Non-cardiac comorbidities in heart failure with preserved ejection fraction
Streng, Koen Wouter
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Chapter 8
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Summary and future perspectives
Aims of this thesis
The main aims of this thesis were:
• To assess the prevalence of non-cardiac comorbidities between patients with HFrEF, HFmrEF and HFpEF and the associations between these comorbidities and clinical outcome.
• To study the association of obesity and nutritional status in patients with heart failure and clinical outcome.
• To use established and novel renal markers to explore the pathophysiological differ-ences in renal dysfunction in patients with HFrEF and HFpEF.
Summary
Heart failure is often accompanied by several comorbidities. The presence of these co-morbidities is associated with even worse symptoms, quality of life and clinical outcome compared to those patients with heart failure without comorbidities.1-3 Comorbidities
might particularly affect patients with HFpEF, since the prevalence of comorbidities is higher than in patients with HFrEF. Moreover, no evidence based treatments are avail-able for patients with HFpEF, in contrast to patients with HFrEF. Therefore, particularly in patients with HFpEF, optimal treatment for concurrent comorbidities can be impor-tant.4-6 Nevertheless, the impact of individual comorbidities on quality of life in patients
with HFpEF remains unknown.
In Chapter 2 we studied the associations between eight different non-cardiac
comor-bidities and mortality, hospitalization and quality of life in 4,254 patients with HFrEF, HFmrEF and HFpEF. For this purpose, we used the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort.7 Results of this study
showed that chronic kidney disease, anaemia, diabetes and obesity were the most prevalent comorbidities in the overall cohort. Patients with HFpEF had the highest mean number of comorbidities, followed by patients with HFmrEF, and HFrEF respectively. In addition, the presence of non-cardiac comorbidities was more strongly related to quality of life in patients with HFrEF, while this association was less pronounced in patients with HFpEF. This can be explained by the fact that comorbidities are known to influence quality of life due to the presence of accompanying symptoms such as dyspnoea, decreased general condition of fatigue. On top of that, patients with multiple comorbidities are often treated, resulting in polypharmacy, which is also associated with a lower quality of life.8-10 Lastly, this study showed that the presence of chronic kidney
disease and anaemia was associated with a higher mortality, whereas obesity was associated with a lower mortality in both patients with HFrEF and HFpEF. Therefore,
we decided to focus on renal dysfunction and obesity as the two comorbidities of main interest in the remainder of this thesis.
In Chapter 3 the association of body mass index (BMI) with other circulating biomarkers
is investigated. The presence of obesity could impede the diagnosis of heart failure. First, physical examination is often difficult due to an increased fat layer, and for example troubling pulmonary auscultation. Second, the use of echocardiography is hampered because image quality if negatively affected due to increased subcutaneous fat. Third, obesity is known to result in lower levels of brain natriuretic peptides (BNP) and/or N-terminal BNP (NT-proBNP), which are essential in the diagnosis of heart failure.11
Lower circulating levels of natriuretic peptides could result in incorrectly rejecting the diagnosis of heart failure.12-14 Much less is known about the influence of obesity on other
circulating biomarkers, and if obesity influences the prognostic value of the biomarker. The analyses were performed in 2,033 acute heart failure patients from the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolo-fylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT). This study assessed the beneficial effects of rolofylline in acute heart failure patients, with neutral results.15,16 Results of this study showed that besides BNP, six circulating
biomarkers were either positively or negatively associated with BMI. Additionally, we found that five markers were significantly associated with mortality up to 180 days, and this association remained present in both obese and non-obese patients with heart failure. This suggests that obese patients with heart failure may have lower levels of circulating BNP, but this does not influence the prognostic value of the marker. Although our study did not provide any specific cut-off values for BNP, it does encourage clini-cians to assess BNP levels according to BMI. Patients with a high BMI are expected to have lower levels of circulating BNP, and should therefore be assessed accordingly. Secondly, we found that patients with a higher BMI had a significantly lower mortality risk up to 180 days. When assessing the different BMI groups, a BMI between 25 and 35 kg/m2 showed to be more favourable compared to a BMI below 25 kg/m2, which is
usually seen as a normal weight. This phenomenon has been extensively described in previous research, and has been referred to as the obesity paradox.17-20 Obesity is a
known risk factor for the onset of heart failure. Nevertheless, patients with heart failure and a higher BMI have significantly lower mortality rates compared to patients who have a low or normal BMI. Although this paradox has been extensively studied, the pathophysiological mechanisms behind this paradox remain unclear. However, over the past decades criticism regarding this paradox is swelling.21 One of the explanations for
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this apparent paradox might lie in the dependency on BMI for the definition of obesity. Previous studies regarding the obesity paradox found that, regardless of BMI, fitness and fatness were strongly associated with clinical outcome. A slightly higher BMI could be the result of an increased fat mass, but could also be due to an increased muscle mass.22,23 Another disadvantage of BMI is that it does not provide any information about
the fat distribution in the body. Abdominal fat is known to be more hazardous compared to subcutaneous fat, which is even thought to have positive health effects.24-26
In Chapter 4 we investigated the association of waist-to-hip ratio and clinical outcome
in 1,738 patients from the BIOSTAT-CHF study. Waist-to-hip ratio is an important measurement of visceral obesity. In this study, waist-to-hip ratio was associated with significantly higher mortality rates in women with heart failure, but not in men with heart failure. Furthermore, A higher waist-to-hip ratio is often found in the metabolic syndrome, which is known to induce a pro-inflammatory state.27 Consistent with these findings, we
found a strong association with inflammation in female heart failure patients, while this was less profound in male heart failure patients. Overall, this study showed that beyond BMI, fat distribution matters in patients with heart failure, and could identify patients at risk for adverse outcomes.
Besides fat distribution, nutrition is also an important determinant of health status. A slightly higher BMI might also be an indication of an overall better nutritional status. In current medical practice nutrition is an emerging target of research, but also in patient care. It is easy to implement for the patient. However, within heart failure research proper data regarding nutrition and outcome is lacking. It is known that improving nutritional status improves quality of life of a patient with heart failure. But if nutrition is associated with lower mortality rates in heart failure patients, as it is in the general population, is unknown.28 The current ESC heart failure 2016 guidelines provide only a
few recommendations regarding nutrition for a heart failure patient, besides the general advice to maintain a healthy weight and a healthy diet.11
A varied diet is often seen as a healthy diet. Proteins are an essential part of a healthy diet, and sufficient protein intake is association with improved outcome in the general population.29 Humans need dietary proteins to form essential amino acids, which cannot
be formed by the body itself. These amino acids are used to build up or maintain muscle mass among others. In patients with heart failure however, data regarding protein intake and clinical outcome is lacking.
In Chapter 5 we estimated protein intake by measuring urinary urea nitrogen and
in the index cohort from the BIOSTAT-CHF study, and were validated in an independent validation cohort. Results of this study suggested that a lower protein intake was associ-ated with more adverse outcomes. Furthermore, lower protein intake was associassoci-ated with higher levels of malnutrition markers. In extension, this study suggests that patients with heart failure could benefit from a protein enriched diet. Nevertheless, these results should be interpreted in the light of the limitations of this study, where results cannot be interpreted as being causal. Secondly, given the association between protein intake and malnutrition markers, results could suggest that patients with a low protein intake were in a general poor nutritional state.
The second non-cardiac comorbidity of interest in this thesis was renal dysfunction. Renal dysfunction is present in approximately half of the patients with heart failure, and is associated with more adverse outcomes since it could interfere with the treatment for patients with heart failure.30,31 Standard treatment for patients with heart failure consists
of medication given to inhibit the renin-angiotensin aldosterone (RAAS) system. Inhibi-tors of the RAAS system, for example Aliskiren, have shown beneficial effects on the heart and vascular system in patients with HFrEF.11 This effect is not proven for patients
with HFpEF, but they are still frequent prescribed in these patients for concomitant co-morbidities such as hypertension. Although RAAS inhibitors have an overall beneficial effect on mortality, even in patients with renal dysfunction, its use also poses a higher risk of inducing worsening renal function (WRF).32
Therefore, in Chapter 6 we performed a meta-analysis to study the interaction between
heart failure phenotype and RAAS inhibitor induced WRF and outcome. A total of eight studies were identified, of which six solely studied patients with HFrEF, one assessed solely patients with HFpEF and one studied both patients with HFrEF and patients with HFpEF. We found that in both heart failure groups RAAS inhibitors induce WRF, and that WRF is associated with a slight increase in events. However, in patients with HFrEF the beneficial effects of RAAS inhibitors outweigh this small increase in events, and is therefore still considered to be beneficial. In contrast, in patients with HFpEF WRF induced by RAAS inhibitors seems to be more harmful. Therefore the use of RAAS inhibitors should be carefully considered in patients with HFpEF, especially when they induce WRF. An obvious explanation could be that the positive effects in HFpEF are less profound, and therefore do not outweigh the detrimental effects seen with RAAS inhibitor induced WRF. However, it might also be explained by a different pathophysiol-ogy of renal dysfunction in patients with HFpEF and patients with HFrEF.
Renal dysfunction in patients with HFrEF has been associated with hemodynamic changes, while a low-grade state of inflammation and endothelial dysfunction have
8
been recently linked to renal dysfunction in patients with HFpEF.33,34 A more thorough
understanding of the pathophysiology behind the renal dysfunction in patients with HFpEF could provide essential information, and could theoretically lead to a possible medical intervention option. The recent linkage between endothelial dysfunction and renal dysfunction in patients with HFpEF might be more than an explanation for the renal dysfunction alone. Endothelial dysfunction and inflammation might be the com-mon denominator between both HFpEF and renal dysfunction, where one amplifies the other. However data regarding the pathophysiology of renal dysfunction is lacking in patients with HFpEF.
Following the results from Chapter 6, in Chapter 7 we investigated possible
pathophysi-ological differences in renal dysfunction between patients with HFrEF and patients with HFpEF. We studied several urinary markers, some of which are associated with specific nephron segments. We found that markers associated with the proximal tubule were more elevated in patients with HFpEF compared to patients with HFrEF. Furthermore, we found that the intergroup differences were most abundant in patients with a pre-served renal function. In patients with a prepre-served renal function we found significantly higher levels of these urinary markers, suggesting that a damaging process is already present in a preserved renal function in patients with HFpEF. There might be a common denominator present in patients with HFpEF resulting in, or at least contributing to, both cardiac and renal dysfunction. Although our data do not provide any causality, they showed that the biggest difference in renal damage markers is found in a normal renal function, which could be due to a common denominator such as endothelial dysfunc-tion and/or inflammadysfunc-tion. Most of the non-cardiac comorbidities present in patients with HFpEF are also associated with a steady state of low-grade inflammation, and might therefore contribute to the process of cardiac dysfunction. In contrast to HFrEF, HFpEF might be more of a systemic disease of which cardiac dysfunction is merely one of the outings.
FUTURE PERSPECTIVES
Over the past decades several trials have tried to identify novel medical therapies for patients with HFpEF, but so far none have succeeded regarding the improvement of clinical outcome. Although several medical trials are on-going in patients with HFpEF with promising new drugs, positive results are still to be expected in these patients. To date there have been no proven medical therapies in reducing mortality in these patients, and therefore improving quality of life might be the most beneficial option for patients with HFpEF for now. It is beyond dispute that the search for medical therapies
reducing clinical outcome in these patients should continue, but a two-track policy might be a good alternative. At this moment there is one clinical trial assessing the treat-ment of comorbidities in HFpEF patients, the Optimized Managetreat-ment of Comorbidity in Heart Failure With Preserved Ejection Fraction in the Elderly (>60 years) (OPTIMIZE-HFPEF).35 This study includes patients with HFpEF above the age of 60 years, and they
are randomized to care as usual or intensive treatment of 12 possible comorbidities. They will be randomized to either care as usual or intensive screening for comorbidi-ties. If there are any present, they will receive optimal treatment for their comorbidities according to the available recommendations. The follow-up will be a minimum of 2 years and a maximum of 3 years. The primary endpoint consists of change in clinical composite score at 24 months. This composite score not only assesses quality of life, but also changes in NT-proBNP and mortality/hospitalization.
Since the prevalence of HFpEF is only expected to rise in the upcoming years, the need for a treatment for these patients is increasing.36 Over the past years, patient tailored
treatment has been increasing, where instead of a general treatment for all patients the medication is tailored for each patient. Additionally to this tailored medicine, a holistic approach including treatment for the comorbidities in heart failure patients could be of great importance. In this thesis the associations of individual non-cardiac comorbidities and quality of life are shown, which are sometimes underestimated by current medical practice. The focus of current research is often on harder endpoints such as mortality and hospitalization, while quality of life might actually be the most important for the pa-tient. Improving quality of life results in a direct effect for the patient, and is often greatly appreciated. Future treatment of patients with heart failure, and especially patients with HFpEF, might include intensive collaboration with other medical specialties, dieticians and the general practitioner to provide optimal treatment for all comorbidities present. In this thesis the positive effects, but also the negative effects of obesity are extensively descripted. The obesity paradox, which has been studied over the past years, is at least partially challenged by this thesis, and suggests that clinicians should also assess fat distribution, rather than solely measuring BMI. There have been studies performed where weight loss is associated with higher mortality rates in obese patients.37,38
How-ever, when these analyses were performed in a population with higher abdominal fat mass, instead of solely assessing BMI, there were actually significantly lower mortality rates found in these patients.39 Specifically targeting patients with a higher waist-to-hip
ratio, and stimulating regular exercise and participating in a fitness program could help these patients.
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In the coming years fat distribution should become a research topic of interest. Not only visceral fat is linked to adverse outcomes in patients with heart failure, but epicardial fat is often compared with visceral fat regarding its association with adverse events.40,41
Large MRI studies should be performed to assess both epicardial and visceral fat, to extensively evaluate this association with clinical outcome.
However, there are not solely negative effects associated with a higher BMI in patients with heart failure. There are many reasons that could explain the obesity paradox found in patients with heart failure. A slightly higher BMI might also indicate a proper nutritional status in patients with heart failure, and might reflect the functional reserve capacity a patient needs. However, for the next years nutrition should be an important topic in research. In this thesis the possible beneficial effects of a higher protein intake are shown. However, to conclude a causal relationship between protein enriched diet and clinical outcome, randomized controlled trials should be performed. There is much room for improvement in the current heart failure guidelines, where very few recommenda-tions are given, mostly due to the lack of research. However by conducting studies focussed on nutrition, there is much to gain. Research should be focussed on both harder endpoints such as mortality and hospitalization, but also endpoints such as qual-ity of life should be included in these trials. Optimizing nutritional status in heart failure patients is an easy implementable tool in current medical practice, and should include intensive collaboration with a dietician.
In addition, this thesis provides more insight in renal dysfunction in patients with HF-pEF and patients with HFrEF. Since renal dysfunction is one of the most prominent comorbidities present in patients with heart failure, it also one of the most studied comorbidities. However, most of this research is performed in patients with HFrEF, and legitimately assessed in patients with a decreased estimated glomerular function. However, in this thesis we show that the biggest difference is seen in patients with a preserved estimated glomerular function, and research might shift its focus towards these patients. By comparing patients with a decreased renal function in patients with HFrEF and HFpEF, the damage might already be done and any differentiating factors might have already disappeared. Although it might seem counterintuitive, to study renal dysfunction in HFpEF patients, research should also be performed in patients with a normal renal function.
The research presented in this thesis has emphasized the effects of non-cardiac comor-bidities on quality of life, and has led to a better understanding of the role of obesity in patients with heart failure. It has shown that assessing BMI alone might be to bluntly, and assessing different indices could provide essential information about fat
distribu-tion. This thesis has also shown the association of a higher protein intake and mortality in patients with heart failure, with promising results that should be further investigated, since they could be of great importance in the treatment of patients with heart failure. This thesis also shows that, to better understand renal dysfunction in patients with HFpEF, we need to study those with a normal renal function. Finally, this thesis has given more insight in two highly prevalent non-cardiac comorbidities, and future studies based on these findings could help us to provide a holistic approach in the treatment of heart failure patients.
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