Iron Deficiency in Heart Failure and Pulmonary Hypertension

Abstract

Purpose of review

To describe the role of iron deficiency in both heart failure and pulmonary hypertension.

Recent findings

To role of iron deficiency in heart failure is well established and pathophysiologic overlap with pulmonary hypertension exists.

Summary

Iron deficiency is common co-morbidity in heart failure and pulmonary hypertension. The high prevalence is intertwined into the pathophysiology of these conditions (e.g., neurohormonal activation, inflammation). The presence of iron deficiency has a negative impact on cardiomyocytes and cardiac function, skeletal muscle function, and pulmonary vascular function. In heart failure data from over 2000 randomized patients with iron deficiency using a uniform diagnosis, have illustrated beneficial effects on functional status, quality of life, reverse cardiac remodeling, and heart failure admissions. While iron deficiency is recognized to be prevalent in pulmonary hypertension and associated with worse functional status, the absence of a uniform definition and the absence of large prospective randomized controlled trials with iron therapies limits the conclusions on the causal role of iron deficiency such as observed in heart failure.

Introduction

Iron deficiency is worldwide one of the most common nutritional deficits [1]. Iron is an essential co-factor in enzymes and proteins involved in mitochondrial function, oxygen transport and storage (hemoglobin and myoglobin), tricarboxylic acid cycle, and anti-oxidative processes [2]. Iron is especially an important cofactor in tissue with a high energy demand such as cardiomyocytes, skeletal muscles, and central nervous system, given its pivotal role in mitochondrial respiration. Due to the absence of pathways actively excreting iron (e.g., no renal excretion), regulation of iron levels mainly operates at the level of iron uptake and regulating its bioavailability [3].

However, these processes can become disrupted in disease settings associated with inflammation, effectively reducing the systemic and tissue bioavailability of iron [2]. Both heart failure and pulmonary hypertension are associated with chronic inflammation and both are disease conditions in which the bio-availability of iron becomes reduced. This manuscript focuses first on describing key insights into the regulation of iron, and how iron deficiency affects cardiac tissue, skeletal muscles, and the pulmonary vasculature. Afterward, the role of iron deficiency and the treatment of iron deficiency in both heart failure and pulmonary hypertension are discussed.

Regulation of iron and development of iron deficiency

Given the absence of pathways to actively excrete iron and given the toxicity of high levels of free iron (Fenton reactions), there is a strong regulation of iron levels in the body. This occurs mainly through regulation of intestinal uptake of iron or the buffering of iron within cells. In the bloodstream, iron is bound to transferrin which is capable of binding two Fe³⁺ ions, while ferritin is the major protein in the cells, capable of binding numerous iron ions [4]. Because ferritin carries most of the body’s iron and is also secreted in the bloodstream, this reflects relatively well total body iron content. While it is often taught that ferritin best reflects iron levels, it is becoming increasingly recognized that in the setting of heart failure serum iron or transferrin saturation better reflects iron reserves and the functional bioavailability [5••, 6, 7]. The rate-dependent step in intestinal iron uptake is located at the level of ferroportin. A protein is present at the basolateral site of the enterocyte and present on spleen macrophages (that recycle iron from senescent red blood cells). The expression of this protein is regulated through hepcidin. Hepcidin is upregulated in conditions of inflammation and iron excess, while it is downregulated in the presence of an iron deficit or hypoxemia. Hepcidin results in an internalization of ferroportin leading to less uptake of intestinal iron from the gut, but also clustering of iron within the reticuloendothelial system [8].

In general, numerous mechanisms result in the high prevalence of iron deficiency observed in heart failure or pulmonary hypertension. Iron deficiency might be the result of enhanced iron loss due to blood loss (anti-platelet drugs use or anticoagulants), diminished iron uptake (malnutrition, congestion, tea drinking), or reduced iron biological availability (for instance due to inflammation-induced upregulation of hepcidin or processes associated with elevated wall stress and neurohormonal activation) [9]. Additionally, sex difference is observed with a higher prevalence seen in woman, which might relate to menstrual blood less [9–11]. The search for specific reasons for iron deficiency is often challenging and a modifiable reasons may not be found in many cases. However, when diagnosing iron deficiency it is important to always question about intestinal blood loss and changes in bowel pattern. Observational studies have shown that numerous patients with iron deficiency and heart failure during follow-up are diagnosed with intestinal malignancies, especially when ferritin is very low or in the presence of anemia [12]. Because iron plays such an important role in numerous important physiologic pathways, its presence can worsening the disease trajectory of patients with heart failure or pulmonary hypertension.

Mechanistic role of iron deficiency

Effect on cardiac function

To understand the impact of iron deficiency on a macroscopic level it is important to fully appreciate the effects on a cellular level. Cardiomyocytes function by an intertwining of cellular excitation–contraction coupling of cardiomyocytes and energy metabolism. More than any muscle, the heart consumes adenosine triphosphate (ATP) with an astonishing consumption of 6 kg on a daily basis [13]. Most of this myocardial energy requirement is for either actin-myosin uncoupling during myofilament shortening (the cellular basis of systole) or buffering of calcium during diastole (the cellular basis of diastole). Once myocyte become activated by a depolarizing sodium current, this results in cellular calcium influx from both the extracellular compartment and the endoplasmic reticulum. Such calcium influx results in actin-myosin overlap and myofilament shortening. However, some cytoplasmic calcium is taken up by the mitochondria via the mitochondrial calcium uniporter (MCU) [14]. Within the mitochondria, calcium plays a role in determining the rate of substrate utilization in the tricarboxylic acid cycle and the subsequent oxidative phosphorylation, which ultimately determines the rate of ATP production. This energy is converted to phosphocreatine which is shuttled in the subcellular space through creatinine kinase isoforms to regions of high energy demand being the myofilaments for shortening (cellular basis of systole) or the sarcoendoplasmic reticulum calcium transport ATPase (SERCA) pump (element of the cellular basis of diastole) for calcium buffering. In this way, excitation coupling is fine-tuned to energy metabolism forming a streamlined and efficient engine. In disease conditions associated with neurohormonal activation (e.g., elevated levels of aldosterone, endothelin, and norepinephrine such as occurring in heart failure or pulmonary hypertension), intramyocardial iron content drops [15]. The consequences of such drop have been elegantly explored in a study by Hoes and colleagues [16••]. Human embryonic stem cell-derived cardiomyocytes were incubated with an iron chelator (deferoxamine), resulting in a decrease in intracellular iron content. Iron depletion affected mitochondrial function through reduced activity of the iron-sulfur cluster containing complexes I, II, and III, but not complexes IV and V, leading to reduced ATP-linked respiration and respiratory reserve [16••, 17]. This energetic crisis resulted in diminished myocyte shortening and slowed and diminished myocyte relaxation kinetics. As can be expected, myocyte iron deficiency resulted in upregulation of membrane-bound transferrin receptors. Interestingly administration of soluble transferrin-bound iron allowed for a recovery of the morphologic and functional consequences induced by iron deficiency.

On a macroscopic level, numerous studies show that iron deficiency stimulates progressive cardiac remodeling [18]. Additionally, implantation of cardiac resynchronization therapy in patients with heart failure and reduced ejection fraction and the presence of iron deficiency is associated with less degree of left ventricular reverse remodeling [19, 20]. Given the important role of iron deficiency in cardiac energy metabolism and the increased energy demand during exercise, myocardial alterations become more apparent during exercise. An invasive hemodynamic study has shown that during exercise, patients with iron deficiency are less capable of increasing their cardiac output. One of several operating mechanisms resulting in an increase in cardiac contractility during exercise is the force-frequency relationship [21]. This relation, also known as the Bowditch-Treppe phenomena, indicates that at higher heart rates the myocardium contracts with increased force in order to meet the enhanced contractile requirements to support stroke volume increase during exercise. While such a phenomena plays in healthy individual, as they exhibit a positive force-frequency relationship (increase in force at higher heart rates), this mechanism is defected in a state of heart failure. Indeed, it has been long recognized that patients with heart failure manifest with the reverse being a negative force-frequency relationship or a decrease in force at higher heart rates [22]. This decrease in cardiac force at higher heart rates in patients with heart failure is a result of intracellular sodium and calcium accumulation and partially the resultant of a cellular energetic deficit. In an elegant experiment, Haddad and colleagues describe a mouse model of iron deficiency assessing the impact of iron deficiency on the force-frequency relationship after stimulation with dobutamine [23]. Iron-deficient mice in comparison to non-iron-deficient mouse showed a similar increase in heart rate, yet had a larger drop in their dp/dt. Using in vivo ³¹P-magnetic resonance spectroscopy, the authors showed that this negative force-frequency relationship was caused by an energetic crisis induced by iron deficiency as documented by a drop in the phosphocreatine/ATP ratio [23]. A similar process occurs in HFrEF patients with a CRT device undergoing incremental biventricular pacing, showing a drop in cardiac contractility. While the majority of evidence regarding the cardiac effects of iron deficiency involved patients with HFrEF, studies investigating in patients with unexplained dyspnea (of whom the majority had exercise-induced pulmonary hypertension) showed that iron deficiency was associated with a reduced right ventricular contractile reserve [7, 24]. Interestingly, once the right ventricle starts to fail in the setting of pulmonary hypertension, metabolic studies have shown an increase in glucose influx on PET-imaging [25]. This is often indicative of a metabolic switch in which mitochondria in cardiomyocytes are not able to oxidize sufficient end-products of fatty acid oxidation and glycolysis and the heart becomes more dependent on anaerobic glycolysis of the pyruvate (converted to lactate) [25]. The metabolic fate of pyruvate is determined by differential activity between pyruvate dehydrogenase (PDH) and lactate dehydrogenase [17]. Iron deficiency is associated with a 15% reduction in the activity of citrate synthase leading to accumulation of acetyl-Coa and ensuing negative inhibition of PDH. Enhanced glucose flux into glycolysis will be met with more pyruvate being broken down to lactate being an energetically less efficient pathway [14].

Effect on skeletal muscle

Despite that the heart is the most energy-demanding muscle, skeletal muscles compromise the abundancy of muscle volume in the body. Exercise intolerance is key pathologic feature in both heart failure and pulmonary hypertension [26]. Next to central (cardiac or pulmonary) mechanisms to this exercise intolerance, peripheral mechanisms to an exercise intolerance occurs. Peak oxygen consumption (VO₂) as the gold standard measurement of exercise capacity is determined by both cardiac output and peripheral skeletal muscle oxygen extraction (Arterial—mixed venous O2 or AvO2-difference = CaO2-CvO2). Several studies have shown that the arteria-mixed venous oxygen capacity (AvO2) difference is reduced or similar in patients with iron deficiency (however it should be noted that finding a similar AvO2 difference in the setting of a lower cardiac output is abnormal as lower cardiac output is normally associated with a larger AvO2 difference) [7, 27•]. Next to limited oxygen extraction, skeletal muscle biopsy in patients with iron deficiency has shown impaired energy metabolism and mitochondrial respiration [28]. Several studies using ³¹P-magnetic resonance spectroscopy in patients with heart failure during exercise have illustrated that iron deficiency is associated with diminished energy reserve (higher ADP, less phosphocreatine, lower pH, and slowed recovery kinetics) [29••, 30]. Not surprisingly during cardiopulmonary exercise testing, iron deficiency is associated with a lower peak VO₂, lower workload, lower O₂-pulse, and early muscle acidification (low VO₂ at anaerobic threshold [AT] and early attainment of AT) in patients with heart failure and/or pulmonary hypertension.

Effect on pulmonary vasculature

Iron is an essential cofactor in Fe-Sulfur (Fe-S) clusters in the mitochondrial electron transport chain. Interestingly, several rare genetic mutations (NFU1, BOLA3, and IBA57) have been identified that lead to abnormal incorporation of these iron-sulfur clusters in mitochondria, and these patients develop early onset pulmonary hypertension [31]. Patients with heart failure and iron deficiency tend to have higher pulmonary pressure on echocardiography. It is unknown if this reflects purely passive post-capillary pulmonary hypertension or if there is associated pulmonary vascular remodeling. Mice who are fed an iron-deficient diet express higher levels of hypoxia-induced factor-1α and hypoxia-induced factor-2α and analysis of their pulmonary vasculature document reduced mitochondrial complex I activity and mitochondrial membrane hyperpolarization in mitochondria from pulmonary arteries [32, 33]. In human pulmonary artery vascular and endothelial cells hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 downregulated Fe-S levels, leading to progressive pulmonary vascular remodeling [34, 35].

Iron deficiency in heart failure

Both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) heart failure clinical guidelines recommend for the screening of the presence of iron deficiency at the time of heart failure diagnosis [36, 37]. Additionally, the ESC heart failure guidelines recommend to periodically screen patients with iron deficiency [36]. Serial screening is potentially important because it is becoming increasingly recognized that iron deficiency is not necessarily a static disease, but iron parameters can fluctuate. Indeed in an observational studies around 30% of previously iron-replete patients developed iron deficiency over a 1 year period [38].

Definitions and prevalence of iron deficiency in heart failure

Iron deficiency is commonly defined as a serum ferritin level below 100 ng/ml or a serum ferritin level between 100–300 ng/ml in the presence of a transferrin saturation (TSAT) below 20%. This definition has been both recognized by ESC and ACC/AHA guidelines and has been used in most randomized controlled trials with intravenous ferric carboxymaltose and has been shown to adequately identify a patient population that benefits from intravenous iron [36, 37]. However, some controversy remains regarding this definition as no formal validation of this definition of iron deficiency was undertaken before its use in clinical practice [5, 6]. A recent study looking bone marrow iron staining as the gold standard to define the presence of iron deficiency illustrated that a TSAT < 20% or serum iron ≤ 13 μmol/L had the best sensitivity and specificity to detect the presence of iron deficiency [39]. While patients with a ferritin below 100 ng/ml in the presence of a TSAT above 20% (also called isolated hypoferritinemia) were almost always iron repleted on bone marrow staining. Indeed some heterogeneity in treatment effect with intravenous iron has been observed in iron-deficient patients with or without a TSAT < 20%, suggesting that patients with isolated hypoferritinemia had a reduced treatment effect [40, 41••]. Although, this was not convincingly reproduced in the largest IV iron study to date (AFFIRM-AHF trial) [42]. Some slight differences in prevalence can be found depending on the use of certain definitions or the setting in which is being screened (acute vs chronic heart failure). Using the guideline recognized definition of iron deficiency in the setting of chronic heart failure documents a prevalence of iron deficiency of around 40–68%, which can be around 80% in the setting of acute heart failure. Using the definition of a TSAT < 20% around 43–46% and using a serum iron ≤ 13 μmol/L around 48% of patients with chronic heart failure have iron deficiency, but less is known about the setting of acute heart failure [10, 43–45].

Treatment of iron deficiency in heart failure

Iron deficiency is associated with more pronounced heart failure-related symptoms, reduced maximal (peakVO₂) and submaximal (6-min walk test [6MWT]) exercise capacity, progressive cardiac remodeling, and higher risk for heart failure hospitalization and all-cause mortality. The effect of intravenous ferric carboxymaltose on these endpoints has been assessed in numerous double-blind randomized controlled trials and their key findings are reflected in Table 1. In chronic heart failure, the use of IV ferric carboxymaltose has been shown to improve patient functionality and 6MWT [46, 47]. Cardiac reverse remodeling of both the left and right ventricles has also been observed in the IRON-CRT and Myocardial-IRON trials [41••, 48•, 49, 50]. Additionally, the EFFECT-HF in combination with the IRON-CRT trial shows that IV ferric carboxymaltose can improve peak VO₂ [48•, 49, 51]. Next to a potential effect on central mechanisms the FERRIC-HF II trial illustrated that intravenous iron was capable of improving skeletal muscle phosphocreatine recovery half times and diminished ADP content, indicative that exercise capacity can also improve due to an effect on peripheral (skeletal muscle) mechanisms [29••]. The treatment effect of ferric carboxymaltose if driven by modest improvements in the intervention groups and to the occurrence of deterioration in patients treated with placebo, hereby underscoring that the natural evolution of many patients with iron deficiency is one of progressive functional decline. The AFFIRM-AHF trial showed that intravenous ferric carboxymaltose reduces the risk of heart failure admissions and improves functional status in patients with a recent acute heart failure episode [42, 52]. While a consistent effect has been observed with intravenous iron therapy, no convincing effect has been observed with oral iron treatment [53]. The positive effects of these studies have led to the class IIa recommendations in most recent heart failure guidelines [36, 37].

Table 1.

Overview of trials with iron therapies in heart failure and pulmonary hypertension

Studies in heart failure
Study	N	Definition	Pop	Design	Treatment	Outcome	Ref
FAIR-HF	459	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF, LVEF < 45%	Double-blind placebo-controlled RCT	IV FCM	Improvement functional status, QoL and 6MWT	[46]
CONFIRM-HF	304	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF, LVEF < 45%	Double-blind placebo-controlled RCT	IV FCM	Long-term Improvement functional status, QoL and 6MWT	[47]
AFFIRM-AHF	1132	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HF LVEF < 50% after AHF	Double-blind placebo-controlled RCT	IV FCM	Reduced HF-readmissions and improvement QoL	[42, 52]
EFFECT-HF	172	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF, LVEF < 45%	Double-blind placebo-controlled RCT	IV FCM	Prevents deterioration of peakVO2, improvement PGA and NYHA-class	[51]
Myocardial-IRON	53	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HF LVEF < 50%	Double-blind placebo-controlled RCT	IV FCM	Improves myocardial iron content, LV and RV function	[48•, 49••]
IRON-CRT	75	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF + CRT, LVEF < 45%	Double-blind placebo-controlled RCT	IV FCM	Improves, LV and RV function, contractile reserve, KCCQ, and peakVO2	[41••, 50••]
FERRIC-HF II	40	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF, LVEF < 45%	Double-blind placebo-controlled RCT	IV iron isomalto-side	Skeletal muscle PCr tl/2 and ADP	[29••]
IRNOUT-HF	225	ferritin < 100 μg/L or 100–300 if TSAT < 20%	HFrEF, LVEF < 40%	Double-blind placebo-controlled RCT	Oral iron polysaccharide	No effect on peak V02, 6MWT, KCCQ, NTproBNP	[53]
Studies in pulmonary hypertension
Study	N	Definition	Pop	Design	Treatment	Outcome	Ref
Tay et al.	25	Ferritin < 30 μg/L or Ferritin < 50 μg/L if TSAT < 15%	Cyanotic CHD	Observational, uncontrolled, unblind	Oral ferrous fumarate	Improvement CHAMPHOR score, Hb and 6MWT	[57]
Viethen et al.	20	iron < 10 μmol/L, ferritin < 150 μg/L + TSAT < 15%	PAH	Observational, uncontrolled, unblind	FCM	Improvement in 6MWT and SF-36	[58]
Blanche et al.	142	Ferritin < 30 μg/L or TSAT < 15%	CHD+/−PH	Observational, uncontrolled, unblind	FCM	Increase in Hb	[59]
Ruiter et al.	15	iron < 10 μmol/L, TSAT < 15% [women] or < 20% [men], + ferritin < 100 μg/L	iPAH	Observational, uncontrolled, unblind	FCM	No change in 6MWT or PeakVO2; but exercise time and aerobic capacity improved	[60]
Howard et al.	39 + 17	Ferritin < 37 μg/L or iron < 10.3 umol/L or TSAT < 16.4%	iPAH or hPAH	Double-blind, randomized, placebo-controlled, cross-over	39: FCM 17: iron dextran	No impact on CPET variables (endurance time, peakVO2), 6MWT, PVR	[61]
Kramer et al.	117	ferritin < 100 μg/L or 100–300 if TSAT < 20%	PAH	Observational, uncontrolled, unblind	FCM	Improvement 6MWT, WHO-class, and ESC/ERS risk score	[62]
Smith et al.	22 + 11	Venesection-induced iron deficiency	Healthy individuals at high altitude	Double-blind, randomized, placebo-controlled	Iron sucrose	Decrease in sPAP at high altitude	[63]
Olsson	22	ferritin < 100 μg/L or 100–300 if TSAT < 20%	WSPH groups 1, 2, and 4	Observational, uncontrolled, unblind	Ferric Maltol	Improvement iron parameters, 6MWT, NTproBNP, RV FAC	[64]

Areas of uncertainty in heart failure

While evidence has been generated regarding the functional and exercise capacity improvement with ferric carboxymaltose in chronic heart failure, no such data exist in the field of heart failure with preserved ejection fraction. Additionally, outcome data as generated in the AFFIRM-AHF has only been generated for patients recovering from acute heart failure and no outcome data has been generated regarding in patients with chronic heart failure with reduced or preserved ejection fraction. The ongoing HEART-FID trial is enrolling patients with chronic heart failure with reduced ejection fraction testing the effect of ferric carboxymaltose on a hierarchical composite of death and heart failure hospitalization at 12 months and change from baseline to 6 months in the 6-min walk test distance [54].

Iron deficiency in pulmonary hypertension

Definitions and prevalence of iron deficiency in pulmonary hypertension

Pulmonary hypertension is a syndrome characterized by marked remodeling of the pulmonary vasculature and a progressive rise in the pulmonary vascular load, leading to hypertrophy and remodeling of the right ventricle [55]. Patients experience a significant functional limitation. Overall, morbidity and mortality are predominantly driven by right ventricular failure. Given the association found between iron deficiency and alterations in the pulmonary vascular function, cardiac (right ventricular function), and skeletal muscle function, iron deficiency might be a valuable treatment target in patients with pulmonary hypertension. ESC/European Respiratory Society (ERS) guidelines recognize that both iron deficiency and anemia can be associated with worse disease status and give a class IIb recommendation to correct its presence [56]. However, a review of the data on which this recommendation is based, illustrates that difference exist in the definitions used to describe iron deficiency in pulmonary hypertension (Table 2), which result in a wide range in prevalence between 3 and 71%. More recently the 2022 ESC/ERS guidelines have defined iron deficiency similarly as the field of heart failure (ferritin < 100 μg/L irrespective of TSAT or ferritin 100–300μg/L if TSAT < 20%). However, this definition requires more validation in the field of pulmonary hypertension, as it is increasingly recognized that patients with isolated hypoferritinemia (ferritin < 100μg/L but TSAT > 20%) seem to behave differently in terms of limited disease severity and altered treatment response towards intravenous iron. Overall, the presence of iron deficiency in pulmonary hypertension is associated with the presence of both lower maximal and submaximal exercise capacity and some data suggest a higher pulmonary vascular resistance and depressed indices of right ventricular function and worse clinical outcome.

Table 2.

Definitions and prevalence of iron deficiency in pulmonary hypertension

Publication	Population	Definition	Prevalence	ref
Vinke et al. 2021	PAH and CTEPH	Iron < 10 μmol/L	33%	[65]
Vinke et al. 2021	PAH and CTEPH	Ferritin < 10 μmol/L	3%	[65]
Vinke et al. 2021	PAH and CTEPH	TSAT < 15% (F) or < 20% (M)	36%	[65]
Panagiota Xanthouli et al. 2021	PAH	Iron < 12 μmol/L (F), < 13 μmol/L (M)	54%	[66]
Jasmine Tatah et al. 2022	Group 3 PH	sTfR > 4.4 mg/L	53%	[67]
Ioan Tilea et al. 2022	Precapillary PH (PAH and CTEPH)	ferritin < 30 μg/L and TSAT < 16%	70%	[68]
Stefano Ghio et al. 2021	PAH	Iron < 10 μmol/L or Ferritin < 10 μmol/L TSAT < 15% (F) or < 20% (M)	71%	[69]
Xue Yu et al. 2018	Congenital heart disease PH	TSAT < 20% in male and female < 25%	39%	[70]
Xue Yu et al. 2018	Group1-5 PH	TSAT < 20% in male and female < 25%	38%	[71]
Vanessa P M van Empel et al. 2014	PAH	(sTfR), > 4.4 mg/l in females, > 5.0 mg/l in males	44.8%	[72]
Rhodes et al.	PAH	sTfR > 4.4 mg/L	63%	[73]
Alexander Van De Bruaene	Cyanogenic congenital heart disease PH	Ferritine 30 ng/mL or ferritine 30–100 ng/mL + TSAT < 20%	62%	[74]

TSAT transferrin saturation, PAH pulmonary arterial hypertension, CTEPH Chronic thromboembolic pulmonary hypertension

Treatment of iron deficiency in pulmonary hypertension

Several studies have investigated the role of treatment with iron therapies to improve functional status in patients with PH. Overall the studies significantly suffer from differences in the included population, the used definition of iron deficiency, the design with most studies being open-label uncontrolled and unblended. The few randomized double-blind controlled trials suffering from a small sample size. Results of available studies are reported and reflected in Table 1. Overall unblinded and observational studies (using different inclusion criteria) do suggest an improvement in 6MWT and functional status. However, due to their non-randomized design, any conclusion on causality is not possible and these results can merely be interpreted as hypothesis generating. The results of the randomized controlled trials do not exhibit a convincing effect of intravenous iron on exercise capacity however numerous limitations include the early termination of the studies due to slow enrollment and generally underpowered designs. Clearly, a major deficit in the field of pulmonary hypertension is the absence of an uniform definition best to identify patients with iron deficiency and adequately powered randomized controlled trials to test if treatment of patients with this definition of iron deficiency is capable of improving patient functionality and exercise capacity (and potentially episodes of decompensated right ventricular failure), in line to what is observed in heart failure with reduced ejection fraction, as reflected in Table 1.

Areas of uncertainty in pulmonary hypertension

Several opportunities exist in the field of iron deficiency in pulmonary hypertension being the generation of a definition that separates patients in an optimal way regarding patient-centered outcomes (QoL), exercise capacity, and clinical outcome. Further mechanistic studies are necessary to determine the way such definition of iron deficiency alters exercise capacity and functional status. Finally larger randomized controlled are needed testing the effect of iron therapies in methodologic rigorous ways.

Conclusion

Iron deficiency is a common co-morbidity in heart failure and pulmonary hypertension. In heart failure, iron deficiency is a well-established causal risk factor in functional status, exercise capacity, and clinical outcome. Ongoing work is necessary in the field of pulmonary hypertension to determine a potential similar role of iron deficiency.

Abbreviations

HFrEF

Heart failure with reduced ejection fraction

LVEF

Left ventricular ejection fraction

IV

Intra-venous

FCM

Ferric carboxymaltose

TSAT

Transferrin saturation

QoL

Quality of life

6MWT

Six-minute walk test

HF

Heart failure

AHF

Acute heart failure

KCCQ

Kansas city cardiomyopathy questionnaire

CRT

Cardiac resynchronization therapy

CHD

Congenital heart disease

PAH

Pulmonary arterial hypertensioni

iPAH

Idiopathic pulmonary arterial hypertension

hPAH

Hereditary pulmonary arterial hypertension

PH

Pulmonary hypertension

RV

Right ventricle

LV

Left ventricle

sPAP

Systolic pulmonary artery pressure

WHO

World health organization