Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction Julio N´un˜ ez, Eloy Dom´ınguez, Jos´e Mar´ıa Ram´on, Eduardo N´un˜ ez, Juan Sanchis, Enrique Santas, Raquel Heredia, Jessika Gonz´alez, Gema Mi˜nana, Laura L´opez, Francisco J. Chorro, Patricia Palau PII: DOI: Reference:
S0167-5273(16)30185-1 doi: 10.1016/j.ijcard.2016.01.187 IJCA 21942
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
2 December 2015 11 January 2016 13 January 2016
Please cite this article as: N´ un ˜ ez Julio, Dom´ınguez Eloy, Ram´ on Jos´e Mar´ıa, N´ un ˜ ez Eduardo, Sanchis Juan, Santas Enrique, Heredia Raquel, Gonz´alez Jessika, Mi˜ nana Gema, L´opez Laura, Chorro Francisco J., Palau Patricia, Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.01.187
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 Iron Deficiency and Functional Capacity in Patients with Advanced Heart Failure
T
with Preserved Ejection Fraction
IP
Julio Núñez MDa, Eloy Domínguez MDb, José María Ramóna, Eduardo Núñez MDa,
SC R
Juan Sanchis MDa, Enrique Santas MDa, Raquel Heredia MDa, Jessika González MDa, Gema Miñana MDa, Laura Lópezc, Francisco J. Chorro MDa, and Patricia Palau MDd
Cardiology Department. Hospital Clínico Universitario, INCLIVA. Universitat de
NU
a
b
MA
València. Valencia, Spain.
Cardiology Department. Hospital General de Castellón. Universitat Jaume I, Castellón,
Spain.
Facultat de Fisioteràpia. Universitat de València, Spain.
d
Cardiology Department. Hospital de La Plana. Universitat Jaume I, Castellón, Spain.
CE P
TE
D
c
Corresponding author
AC
Dr. Julio Núñez
Cardiology Department. Hospital Clinico Universitario de Valencia, Universitat de Valencia
Address: Avda. Blasco Ibáñez 17, CP 46010, Valencia-Spain E-mail: [email protected]
Funding sources This work was supported in part by a grants from: Sociedad Española de Cardiología: Investigación Clínica en Cardiología, Grant SEC 2015 and Red de Investigación Cardiovascular; Programa 7 (RD12/0042/0010) and PIE15/00013.
ACCEPTED MANUSCRIPT
Conflict of Interest
IP
T
The authors have no funding, financial relationships, or conflicts of interest to disclose.
SC R
Keywords: Iron Deficiency; Functional Capacity; Peak Oxygen Uptake; Heart Failure
AC
CE P
TE
D
MA
NU
with Preserved Ejection Fraction
ACCEPTED MANUSCRIPT Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome characterized for an elevated morbimortality [1]. The pathophysiological
T
mechanisms involved in the progression of the disease are multifactorial and in many
IP
cases poorly described [2,3]. Iron deficiency (ID) has emerged as a novel
SC R
pathophysiological factor and therapeutic target in patients with heart failure with reduced ejection fraction (HFrEF). In these patients, ID is associated to a decreased functional capacity and higher risk of adverse outcomes [4,5]. Interestingly, treatment
NU
with intravenous ferric carboximaltose resulted in improvement if functional capacity
MA
and decreased the risk of hospitalizations in randomized clinical trials [6,7]. Despite the prevalence of ID in patients with HFpEF has been reported to be high [5,8], there are no studies aiming to evaluate the pathophysiological implications
TE
D
of ID in patients with advanced HFpEF. In this work we sought to evaluate whether standard parameters of ID [plasma ferritin and transferrin saturation index (TSAT)]
CE P
were related to functional capacity evaluated by peak oxygen uptake (peakVO2) in patients with HFpEF.
AC
Between March 11, 2015 and October 1, 2015, we prospectively studied a cohort of 40 patients with advanced HFpEF. Patients fulfilled all the following inclusion criteria: a) New York Heart Association (NYHA) functional class ≥II, b) previous admission for acute heart failure (AHF), c) clinical stability during the last 3 months, d) left ventricular ejection fraction>50%, and, e) left ventricle hypertrophy and/or left atrial enlargement and/or diastolic dysfunction estimated by two-dimensional echocardiography. Exclusion criteria were: a) inability to perform a valid exercise test, b) significant primary moderate to severe valvular disease, c) acute coronary syndrome, cardiac surgery or revascularization within the previous three months and, d) significant
ACCEPTED MANUSCRIPT primary pulmonary disease, including pulmonary arterial hypertension, chronic thromboembolic pulmonary disease or chronic obstructive pulmonary disease.
T
Informed consent was obtained from each patient and the study protocol
approval
by
the
institution's
human
research
committee.
Clinical,
SC R
priori
IP
conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a
electrocardiographic and treatment characteristics were recorded in electronic forms. Patients enrolled underwent a cardiopulmonary exercise testing (CPET), two-
NU
dimensional transthoracic echocardiography and a blood laboratory test including NT-
MA
pro-brain natriuretic peptide (NTproBNP), renal function, electrolytes, haemoglobin, ferritin and TSAT.
Maximal functional capacity was evaluated with an incremental and symptom-
TE
D
limited cardiopulmonary exercise testing (CORTEX Metamax 3B) on a bicycle ergometer, beginning with a workload of 10W and increasing stepwise at 10W
CE P
increments every 1 min. During exercise, patients were continuously monitored with twelve-lead electrocardiogram and blood pressure measurements every 2 min. Gas
AC
exchange data and cardiopulmonary variables were averaged every 10 seconds values. Peak VO2 was considered the highest value of VO2 during the last 20 seconds of exercise.
Baseline characteristics and ID-related parameters were tested against logtransformed peakVO2 using the Pearson correlation coefficient. Then, we performed a multivariable linear regression analysis to determine their association with mean peakVO2, while adjusting for commonly used covariates in this setting. Demographic, medical history, vital signs, laboratory and echocardiographic parameters listed in table 1 were evaluated. A reduced model was achieved through a stepwise-backward selection procedure with simultaneous transformation of continuous variable using
ACCEPTED MANUSCRIPT fractional polynomials of a 2nd degree. A 2-sided p-value
S0167-5273(16)30185-1 doi: 10.1016/j.ijcard.2016.01.187 IJCA 21942
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
2 December 2015 11 January 2016 13 January 2016
Please cite this article as: N´ un ˜ ez Julio, Dom´ınguez Eloy, Ram´ on Jos´e Mar´ıa, N´ un ˜ ez Eduardo, Sanchis Juan, Santas Enrique, Heredia Raquel, Gonz´alez Jessika, Mi˜ nana Gema, L´opez Laura, Chorro Francisco J., Palau Patricia, Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction, International Journal of Cardiology (2016), doi: 10.1016/j.ijcard.2016.01.187
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 Iron Deficiency and Functional Capacity in Patients with Advanced Heart Failure
T
with Preserved Ejection Fraction
IP
Julio Núñez MDa, Eloy Domínguez MDb, José María Ramóna, Eduardo Núñez MDa,
SC R
Juan Sanchis MDa, Enrique Santas MDa, Raquel Heredia MDa, Jessika González MDa, Gema Miñana MDa, Laura Lópezc, Francisco J. Chorro MDa, and Patricia Palau MDd
Cardiology Department. Hospital Clínico Universitario, INCLIVA. Universitat de
NU
a
b
MA
València. Valencia, Spain.
Cardiology Department. Hospital General de Castellón. Universitat Jaume I, Castellón,
Spain.
Facultat de Fisioteràpia. Universitat de València, Spain.
d
Cardiology Department. Hospital de La Plana. Universitat Jaume I, Castellón, Spain.
CE P
TE
D
c
Corresponding author
AC
Dr. Julio Núñez
Cardiology Department. Hospital Clinico Universitario de Valencia, Universitat de Valencia
Address: Avda. Blasco Ibáñez 17, CP 46010, Valencia-Spain E-mail: [email protected]
Funding sources This work was supported in part by a grants from: Sociedad Española de Cardiología: Investigación Clínica en Cardiología, Grant SEC 2015 and Red de Investigación Cardiovascular; Programa 7 (RD12/0042/0010) and PIE15/00013.
ACCEPTED MANUSCRIPT
Conflict of Interest
IP
T
The authors have no funding, financial relationships, or conflicts of interest to disclose.
SC R
Keywords: Iron Deficiency; Functional Capacity; Peak Oxygen Uptake; Heart Failure
AC
CE P
TE
D
MA
NU
with Preserved Ejection Fraction
ACCEPTED MANUSCRIPT Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome characterized for an elevated morbimortality [1]. The pathophysiological
T
mechanisms involved in the progression of the disease are multifactorial and in many
IP
cases poorly described [2,3]. Iron deficiency (ID) has emerged as a novel
SC R
pathophysiological factor and therapeutic target in patients with heart failure with reduced ejection fraction (HFrEF). In these patients, ID is associated to a decreased functional capacity and higher risk of adverse outcomes [4,5]. Interestingly, treatment
NU
with intravenous ferric carboximaltose resulted in improvement if functional capacity
MA
and decreased the risk of hospitalizations in randomized clinical trials [6,7]. Despite the prevalence of ID in patients with HFpEF has been reported to be high [5,8], there are no studies aiming to evaluate the pathophysiological implications
TE
D
of ID in patients with advanced HFpEF. In this work we sought to evaluate whether standard parameters of ID [plasma ferritin and transferrin saturation index (TSAT)]
CE P
were related to functional capacity evaluated by peak oxygen uptake (peakVO2) in patients with HFpEF.
AC
Between March 11, 2015 and October 1, 2015, we prospectively studied a cohort of 40 patients with advanced HFpEF. Patients fulfilled all the following inclusion criteria: a) New York Heart Association (NYHA) functional class ≥II, b) previous admission for acute heart failure (AHF), c) clinical stability during the last 3 months, d) left ventricular ejection fraction>50%, and, e) left ventricle hypertrophy and/or left atrial enlargement and/or diastolic dysfunction estimated by two-dimensional echocardiography. Exclusion criteria were: a) inability to perform a valid exercise test, b) significant primary moderate to severe valvular disease, c) acute coronary syndrome, cardiac surgery or revascularization within the previous three months and, d) significant
ACCEPTED MANUSCRIPT primary pulmonary disease, including pulmonary arterial hypertension, chronic thromboembolic pulmonary disease or chronic obstructive pulmonary disease.
T
Informed consent was obtained from each patient and the study protocol
approval
by
the
institution's
human
research
committee.
Clinical,
SC R
priori
IP
conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a
electrocardiographic and treatment characteristics were recorded in electronic forms. Patients enrolled underwent a cardiopulmonary exercise testing (CPET), two-
NU
dimensional transthoracic echocardiography and a blood laboratory test including NT-
MA
pro-brain natriuretic peptide (NTproBNP), renal function, electrolytes, haemoglobin, ferritin and TSAT.
Maximal functional capacity was evaluated with an incremental and symptom-
TE
D
limited cardiopulmonary exercise testing (CORTEX Metamax 3B) on a bicycle ergometer, beginning with a workload of 10W and increasing stepwise at 10W
CE P
increments every 1 min. During exercise, patients were continuously monitored with twelve-lead electrocardiogram and blood pressure measurements every 2 min. Gas
AC
exchange data and cardiopulmonary variables were averaged every 10 seconds values. Peak VO2 was considered the highest value of VO2 during the last 20 seconds of exercise.
Baseline characteristics and ID-related parameters were tested against logtransformed peakVO2 using the Pearson correlation coefficient. Then, we performed a multivariable linear regression analysis to determine their association with mean peakVO2, while adjusting for commonly used covariates in this setting. Demographic, medical history, vital signs, laboratory and echocardiographic parameters listed in table 1 were evaluated. A reduced model was achieved through a stepwise-backward selection procedure with simultaneous transformation of continuous variable using
ACCEPTED MANUSCRIPT fractional polynomials of a 2nd degree. A 2-sided p-value
