors of CRT response.1-2 We present two patients with long-lasting (≥6 months) HF symptoms and extreme LV dilatation who experienced very late continued and sustained LV reverse remodeling over a very long period of
EP
time (≥4 years).3 In accordance with our results, Gaspirini et al have demonstrated in a population
AC C
of 48 patients with CRT that the greatest changes in LVEF and reverse remodeling usually occurred within the first 6 months but can continue ≥ 2 years. In that study, LV end-systolic diameter decreased by approximately 35% at 12 months, but continued LV reverse remodeling occurred after 12 months allowing the LV end-systolic diameter to decrease by ≥50% of the initial volume.4 In our patients, more than 2 years after CRT implantation LV end-diastolic diameter/volume decreased by ≥1/3 of the initial volume suggesting that significant late continue reverse remodeling is possible in a sub-group of patients. In our cases, significant MR reduction
ACCEPTED MANUSCRIPT
mainly appears in the first year after CRT implantation. In accordance with our results, previous studies have shown that CRT may improve the degree of MR, both immediately (by resynchronization of the papillary muscles from short-term increase in LV closing force) and in
RI PT
the longer-term as a consequence of reverse remodeling (resulting in a reduction of mitral valve tethering forces).5
In patients with LBBB, it could be suggested that LBBB-induced dyssynchrony can leads to
SC
reduce LV contractility which may increase intraventricular conduction leading to larger QRS duration. Per se this phenomenon may be the cause of our 2 patients severe NIDCM that
M AN U
eventually regressed and even completely recovered with medical treatment and CRT.1-2-3 Conflict of Interest None
EP AC C
None
TE D
Financial support
ACCEPTED MANUSCRIPT
References 1. Cappola TP, Harsh MR, Jessup M, et al. Predictors of remodeling in the CRT era:
RI PT
influence of mitral regurgitation, BNP, and gender. J Card Fail 2006;12:182-8. 2. Castellant P, Fatemi M, Orhan E, Etienne Y, Blanc JJ. Patients with non-ischaemic dilated cardiomyopathy
and
hyper-responders
to
cardiac
resynchronization
therapy:
characteristics and long-term evolution. Europace 2009;11:350-5.
M AN U
heart failure. Curr Cardiol Rep 2009;11:175-83.
SC
3. Khoo M, Kelly PA, Lindenfeld J. Cardiac resynchronization therapy in NYHA class IV
4. Gasparini M, Auricchio A, Regoli F, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol 2006;48:734-43.
TE D
5. Verhaert D, Popović ZB, De S, et al. Impact of mitral regurgitation on reverse remodeling and outcome in patients undergoing cardiac resynchronization therapy. Circ Cardiovasc
AC C
EP
Imaging 2012;5:21-6.
ACCEPTED MANUSCRIPT
Figure legends Figure 1 (A) Modification of LV end-diastolic diameter after CRT; (B) Modification of indexed
RI PT
LV end-diastolic volume after CRT; (C) Modification of orifice regurgitant area after CRT. Abbreviations; CRT (cardiac resynchronization therapy), LVEDD (left ventricle end-diastolic diameter), LVEDV (left ventricle end-diastolic volume), MR (mitral regurgitation), ORA (orifice
SC
regurgitant area).
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M AN U
Figure 2 Modification of LVEF after CRT. Abbreviations; LVEF (left ventricular ejection fraction).
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