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Biological phenotypes of heart failure with preserved ejection fractionLewis. Biological phenotypes of HFpEFGavin A. Lewis, MBChB,1,2 Erik B. Schelbert, MD, MS,3-5 Simon G. Williams, MD,2 Colin Cunnington, MBChB, DPhil,1,6 Fozia Ahmed, MBChB, MD,1,6 Theresa McDonagh, MBChB, MD,7 Christopher A. Miller MBChB, PhD1,2,8Total Word Count: (9,968)Affiliations1. Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PL2. University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Wythenshawe, Manchester, M23 9LT3. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA4. UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA, USA5. Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, USA6. Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL7. King’s College Hospital, Denmark Hill, London, SE5 9RS.8. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology & Regenerative Medicine, School of Biology, Faculty of Biology, Medicine & Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PTFrom University of Manchester, Manchester, UK (GAL, CC, FA, CAM); University Hospital of South Manchester, Manchester, UK (GAL, SGW, CAM); University of Pittsburgh, PA, USA (EBS); Central Manchester University Hospitals Manchester, UK (CC, FA); King’s College Hospital (TM).Sources of fundingDr Lewis is funded by a fellowship grant from the National Institute for Health Research. ?Dr Miller is?funded by a Clinician Scientist Award (CS-2015-15-003)?from the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.DisclosuresNone declared. Address for CorrespondenceDr. Christopher A. Miller, Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PLTelephone: 0044 161 291 2034. Fax: 0044 161 291 2389Email: Christopher.Miller@manchester.ac.ukAcknowledgments NoneAbstractHeart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, which result in the heterogeneous phenotypes that are evident clinically, and which have potentially confounded previous HFpEF trials. A greater understanding of the in vivo human processes involved, and in particular, which are the causes and which are the downstream effects, may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on the underlying biology. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotype. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes.Condensed AbstractHeart failure with preserved ejection fraction (HFpEF) involves multiple pathophysiological mechanisms, resulting in clinically evident heterogeneous phenotypes. A greater understanding of the in vivo human process involved may allow the syndrome of HFpEF to be distilled into distinct diagnoses based on underlying biology, allowing targeted intervention based on their ‘biological phenotype’. This review describes the biological phenotypes of HFpEF and therapeutic interventions aimed at targeting these phenotypes. Key WordsHeart failure with preserved ejection fraction, heart failure, diastolic dysfunction, myocardial fibrosis, titin, ejection fraction.Abbreviations ListCMR = cardiovascular magnetic resonanceCVF = collagen volume fractionECM = extracellular matrixEF = ejection fractionHF = heart failureHFpEF = heart failure with preserved ejection fractionHFrEF = heart failure with reduced ejection fractionLV = left ventricularLVH = left ventricular hypertrophyLA = left atrialIntroductionDescribed as the “single largest unmet need in cardiovascular medicine”, heart failure with preserved ejection fraction (HFpEF) potentially accounts for up to half of heart failure (HF), indeed, as the population ages and its risk factors become more prevalent, the impact of HFpEF is set to rise considerably.However, reflecting the ongoing lack of understanding of HFpEF, its definition, even its name, continues to change in clinical guidelines and randomised controlled trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb25pa293c2tpPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh
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ADDIN EN.CITE.DATA (2). Even after leaving aside specific causes of HF in the context of a normal or near normal ejection fraction (EF) (e.g. hypertrophic cardiomyopathy, cardiac amyloidosis, Fabry disease), it is true that HFpEF represents a broad cohort of patients with a range of comorbid conditions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXRsZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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AG==
ADDIN EN.CITE.DATA (4). Whilst this acknowledges the heterogeneity and need for individualised management, it is the ‘biological phenotypes’, i.e. the underlying disease mechanisms of HFpEF, that ultimately need to be addressed, and which will be the focus of the current discussion (Figure 1). When interpreting the presented data, it is important to note that study findings reflect the population studied, which often differs according to data source (clinical trials vs. registries vs. mechanistic studies), and may itself contribute to the heterogeneity. Morphological heterogeneity Left ventricular hypertrophy (LVH) and left atrial (LA) dilatation are considered hallmarks of HFpEF and are included in its definition in recent guidelines PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb25pa293c2tpPC9BdXRob3I+PFllYXI+MjAxNjwvWWVh
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ADDIN EN.CITE.DATA (1) and in the inclusion criteria of current randomised controlled trials, however there is considerable morphologic heterogeneity. In clinical trials and contemporary registries, approximately one-third to two-thirds of patients with HFpEF do not have LVH (Figure 2A) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWxlPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (7) respectively) have eccentric LVH rather than the conventional concentric pattern. Hypertrophic remodelling is more common in HFpEF patients with hypertension, although approximately half of patients with HFpEF and normal left ventricular (LV) mass have hypertension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXR6PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (6). Furthermore, LVH is not exclusive to HFpEF, indeed the prevalence of LVH is similar in patients with hypertension and no history of HF as compared to patients with hypertension and HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW08L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (5,6,9).Similarly, a third to a half of patients in HFpEF studies have normal LA size (Figure 2B) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWxlPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (5,7,10). In comparison, a third of patients with hypertension without HF have LA enlargement ADDIN EN.CITE <EndNote><Cite><Author>Cuspidi</Author><Year>2013</Year><RecNum>4039</RecNum><DisplayText>(11)</DisplayText><record><rec-number>4039</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491474667">4039</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cuspidi, C.</author><author>Rescaldani, M.</author><author>Sala, C.</author></authors></contributors><auth-address>Department of Health Science, University of Milano-Bicocca, Milan, Italy. cesare.cuspidi@unimib.it</auth-address><titles><title>Prevalence of echocardiographic left-atrial enlargement in hypertension: a systematic review of recent clinical studies</title><secondary-title>Am J Hypertens</secondary-title></titles><periodical><full-title>Am J Hypertens</full-title><abbr-1>American journal of hypertension</abbr-1></periodical><pages>456-64</pages><volume>26</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>Cardiovascular Diseases/etiology</keyword><keyword>*Echocardiography</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hypertension/*complications/diagnostic imaging</keyword><keyword>Hypertrophy, Left Ventricular/diagnostic imaging/*etiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Risk</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1941-7225 (Electronic)
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ADDIN EN.CITE.DATA (7,12), patients who were enrolled on the basis of elevated natriuretic peptides had significantly larger LA volumes than patients who were enrolled on the basis of previous hospitalisation, but had thinner LV walls, lower mass and a lower prevalence of LVH. LA size has an inconsistent association with adverse outcome in HFpEF; dichotomous LA enlargement was associated with adverse outcome in the Irbesartan in Heart Failure With Preserved Ejection Fraction (I-PRESERVE) trial on multivariable analysis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWxlPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (1). Using invasive conductance pressure-volume assessments, Westermann et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZXN0ZXJtYW5uPC9BdXRob3I+PFllYXI+MjAwODwvWWVh
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ADDIN EN.CITE.DATA (15) found mean LV relaxation time constant, end-diastolic pressure, diastolic stiffness and stiffness constant to be higher in HFpEF patients (EF > 50%) at rest, and mean end-diastolic volume, stroke volume and cardiac output to be reduced during tachycardic atrial pacing, compared to mean values in age, gender and co-morbidity-matched controls, although there was a strong trend towards a higher prevalence of hypertension in the HFpEF group (37% vs. 20%; p=0.05). However, consistently, a third of patients in the echocardiographic substudies of HFpEF RCTs have normal diastolic function, even in the context of elevated natriuretic peptides, and a further 20-30% have only mild or grade 1 diastolic dysfunction (Figure 2C) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXJzc29uPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA (6) found diastolic function to be worse in patients with HFpEF and concentric LVH compared to eccentric LVH, but outcome was equivalent. The load-dependency and variability of echocardiographic diastolic assessment are well documented ADDIN EN.CITE <EndNote><Cite><Author>Tschope</Author><Year>2009</Year><RecNum>4068</RecNum><DisplayText>(17)</DisplayText><record><rec-number>4068</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491475220">4068</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tschope, C.</author><author>Paulus, W. J.</author></authors></contributors><auth-address>Institute for Cardiovascular Research VU, VU University Medical Center Amsterdam, Van der Boechorststraat 7, 1081 BT Amsterdam, the Netherlands.</auth-address><titles><title>Is echocardiographic evaluation of diastolic function useful in determining clinical care? Doppler echocardiography yields dubious estimates of left ventricular diastolic pressures</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>810-20; discussion 820</pages><volume>120</volume><number>9</number><keywords><keyword>Diastole</keyword><keyword>Echocardiography, Doppler/*standards</keyword><keyword>Heart Failure, Diastolic/*diagnostic imaging/physiopathology</keyword><keyword>Humans</keyword><keyword>Prognosis</keyword><keyword>Reproducibility of Results</keyword><keyword>Ventricular Dysfunction, Left/*diagnostic imaging/physiopathology</keyword><keyword>Ventricular Pressure</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep 01</date></pub-dates></dates><isbn>1524-4539 (Electronic)
0009-7322 (Linking)</isbn><accession-num>19720947</accession-num><urls><related-urls><url>;(17). In a condition in which diastolic dysfunction has been considered a defining pathophysiology (‘diastolic heart failure’), it is unclear whether the variation in presence, and prognostic significance, of diastolic dysfunction in HFpEF reflects the inadequacy of its assessment with echocardiography, or a pathophysiological mechanism independent of diastolic function in a substantial proportion of patients. Atrial function may be abnormal in approximately 25% to 50% of patients with HFpEF, although it has not been assessed in large cohorts, reference ranges are not well defined for all analysis techniques and atrial dysfunction is prevalent in patients with hypertension without HF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVlZDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (19). Myocyte structure and functionTitinElevated cardiomyocyte resting tension or passive stiffness (FPassive) has been demonstrated in both isolated cardiomyocytes and strips of myocardium from patients with HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JiZWx5PC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (20-22). Resting tension in cardiomyocytes is highly dependent on titin, a large sarcomeric protein that functions as a molecular spring, storing energy during contraction and releasing it during relaxation. The compliance of titin itself is dependent on post-transcriptional and post-translational modifications, including isoform expression and phosphorylation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5rZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (23).Differential splicing results in two adult myocardial titin isoforms; N2B and N2BA. Van Heerebeek et al ADDIN EN.CITE <EndNote><Cite><Author>van Heerebeek</Author><Year>2006</Year><RecNum>2965</RecNum><DisplayText>(22)</DisplayText><record><rec-number>2965</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1478699291">2965</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Heerebeek, L.</author><author>Borbely, A.</author><author>Niessen, H. W.</author><author>Bronzwaer, J. G.</author><author>van der Velden, J.</author><author>Stienen, G. J.</author><author>Linke, W. A.</author><author>Laarman, G. J.</author><author>Paulus, W. J.</author></authors></contributors><auth-address>Department of Physiology, Institute for Cardiovascular Research, VU Medical Center, Amsterdam, The Netherlands.</auth-address><titles><title>Myocardial structure and function differ in systolic and diastolic heart failure</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>1966-73</pages><volume>113</volume><number>16</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Cardiomegaly/pathology</keyword><keyword>Diastole/*physiology</keyword><keyword>Female</keyword><keyword>Heart Failure/*pathology/physiopathology</keyword><keyword>Heart Ventricles/*pathology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocytes, Cardiac/pathology/physiology</keyword><keyword>Systole/*physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr 25</date></pub-dates></dates><isbn>1524-4539 (Electronic)
0009-7322 (Linking)</isbn><accession-num>16618817</accession-num><urls><related-urls><url>;(22) demonstrated a significant shift towards expression of the shorter, stiffer N2B-isoform in myocardium from patients with HFpEF, which was hypothesised as being responsible for the observed higher cardiomyocyte passive stiffness. RNA binding motif-20 is a major splicing factor of titin and inhibition of RNA binding motif-20 results in expression of highly compliant titin isoforms. Recently, in a murine HFpEF-like model (transverse aortic constriction and deoxycorticosterone acetate pellet implantation), Methawasin et al ADDIN EN.CITE <EndNote><Cite><Author>Methawasin</Author><Year>2016</Year><RecNum>4176</RecNum><DisplayText>(24)</DisplayText><record><rec-number>4176</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491475671">4176</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Methawasin, M.</author><author>Strom, J. G.</author><author>Slater, R. E.</author><author>Fernandez, V.</author><author>Saripalli, C.</author><author>Granzier, H.</author></authors></contributors><auth-address>From Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson.
From Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson. granzier@email.arizona.edu.</auth-address><titles><title>Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>1085-1099</pages><volume>134</volume><number>15</number><keywords><keyword>compliance</keyword><keyword>diastole</keyword><keyword>heart failure</keyword></keywords><dates><year>2016</year><pub-dates><date>Oct 11</date></pub-dates></dates><isbn>1524-4539 (Electronic)
0009-7322 (Linking)</isbn><accession-num>27630136</accession-num><urls><related-urls><url>;(24) found that inactivating RNA binding motif-20 resulted in upregulation of compliant titin isoforms and a large reduction in cellular passive stiffness, which translated into attenuation of concentric LVH and normalisation of diastolic function and exercise tolerance. The improvements occurred despite persistent, and unchanged, myocardial fibrosis, suggesting they were cardiomyocyte-specific. Titin stiffness is acutely modulated by phosphorylation. Titin is phosphorylated by a number of pathways including cyclic adenosine monophosphate (cAMP)-dependent protein kinase-A (PKA), activated in response to β-adrenergic stimulation by catecholamines, cyclic guanosine monophosphate (cGMP)-dependent protein kinase-G (PKG), activated by nitric oxide (NO) or natriuretic peptides, and protein kinase Cα (PKCα), calcium/calmodulin-dependent protein kinase II (CaMKII), and extracellular signal-regulated kinase-2 (ERK2), activated by endothelin-1 and angiotensin-II PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZVdpbnRlcjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA (23,25). PKA, PKG, and ERK2 signalling appear to decrease cardiomyocyte resting tension, whereas PKCα phosphorylation increases it (Figure 3).Hypophosphorylation of the N2B-isoform of titin has been demonstrated in myocardial tissue from patients with HFpEF and in preclinical models, and is associated with elevated passive stiffness of cardiomyocytes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JiZWx5PC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA (28) found augmentation of cGMP levels via natriuretic peptide stimulation and phosphodiesterase-5 inhibition resulted in a significant relative increase in the phosphorylation of N2B, and hence a reduction in the ratio of phosphorylated N2BA:N2B, which was associated with a lower cardiomyocyte resting tension and improved diastolic function. The beneficial effects were seen without changes to the phosphorylation status of other sarcolemmic proteins and after excluding potential effects of transmembrane calcium currents and myocardial fibrosis. Fukada et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWt1ZGE8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (29) showed that the extent of the reduction in resting tension during protein kinase A-mediated phosphorylation of titin was greater in myocardial tissue with higher N2B-isoform expression. Thus, manipulation of myocardial titin isoform expression and the phosphorylation state of each isoform represent attractive therapeutic targets.The combined angiotensin-II receptor and neprilysin inhibitor, valsartan/sacubitril, the neprilysin inhibitor component of which augments active natriuretic peptides resulting in an increase in cGMP, was associated with a greater reduction in serum NT-proBNP levels than valsartan alone in patients with HFpEF after 12 weeks of treatment in the PARAMOUNT trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2xvbW9uPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48
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ADDIN EN.CITE.DATA (32). Selby et al ADDIN EN.CITE <EndNote><Cite><Author>Selby</Author><Year>2011</Year><RecNum>4222</RecNum><DisplayText>(33)</DisplayText><record><rec-number>4222</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491476735">4222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Selby, D. E.</author><author>Palmer, B. M.</author><author>LeWinter, M. M.</author><author>Meyer, M.</author></authors></contributors><auth-address>Cardiology Division and Department of Physiology, University of Vermont College of Medicine, Burlington, Vermont 05401, USA.</auth-address><titles><title>Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>147-54</pages><volume>58</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Calcium/metabolism</keyword><keyword>Coronary Artery Disease/complications</keyword><keyword>Diastole/*physiology</keyword><keyword>Exercise</keyword><keyword>Female</keyword><keyword>Heart Rate</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocardium/*pathology</keyword><keyword>Tachycardia/*metabolism/therapy</keyword><keyword>Time Factors</keyword><keyword>Ventricular Dysfunction, Left/*pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 05</date></pub-dates></dates><isbn>1558-3597 (Electronic)
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ADDIN EN.CITE.DATA (32,34).In the study by Selby et al, diastolic tension increased further as heart rate increased, as a result of increasing amounts of calcium entering the cell, in ventricular myocardium from patients with LVH and LA dilatation, whereas no significant change was seen in myocardium from patients with normal LV mass and LA size, findings which are in keeping with those from a single cell model of HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZWxieTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (15), and potentially provide a mechanism for the observed exercise limitation and intolerance to tachycardia seen in HFpEF. Heart rate restriction may therefore be a potential therapeutic strategy. Nevertheless, in the study by Selby et al, increased diastolic tension was seen to prevent complete cardiomyocyte relaxation even at low normal heart rates (e.g. 60 beats/min), hence while such interventions may be beneficial for preventing excessive tachycardias, reducing heart rate to less than physiological rates is unlikely to be of therapeutic value ADDIN EN.CITE <EndNote><Cite><Author>Zile</Author><Year>2011</Year><RecNum>4223</RecNum><DisplayText>(35)</DisplayText><record><rec-number>4223</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491476894">4223</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zile, M. R.</author><author>Gaasch, W. H.</author></authors></contributors><titles><title>Abnormal calcium homeostasis: one mechanism in diastolic heart failure</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>155-7</pages><volume>58</volume><number>2</number><keywords><keyword>Biopsy</keyword><keyword>Calcium/*metabolism</keyword><keyword>Echocardiography/methods</keyword><keyword>Heart Failure, Diastolic/diagnosis/*metabolism/physiopathology</keyword><keyword>Heart Rate</keyword><keyword>Heart Ventricles/pathology</keyword><keyword>Humans</keyword><keyword>Myocardial Contraction</keyword><keyword>Myocardium/pathology</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Tachycardia/prevention & control</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 05</date></pub-dates></dates><isbn>1558-3597 (Electronic)
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ADDIN EN.CITE.DATA (36-38).Increased intracellular sodium concentration is also observed in HFpEF and may contribute to the increased diastolic cytosolic calcium concentration via sodium-calcium exchange PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW5uaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (2). Ranolazine inhibits the late sodium current, minimising intracellular sodium accumulation and hence reducing calcium concentration, and is associated with reduced diastolic tension and improved diastolic function in human myocardium in vitro PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb3NzYWxsYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA (39). In an in vivo proof of concept study in patients with HFpEF, ranolazine was associated with an acute improvement in LV end-diastolic pressure and pulmonary capillary wedge pressure (PCWP) but it had no effect on invasive relaxation parameters, and it also had no effect on diastolic function, exercise parameters or NT-pro-BNP levels after 14 days of treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWNvYnNoYWdlbjwvQXV0aG9yPjxZZWFyPjIwMTE8L1ll
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ADDIN EN.CITE.DATA (42). Such work requires translation into human tissue, but nevertheless, abnormal calcium handling is a potential therapeutic target in HFpEF.Myocardial energeticsVentricular diastole is an active process that utilises ATP, and excessive energy is consumed maintaining the abnormally increased diastolic tension in HFpEF ADDIN EN.CITE <EndNote><Cite><Author>Selby</Author><Year>2011</Year><RecNum>4222</RecNum><DisplayText>(33)</DisplayText><record><rec-number>4222</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491476735">4222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Selby, D. E.</author><author>Palmer, B. M.</author><author>LeWinter, M. M.</author><author>Meyer, M.</author></authors></contributors><auth-address>Cardiology Division and Department of Physiology, University of Vermont College of Medicine, Burlington, Vermont 05401, USA.</auth-address><titles><title>Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>147-54</pages><volume>58</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Calcium/metabolism</keyword><keyword>Coronary Artery Disease/complications</keyword><keyword>Diastole/*physiology</keyword><keyword>Exercise</keyword><keyword>Female</keyword><keyword>Heart Rate</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocardium/*pathology</keyword><keyword>Tachycardia/*metabolism/therapy</keyword><keyword>Time Factors</keyword><keyword>Ventricular Dysfunction, Left/*pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 05</date></pub-dates></dates><isbn>1558-3597 (Electronic)
0735-1097 (Linking)</isbn><accession-num>21718911</accession-num><urls><related-urls><url>;(33). In addition, microvascular dysfunction (see below) and myocardial extracellular matrix expansion (see below), which increases the oxygen diffusion distance between the capillary and collagen-encircled cardiomyocyte, potentially render the cardiomyocyte prone to hypoxia ADDIN EN.CITE <EndNote><Cite><Author>Sabbah</Author><Year>1995</Year><RecNum>498</RecNum><DisplayText>(43)</DisplayText><record><rec-number>498</rec-number><foreign-keys><key app="EN" db-id="s99ffrsartefz0ee25dvaszora00azrsfrap">498</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sabbah, H. N.</author><author>Sharov, V. G.</author><author>Lesch, M.</author><author>Goldstein, S.</author></authors></contributors><auth-address>Department of Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan, USA.</auth-address><titles><title>Progression of heart failure: a role for interstitial fibrosis</title><secondary-title>Mol Cell Biochem</secondary-title><alt-title>Molecular and cellular biochemistry</alt-title></titles><periodical><full-title>Mol Cell Biochem</full-title><abbr-1>Molecular and cellular biochemistry</abbr-1></periodical><alt-periodical><full-title>Mol Cell Biochem</full-title><abbr-1>Molecular and cellular biochemistry</abbr-1></alt-periodical><pages>29-34</pages><volume>147</volume><number>1-2</number><keywords><keyword>Animals</keyword><keyword>Capillaries/pathology</keyword><keyword>Cardiac Output, Low</keyword><keyword>Collagen/analysis</keyword><keyword>Coronary Vessels/pathology</keyword><keyword>Disease Models, Animal</keyword><keyword>Disease Progression</keyword><keyword>Dogs</keyword><keyword>Fibrosis/pathology</keyword><keyword>Heart Failure/pathology/*physiopathology</keyword><keyword>Hemodynamics</keyword><keyword>Hypoxia/metabolism</keyword><keyword>Myocardium/*pathology</keyword><keyword>Oxygen/metabolism</keyword><keyword>Ventricular Dysfunction, Left/physiopathology</keyword></keywords><dates><year>1995</year><pub-dates><date>Jun 7-21</date></pub-dates></dates><isbn>0300-8177 (Print)
0300-8177 (Linking)</isbn><accession-num>7494551</accession-num><urls><related-urls><url>;(43). In keeping with the resultant lower resting energy reserve, myocardial phosphocreatine (PCr)/ATP ratio, measured using phosphorus-31 magnetic resonance spectroscopy (31P-MRS), is significantly lower in patients with hypertensive heart disease compared to healthy controls, and in patients with HFpEF compared to controls, and is associated with diastolic dysfunction PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaGFuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (44,45). Furthermore, Lamb et al ADDIN EN.CITE <EndNote><Cite><Author>Lamb</Author><Year>1999</Year><RecNum>4254</RecNum><DisplayText>(45)</DisplayText><record><rec-number>4254</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491477169">4254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lamb, H. J.</author><author>Beyerbacht, H. P.</author><author>van der Laarse, A.</author><author>Stoel, B. C.</author><author>Doornbos, J.</author><author>van der Wall, E. E.</author><author>de Roos, A.</author></authors></contributors><auth-address>Department of Radiology and Cardiology, University Medical Center, Leiden The Netherlands. Lamb@RULLF2.Medfac.Leidenuniv.nl</auth-address><titles><title>Diastolic dysfunction in hypertensive heart disease is associated with altered myocardial metabolism</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>2261-7</pages><volume>99</volume><number>17</number><keywords><keyword>Adenosine Triphosphate/metabolism</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>*Diastole</keyword><keyword>Humans</keyword><keyword>Hypertension/complications/*metabolism</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocardium/*metabolism</keyword><keyword>Phosphocreatine/metabolism</keyword><keyword>Ventricular Dysfunction, Left/*metabolism</keyword></keywords><dates><year>1999</year><pub-dates><date>May 04</date></pub-dates></dates><isbn>1524-4539 (Electronic)
0009-7322 (Linking)</isbn><accession-num>10226091</accession-num><urls><related-urls><url>;(45) demonstrated that PCr/ATP ratio declined more severely in patients with hypertensive heart disease than in healthy controls during exercise, suggesting the energy reserve equilibrium declines further during exercise, which is consistent with the findings of Selby et al ADDIN EN.CITE <EndNote><Cite><Author>Selby</Author><Year>2011</Year><RecNum>4222</RecNum><DisplayText>(33)</DisplayText><record><rec-number>4222</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491476735">4222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Selby, D. E.</author><author>Palmer, B. M.</author><author>LeWinter, M. M.</author><author>Meyer, M.</author></authors></contributors><auth-address>Cardiology Division and Department of Physiology, University of Vermont College of Medicine, Burlington, Vermont 05401, USA.</auth-address><titles><title>Tachycardia-induced diastolic dysfunction and resting tone in myocardium from patients with a normal ejection fraction</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>147-54</pages><volume>58</volume><number>2</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Calcium/metabolism</keyword><keyword>Coronary Artery Disease/complications</keyword><keyword>Diastole/*physiology</keyword><keyword>Exercise</keyword><keyword>Female</keyword><keyword>Heart Rate</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocardium/*pathology</keyword><keyword>Tachycardia/*metabolism/therapy</keyword><keyword>Time Factors</keyword><keyword>Ventricular Dysfunction, Left/*pathology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 05</date></pub-dates></dates><isbn>1558-3597 (Electronic)
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ADDIN EN.CITE.DATA (47-49). Myocardial extracellular matrixChanges in extracellular matrix (ECM) composition and structure appear to be important pathophysiological mechanisms in HFpEF. ECM expansion secondary to collagen accumulation is consistently demonstrated on a group level in myocardial tissue from patients with HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JiZWx5PC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA (20-22,30), the magnitude of which is similar to that seen in HF with reduced EF ADDIN EN.CITE <EndNote><Cite><Author>van Heerebeek</Author><Year>2006</Year><RecNum>2965</RecNum><DisplayText>(22)</DisplayText><record><rec-number>2965</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1478699291">2965</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Heerebeek, L.</author><author>Borbely, A.</author><author>Niessen, H. W.</author><author>Bronzwaer, J. G.</author><author>van der Velden, J.</author><author>Stienen, G. J.</author><author>Linke, W. A.</author><author>Laarman, G. J.</author><author>Paulus, W. J.</author></authors></contributors><auth-address>Department of Physiology, Institute for Cardiovascular Research, VU Medical Center, Amsterdam, The Netherlands.</auth-address><titles><title>Myocardial structure and function differ in systolic and diastolic heart failure</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>1966-73</pages><volume>113</volume><number>16</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Cardiomegaly/pathology</keyword><keyword>Diastole/*physiology</keyword><keyword>Female</keyword><keyword>Heart Failure/*pathology/physiopathology</keyword><keyword>Heart Ventricles/*pathology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocytes, Cardiac/pathology/physiology</keyword><keyword>Systole/*physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr 25</date></pub-dates></dates><isbn>1524-4539 (Electronic)
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ADDIN EN.CITE.DATA (21,51).Borbely et al found collagen volume fraction (CVF) was normal in a third of patients with HFpEF despite evidence of diastolic dysfunction. This is in keeping with the proportion (14% to 56% depending on the cut off used) of HFpEF patients with a normal myocardial ECM volume measured using cardiovascular magnetic resonance (CMR) imaging in a recent large cohort, and demonstrates the pathophysiological variation.Collagen content in myocardial tissue from patients with HFpEF, and CMR-derived myocardial ECM volume in patients with HFpEF, are associated with echocardiographic parameters of diastolic function and LA size PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWxlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (21,52,53). In an important study, Rommel et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb21tZWw8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (54) found CMR-derived myocardial ECM volume was the only independent predictor of load-independent intrinsic LV stiffness, as measured using invasive pressure-volume assessment, in patients with HFpEF. Furthermore, when patients were dichotomised according to median ECM volume, both groups showed a pathological upward shift of the end-diastolic pressure volume relationship during exercise, but in patients with elevated ECM volume, the dominant pathophysiology was an increase in myocardial passive stiffness, whereas in patients with a below median ECM volume the dominant mechanisms were arterial stiffness and impaired active relaxation. Interestingly, both groups demonstrated similar echocardiographic diastolic parameters. As such, this study serves to demonstrate the variations in biological phenotypes that exist between individuals that are broadly classified as having HFpEF, the inadequacy of echocardiographic diastolic parameters for detecting these phenotypic variations, and, more broadly, the inadequacy of echocardiography for determining intrinsic LV stiffness. In a substudy of the I-PRESERVE trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcnVtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (55), circulating markers of collagen deposition (procollagen type I amino-terminal peptide and osteopontin) were associated with adverse outcome (death and hospitalisation for pre-specified cardiovascular causes) on univariable analysis, but not on multivariable analysis, although circulating collagen markers are not specific to the heart and confounded by numerous factors such as renal function ADDIN EN.CITE <EndNote><Cite><Author>Ahmad</Author><Year>2012</Year><RecNum>194</RecNum><DisplayText>(56)</DisplayText><record><rec-number>194</rec-number><foreign-keys><key app="EN" db-id="s99ffrsartefz0ee25dvaszora00azrsfrap">194</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahmad, Tariq</author><author>Fiuzat, Mona</author><author>Felker, G Michael</author><author>O&apos;Connor, Christopher</author></authors></contributors><titles><title>Novel biomarkers in chronic heart failure</title><secondary-title>Nature Publishing Group</secondary-title></titles><periodical><full-title>Nature Publishing Group</full-title></periodical><pages>347-359</pages><volume>9</volume><number>6</number><dates><year>2012</year><pub-dates><date>Apr 27</date></pub-dates></dates><publisher>Nature Publishing Group</publisher><label>r05218</label><urls><related-urls><url>;(56). In a study of HFpEF patients by Duca et al ADDIN EN.CITE <EndNote><Cite><Author>Duca</Author><Year>2016</Year><RecNum>4264</RecNum><DisplayText>(53)</DisplayText><record><rec-number>4264</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491477603">4264</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Duca, F.</author><author>Kammerlander, A. A.</author><author>Zotter-Tufaro, C.</author><author>Aschauer, S.</author><author>Schwaiger, M. L.</author><author>Marzluf, B. A.</author><author>Bonderman, D.</author><author>Mascherbauer, J.</author></authors></contributors><auth-address>From the Department of Cardiology, Medical University of Vienna, Austria (F.D., A.A.K., C.Z-T., S.A., M.L.S., D.B., J.M.); and Department of Thoracic Surgery, Otto Wagner Hospital, Vienna, Austria (B.A.M.).
From the Department of Cardiology, Medical University of Vienna, Austria (F.D., A.A.K., C.Z-T., S.A., M.L.S., D.B., J.M.); and Department of Thoracic Surgery, Otto Wagner Hospital, Vienna, Austria (B.A.M.). julia.mascherbauer@meduniwien.ac.at.</auth-address><titles><title>Interstitial Fibrosis, Functional Status, and Outcomes in Heart Failure With Preserved Ejection Fraction: Insights From a Prospective Cardiac Magnetic Resonance Imaging Study</title><secondary-title>Circ Cardiovasc Imaging</secondary-title></titles><periodical><full-title>Circ Cardiovasc Imaging</full-title></periodical><volume>9</volume><number>12</number><keywords><keyword>heart failure</keyword><keyword>magnetic resonance imaging</keyword><keyword>mapping</keyword></keywords><dates><year>2016</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1942-0080 (Electronic)
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ADDIN EN.CITE.DATA (57), in a considerably large cohort of patients (n=410) with HFpEF or at risk for HFpEF (BNP>100pg/mL but no clinical HF), found CMR-derived myocardial ECM volume was strongly associated with adverse outcome on univariable and multivariable analyses (Figure 4). Indeed, myocardial ECM volume was more strongly associated with outcome than factors such as age, LV mass, atrial fibrillation or previous myocardial infarction, and a clear ‘dose-response’ relationship was observed between ECM volume and outcome. Considerable data demonstrate both the potential for myocardial ECM to have a primary aetiological role in HFpEF, and the adverse impact that ECM expansion has on myocardial mechanical, electrical and microvascular function, which is in keeping the adverse impact in other organs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb21tZWw8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (21,54,58,59). Importantly, myocardial ECM expansion is reversible. Brilla et al ADDIN EN.CITE <EndNote><Cite><Author>Brilla</Author><Year>2000</Year><RecNum>4294</RecNum><DisplayText>(60)</DisplayText><record><rec-number>4294</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491477858">4294</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brilla, C. G.</author><author>Funck, R. C.</author><author>Rupp, H.</author></authors></contributors><auth-address>Division of Cardiology, Philipps University of Marburg, Marburg, Germany.</auth-address><titles><title>Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>1388-93</pages><volume>102</volume><number>12</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Analysis of Variance</keyword><keyword>Angiotensin-Converting Enzyme Inhibitors/*therapeutic use</keyword><keyword>Antihypertensive Agents/*therapeutic use</keyword><keyword>Blood Pressure/drug effects</keyword><keyword>Cardiomyopathies/*drug therapy</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>Fibrosis/drug therapy</keyword><keyword>Humans</keyword><keyword>Hydrochlorothiazide/*therapeutic use</keyword><keyword>Lisinopril/*therapeutic use</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Myocardium/*pathology</keyword><keyword>Prospective Studies</keyword><keyword>Ventricular Dysfunction, Left/drug therapy</keyword></keywords><dates><year>2000</year><pub-dates><date>Sep 19</date></pub-dates></dates><isbn>1524-4539 (Electronic)
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ADDIN EN.CITE.DATA (50) demonstrated regression of myocardial fibrosis in patients with hypertensive heart disease, which was associated with improvement in diastolic function, after 6 months of lisinopril and 12 months of losartan respectively. Izawa et al (61) demonstrated regression of myocardial fibrosis after 12 months of spironolactone, albeit in a different population (dilated cardiomyopathy). In patients with HFpEF, Deswal et al (62) found 6 months of treatment with eplerenone was associated with a significant reduction in circulating markers of collagen deposition, compared to placebo. Interestingly, in the studies by Diez et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWV6PC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (65), and thus, given the effect of the neprilysin inhibitor component described earlier, two HFpEF biological phenotypes are being targeted in the PARAGON-HF trial (NCT01920711).Lopez et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3BlejwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (66) found it was the degree of collagen cross-linking, rather than total collagen volume, which was associated with LV filling pressures in patients with HFpEF and hypertension. The same group also found torasemide reduced overexpression of lysyl oxidase (which catalyses collagen cross-linking), collagen cross-linking and CVF, although in hypertensive patients with HF and a preserved mean EF (54%), torasemide was not associated with a reduction in circulating collagen markers PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm91cDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (67). Recently, lysyl oxidase-like 2 inhibition was found to essentially eliminate the interstitial fibrosis, LV remodelling and HF associated with transaortic constriction, although lysyl oxidase-like 2 inhibition has not proven beneficial in phase II trials of pulmonary and hepatic fibrosis, possibly because once formed, collagen crosslinks, particularly hydroxyallysine crosslinks, are much less susceptible to degradation, thus lysyl oxidase-like 2 inhibition may need to be given earlier in the disease process PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW5nPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (21) found myocardial fibrosis and abnormal titin function may co-exist in HFpEF, synergistically leading to increased myocardial stiffness, although there is little evidence for common pathophysiological pathways. Manipulation of titin isoform compliance by Methawasin et al ADDIN EN.CITE <EndNote><Cite><Author>Methawasin</Author><Year>2016</Year><RecNum>4176</RecNum><DisplayText>(24)</DisplayText><record><rec-number>4176</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1491475671">4176</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Methawasin, M.</author><author>Strom, J. G.</author><author>Slater, R. E.</author><author>Fernandez, V.</author><author>Saripalli, C.</author><author>Granzier, H.</author></authors></contributors><auth-address>From Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson.
From Department of Cellular and Molecular Medicine and Sarver Molecular Cardiovascular Research Program, University of Arizona, Tucson. granzier@email.arizona.edu.</auth-address><titles><title>Experimentally Increasing the Compliance of Titin Through RNA Binding Motif-20 (RBM20) Inhibition Improves Diastolic Function In a Mouse Model of Heart Failure With Preserved Ejection Fraction</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>1085-1099</pages><volume>134</volume><number>15</number><keywords><keyword>compliance</keyword><keyword>diastole</keyword><keyword>heart failure</keyword></keywords><dates><year>2016</year><pub-dates><date>Oct 11</date></pub-dates></dates><isbn>1524-4539 (Electronic)
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ADDIN EN.CITE.DATA (30,72,73). Myocardial vascular functionMicrovascular endothelial inflammation is known to be associated with endothelial dysfunction and microvascular rarefaction ADDIN EN.CITE <EndNote><Cite><Author>Goligorsky</Author><Year>2010</Year><RecNum>4890</RecNum><DisplayText>(73)</DisplayText><record><rec-number>4890</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1492094794">4890</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goligorsky, M. S.</author></authors></contributors><auth-address>Departments of Medicine, Pharmacology and Physiology, Renal Research Institute, New York Medical College, Valhalla, NY, USA. michael_goligorsky@nymc.edu</auth-address><titles><title>Microvascular rarefaction: the decline and fall of blood vessels</title><secondary-title>Organogenesis</secondary-title></titles><periodical><full-title>Organogenesis</full-title></periodical><pages>1-10</pages><volume>6</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Endothelial Cells/pathology</keyword><keyword>Humans</keyword><keyword>Microvessels/*pathology</keyword><keyword>Vascular Diseases/*pathology</keyword><keyword>cell reprogramming</keyword><keyword>endorepellin</keyword><keyword>endostatin</keyword><keyword>endothelial cell dysfunction</keyword><keyword>endothelial cell migration</keyword><keyword>endothelial-mesenchymal transition</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan-Mar</date></pub-dates></dates><isbn>1555-8592 (Electronic)
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ADDIN EN.CITE.DATA (59). However, whilst statistical adjustments were made for the between group differences, the HFpEF group had substantially higher rates of confounders such as hypertension (79 vs. 31%), diabetes (42 vs. 11%), epicardial coronary disease (65 vs. 0%) and renal dysfunction. Srivaratharajah et al ADDIN EN.CITE <EndNote><Cite><Author>Srivaratharajah</Author><Year>2016</Year><RecNum>4891</RecNum><DisplayText>(74)</DisplayText><record><rec-number>4891</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1492094895">4891</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Srivaratharajah, K.</author><author>Coutinho, T.</author><author>deKemp, R.</author><author>Liu, P.</author><author>Haddad, H.</author><author>Stadnick, E.</author><author>Davies, R. A.</author><author>Chih, S.</author><author>Dwivedi, G.</author><author>Guo, A.</author><author>Wells, G. A.</author><author>Bernick, J.</author><author>Beanlands, R.</author><author>Mielniczuk, L. M.</author></authors></contributors><auth-address>From the Division of Cardiology, University of Ottawa Heart Institute, Ontario, Canada.
From the Division of Cardiology, University of Ottawa Heart Institute, Ontario, Canada. lmielniczuk@ottawaheart.ca.</auth-address><titles><title>Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction</title><secondary-title>Circ Heart Fail</secondary-title></titles><periodical><full-title>Circ Heart Fail</full-title><abbr-1>Circulation. Heart failure</abbr-1></periodical><volume>9</volume><number>7</number><keywords><keyword>comorbidity</keyword><keyword>coronary circulation</keyword><keyword>echocardiography</keyword><keyword>heart failure</keyword><keyword>positron emission tomography</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1941-3297 (Electronic)
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ADDIN EN.CITE.DATA (77) found myocardial oxygen delivery, and potentially oxygen extraction, were reduced in HFpEF and correlated with PCWP. Nevertheless, therapies that reduce inflammation and/or improve endothelial function, (e.g. statins, angiotensin receptor blockers, phosphodiesterase-5 inhibitors), have proved ineffective in improving patient outcomes in HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXZhenppPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA (80-82). Increased afterload, particularly late systolic load, is associated with LVH and impaired systolic and diastolic function in people without cardiovascular disease and in patients undergoing invasive assessment for coronary disease with a LV EF >50%, and is strongly and independently associated with incident HF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JsYXVnPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA (83,86), and in preclinical models increased afterload is associated with LV hypertrophy, fibrosis and HF ADDIN EN.CITE <EndNote><Cite><Author>Kobayashi</Author><Year>1996</Year><RecNum>4966</RecNum><DisplayText>(86)</DisplayText><record><rec-number>4966</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1492096058">4966</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kobayashi, S.</author><author>Yano, M.</author><author>Kohno, M.</author><author>Obayashi, M.</author><author>Hisamatsu, Y.</author><author>Ryoke, T.</author><author>Ohkusa, T.</author><author>Yamakawa, K.</author><author>Matsuzaki, M.</author></authors></contributors><auth-address>Second Department of Internal Medicine, Yamaguchi University School of Medicine, Japan.</auth-address><titles><title>Influence of aortic impedance on the development of pressure-overload left ventricular hypertrophy in rats</title><secondary-title>Circulation</secondary-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><pages>3362-8</pages><volume>94</volume><number>12</number><keywords><keyword>Aldosterone/blood</keyword><keyword>Angiotensin II/blood</keyword><keyword>Animals</keyword><keyword>Aorta, Abdominal/pathology/*physiopathology</keyword><keyword>Aorta, Thoracic/pathology/physiology/*physiopathology</keyword><keyword>Aortic Coarctation/pathology/*physiopathology</keyword><keyword>Blood Pressure</keyword><keyword>Heart/physiopathology</keyword><keyword>Heart Rate</keyword><keyword>*Hemodynamics</keyword><keyword>Hypertrophy, Left Ventricular/pathology/*physiopathology</keyword><keyword>Myocardium/pathology</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reference Values</keyword></keywords><dates><year>1996</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>0009-7322 (Print)
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ADDIN EN.CITE.DATA (90), 6 weeks of isosorbide mononitrate therapy did not improve quality of life or exercise capacity compared to placebo, indeed dose-dependent decreases in physical activity levels were seen in patients receiving isosorbide mononitrate, possibly due to orthostatic hypotension. Inorganic nitrate, converted to nitric oxide via the nitrate-nitrite-nitric oxide pathway in a process enhanced by tissue hypoxia and acidosis, appears to be better tolerated with less risk of resting hypotension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGlyaW5vczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA (92) found sodium nitrite infusion acutely improved exercise PCWP and ventricular performance in patients with HFpEF. Zamani et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYW1hbmk8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (93) found a single dose of inorganic nitrate-rich beetroot juice and subsequently 2 weeks of an oral preparation of inorganic nitrate (potassium nitrate) improved exercise duration and quality of life in patients with HFpEF, and was well tolerated. In addition to a beneficial effect on arterial wave reflections, the authors suggested the positive findings were mediated by replacement of myocardial nitric oxide deficiency and peripheral vasodilation. Further trials of inorganic nitrates are underway (NCT02256345). Angiotensin-converting enzyme and phosphodiesterase-5 inhibition are not associated with improvements in aortic distensibility in HFpEF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXR6bWFuPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA (95-97). Pulmonary vascular functionIn a population-based study of 244 patients with HFpEF, Lam et al ADDIN EN.CITE <EndNote><Cite><Author>Lam</Author><Year>2009</Year><RecNum>6905</RecNum><DisplayText>(97)</DisplayText><record><rec-number>6905</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1504515396">6905</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lam, C. S.</author><author>Roger, V. L.</author><author>Rodeheffer, R. J.</author><author>Borlaug, B. A.</author><author>Enders, F. T.</author><author>Redfield, M. M.</author></authors></contributors><auth-address>Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.</auth-address><titles><title>Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>1119-26</pages><volume>53</volume><number>13</number><keywords><keyword>Aged</keyword><keyword>Echocardiography, Doppler</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Heart Failure/*complications/mortality/*physiopathology</keyword><keyword>Humans</keyword><keyword>Hypertension, Pulmonary/epidemiology/*etiology/physiopathology</keyword><keyword>Male</keyword><keyword>Prevalence</keyword><keyword>Spirometry</keyword><keyword>Stroke Volume/*physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar 31</date></pub-dates></dates><isbn>1558-3597 (Electronic)
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ADDIN EN.CITE.DATA (99). PASP was significantly higher in patients with HFpEF than with hypertension without HF, and was strongly associated with symptoms and mortality (hazard ratio 1.2 per 10 mmHg increase on multivariable analysis). As expected, PASP was associated with pulmonary venous pressure, estimated using E/e’ ratio, but interestingly, after accounting for pulmonary venous pressure, PASP in HFpEF still exceeded that of hypertensive controls without HF, suggesting abnormal pulmonary arterial function. Whether this pulmonary arterial hypertension is due to pulmonary vascular remodeling secondary to sustained pulmonary venous pressure elevation, primary abnormalities in pulmonary arterial function, abnormal RV-PA coupling, or a combination of these factors remains unclear, but nevertheless PA pressure is a potential therapeutic target. However, in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWRmaWVsZDwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA (101) recently found sildenafil for 12 weeks did not reduce PA pressures or improve other invasive haemodynamic or clinical parameters in patients with HFpEF and pulmonary hypertension. In the RELAX trial, plasma cGMP levels did not differ significantly between groups, leading the authors to suggest that the negative results may have been because sildenafil was unable to enhance cGMP sufficiently. Bonderman et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb25kZXJtYW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy
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ADDIN EN.CITE.DATA (106).More than 80% of patients with HFpEF are overweight or obese and in the TOPCAT and RELAX trials, median/mean BMI was 31kg/m2 and over 35kg/m2 respectively ADDIN EN.CITE <EndNote><Cite><Author>Owan</Author><Year>2006</Year><RecNum>89</RecNum><DisplayText>(106)</DisplayText><record><rec-number>89</rec-number><foreign-keys><key app="EN" db-id="s99ffrsartefz0ee25dvaszora00azrsfrap">89</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Owan, Theophilus E</author><author>Hodge, David O</author><author>Herges, Regina M</author><author>Jacobsen, Steven J</author><author>Roger, Veronique L</author><author>Redfield, Margaret M</author></authors></contributors><auth-address>Cardiorenal Research Laboratory, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA.</auth-address><titles><title>Trends in prevalence and outcome of heart failure with preserved ejection fraction.</title><secondary-title>The New England journal of medicine</secondary-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><pages>251-259</pages><volume>355</volume><number>3</number><dates><year>2006</year><pub-dates><date>Jul 20</date></pub-dates></dates><accession-num>16855265</accession-num><label>r04687</label><urls><related-urls><url>;(107). Obokata et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PYm9rYXRhPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA (108) recently described a distinct obese HFpEF phenotype, characterised by greater concentric LV remodelling, higher LV filling pressures at rest and with exercise, greater plasma volume overload (yet lower NT-pro BNP levels), a larger increase in pulmonary arterial pressures with exercise, larger right ventricular size and more significant exercise intolerance compared to non-obese HFpEF. Weight loss following bariatric surgery is associated with reduced LV mass and mass-volume ratio, and improved diastolic function ADDIN EN.CITE <EndNote><Cite><Author>Aggarwal</Author><Year>2015</Year><RecNum>519</RecNum><DisplayText>(108)</DisplayText><record><rec-number>519</rec-number><foreign-keys><key app="EN" db-id="s99ffrsartefz0ee25dvaszora00azrsfrap">519</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aggarwal, Ravi</author><author>Harling, Leanne</author><author>Efthimiou, Evangelos</author><author>Darzi, Ara</author><author>Athanasiou, Thanos</author><author>Ashrafian, Hutan</author></authors></contributors><titles><title>The Effects of Bariatric Surgery on Cardiac Structure and Function: a Systematic Review of Cardiac Imaging Outcomes</title><secondary-title>Obesity Surgery</secondary-title></titles><periodical><full-title>Obesity Surgery</full-title></periodical><pages>1030-1040</pages><volume>26</volume><number>5</number><dates><year>2015</year><pub-dates><date>Sep 02</date></pub-dates></dates><publisher>Springer US</publisher><label>r03409</label><urls><related-urls><url>;(109).Lung disease Approximately 30-40% of patients with HFpEF have COPD ADDIN EN.CITE <EndNote><Cite><Author>Lainscak</Author><Year>2015</Year><RecNum>83</RecNum><DisplayText>(109)</DisplayText><record><rec-number>83</rec-number><foreign-keys><key app="EN" db-id="xzsavfxwie9vene9ta9p9z2902zxfawz95zr">83</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lainscak, M.</author><author>Anker, S. D.</author></authors></contributors><auth-address>Department of CardiologyGeneral Hospital CeljeCeljeSlovenia; Faculty of MedicineUniversity of LjubljanaLjubljanaSlovenia.
Institute of Innovative Clinical Trials, Clinic of Cardiology and Pneumology University Medical Center Gottingen Germany.</auth-address><titles><title>Heart failure, chronic obstructive pulmonary disease, and asthma: numbers, facts, and challenges</title><secondary-title>ESC Heart Fail</secondary-title><alt-title>ESC heart failure</alt-title></titles><periodical><full-title>ESC Heart Fail</full-title><abbr-1>ESC heart failure</abbr-1></periodical><alt-periodical><full-title>ESC Heart Fail</full-title><abbr-1>ESC heart failure</abbr-1></alt-periodical><pages>103-107</pages><volume>2</volume><number>3</number><dates><year>2015</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2055-5822 (Linking)</isbn><accession-num>27708851</accession-num><urls><related-urls><url>;(110). Whilst COPD and HF share a number of risk factors, multiple studies have demonstrated a strong and independent relationship between the severity of airflow limitation and incident HF (adjusted odds ratio of up to 3.9) ADDIN EN.CITE <EndNote><Cite><Author>Agarwal</Author><Year>2012</Year><RecNum>30</RecNum><DisplayText>(110)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="xzsavfxwie9vene9ta9p9z2902zxfawz95zr">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Agarwal, S K</author><author>Heiss, G</author><author>Barr, R G</author><author>Chang, P P</author><author>Loehr, L R</author><author>Chambless, L E</author><author>Shahar, E</author><author>Kitzman, D W</author><author>Rosamond, W D</author></authors></contributors><titles><title>Airflow obstruction, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study</title><secondary-title>Eur J Heart Fail</secondary-title></titles><periodical><full-title>Eur J Heart Fail</full-title></periodical><pages>414-22</pages><volume>14</volume><dates><year>2012</year></dates><urls></urls></record></Cite></EndNote>(111). Indeed in a large, community-based sample, Lam et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW08L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (115).Kidney diseaseApproximately 25-50% of patients with HFpEF have chronic kidney disease (CKD; defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2), the prevalence of which increases with age ADDIN EN.CITE <EndNote><Cite><Author>Ather</Author><Year>2012</Year><RecNum>6971</RecNum><DisplayText>(115)</DisplayText><record><rec-number>6971</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1504517462">6971</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ather, S.</author><author>Chan, W.</author><author>Bozkurt, B.</author><author>Aguilar, D.</author><author>Ramasubbu, K.</author><author>Zachariah, A. A.</author><author>Wehrens, X. H.</author><author>Deswal, A.</author></authors></contributors><auth-address>Baylor College of Medicine, Houston, Texas, USA.</auth-address><titles><title>Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction</title><secondary-title>J Am Coll Cardiol</secondary-title></titles><periodical><full-title>Journal of the American College of Cardiology</full-title><abbr-1>J Am Coll Cardiol</abbr-1></periodical><pages>998-1005</pages><volume>59</volume><number>11</number><keywords><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>*Comorbidity</keyword><keyword>Female</keyword><keyword>Heart Failure/*mortality</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prevalence</keyword><keyword>Retrospective Studies</keyword><keyword>*Stroke Volume</keyword><keyword>United States/epidemiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 13</date></pub-dates></dates><isbn>1558-3597 (Electronic)
0735-1097 (Linking)</isbn><accession-num>22402071</accession-num><urls><related-urls><url>;(116). CKD is consistently associated with adverse outcome in HF, and appears to be of greater prognostic importance in HFpEF than HFrEF (odds ratio for all-cause mortality 2.40 (95% CI 2.18, 2.63) with LVEF > 40% vs. 2.0 (1.81, 2.21) with LVEF <30%) ADDIN EN.CITE <EndNote><Cite><Author>Damman</Author><Year>2014</Year><RecNum>6982</RecNum><DisplayText>(116)</DisplayText><record><rec-number>6982</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1504517571">6982</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Damman, K.</author><author>Valente, M. A.</author><author>Voors, A. A.</author><author>O'Connor, C. M.</author><author>van Veldhuisen, D. J.</author><author>Hillege, H. L.</author></authors></contributors><auth-address>University of Groningen, Department of Cardiology, University Medical Center Groningen, Hanzeplein 1, 9700RB, Groningen, The Netherlands.</auth-address><titles><title>Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis</title><secondary-title>Eur Heart J</secondary-title></titles><periodical><full-title>Eur Heart J</full-title><abbr-1>European heart journal</abbr-1></periodical><pages>455-69</pages><volume>35</volume><number>7</number><keywords><keyword>Aged</keyword><keyword>Cardio-Renal Syndrome/mortality/*physiopathology</keyword><keyword>Disease Progression</keyword><keyword>Epidemiologic Methods</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Kidney Failure, Chronic/mortality/*physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prognosis</keyword><keyword>Heart failure</keyword><keyword>Renal failure</keyword><keyword>Worsening renal function</keyword></keywords><dates><year>2014</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1522-9645 (Electronic)
0195-668X (Linking)</isbn><accession-num>24164864</accession-num><urls><related-urls><url>;(117).Comorbidity pathophysiology and potential interventionsThe pathophysiological mechanisms underlying the associations between these comorbidities and HFpEF remain unclear. Obesity, lung disease and kidney disease are associated with systemic inflammation and, as described earlier, Paulus et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXVsdXM8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (70) hypothesise that chronic inflammation leads to endothelial dysfunction, myocardial hypertrophy, fibrosis and diastolic dysfunction.Circulating inflammatory markers are associated with incident HFpEF, natriuetric peptide levels and diastolic dysfunction ADDIN EN.CITE <EndNote><Cite><Author>Lopez-Sanchez</Author><Year>2015</Year><RecNum>7048</RecNum><DisplayText>(117)</DisplayText><record><rec-number>7048</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1504517914">7048</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lopez-Sanchez, M.</author><author>Munoz-Esquerre, M.</author><author>Huertas, D.</author><author>Montes, A.</author><author>Molina-Molina, M.</author><author>Manresa, F.</author><author>Dorca, J.</author><author>Santos, S.</author></authors></contributors><auth-address>Department of Pulmonary Medicine, Bellvitge University Hospital, Barcelona, Spain.
Pneumology Research Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
CIBERES, Barcelona, Spain.</auth-address><titles><title>Inflammatory markers and circulating extracellular matrix proteins in patients with chronic obstructive pulmonary disease and left ventricular diastolic dysfunction</title><secondary-title>Clin Respir J</secondary-title></titles><periodical><full-title>Clin Respir J</full-title></periodical><keywords><keyword>Copd</keyword><keyword>extracellular matrix proteins</keyword><keyword>inflammatory biomarkers</keyword><keyword>left ventricular diastolic function</keyword><keyword>tenascin-C</keyword></keywords><dates><year>2015</year><pub-dates><date>Dec 10</date></pub-dates></dates><isbn>1752-699X (Electronic)
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ADDIN EN.CITE.DATA (63,78,79). Other proposed pathophysiological mechanisms include abnormal haemodynamics, metabolic dysregulation and neurohumoral activation ADDIN EN.CITE <EndNote><Cite><Author>Cavalera</Author><Year>2014</Year><RecNum>7050</RecNum><DisplayText>(118)</DisplayText><record><rec-number>7050</rec-number><foreign-keys><key app="EN" db-id="p5zp05xwusfdx3e2epc5sfrt95t2rrwvtz00" timestamp="1504518009">7050</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cavalera, M.</author><author>Wang, J.</author><author>Frangogiannis, N. G.</author></authors></contributors><auth-address>Division of Cardiology, Department of Medicine, The Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York.
Division of Cardiology, Department of Medicine, The Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York. Electronic address: ngf@bcm.edu.</auth-address><titles><title>Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities</title><secondary-title>Transl Res</secondary-title></titles><periodical><full-title>Transl Res</full-title></periodical><pages>323-35</pages><volume>164</volume><number>4</number><keywords><keyword>Animals</keyword><keyword>Fibrosis/*etiology/pathology</keyword><keyword>Heart Diseases/*etiology</keyword><keyword>Humans</keyword><keyword>Obesity/*complications</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1878-1810 (Electronic)
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ADDIN EN.CITE.DATA (122). The mechanisms by which empagliflozin may positively impact HF are unclear, but the improvement in HF outcomes was independent of glycaemic control. Hypotheses include a blood pressure lowering effect, sodium and fluid loss, beneficial effects on the renin-angiotensin system, weight loss, maintenance of renal function, decreased atrial stiffness and decreased inflammation. A phase-III trial of empagliflozin in HFpEF is currently in progress, including patients without type II diabetes (NCT03057951).DiscussionIt is clear that HFpEF involves multiple pathophysiological mechanisms, which, to a variable extent, likely co-exist and combine to result in the heterogeneous phenotypes that are evident clinically PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb21hamRhPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA (123).In an eloquent study, Shah et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFoPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (124) applied machine learning techniques to a well characterised HFpEF cohort in order to identify groups of patients based on their clinical phenotypes (“phenomapping”). Patients were recruited following hospitalisation for HF although elevated natriuretic peptides were not required for diagnosis. Three markedly differing phenogroups were identified: (1) younger patients with moderate diastolic dysfunction who had relatively normal BNP (mean 72pg/mL); (2) obese, diabetic patients with a high prevalence of obstructive sleep apnea who had the worst LV relaxation; and (3) older patients with significant chronic kidney disease, electric and myocardial remodeling, pulmonary hypertension, and RV dysfunction. Outcomes (including hospitalisation and death) varied significantly by phenogroup, with a stepwise increase in risk profile from group 1, which had the lowest risk to group 3, which had the highest. The phenogrouping provided more discriminatory risk profiling than BNP and results were confirmed in a validatory cohort. The work by Shah et al demonstrates that the heterogeneity of HFpEF can, at least to some extent, be resolved, and provides the opportunity for future trials to recruit, and determine effect, according to phenotypic characterisation.Nevertheless, it is the biology underlying these clinical phenotypes that ultimately needs to be determined; in particular, which biological mechanisms are root causes and which are downstream effects. Studies are required that simultaneously investigate multiple biological mechanisms, in order to understand the relative contribution of each mechanism, how different mechanisms interact and whether apparently distinct mechanisms share common drivers. For example, in order to more fully understand myocardial stiffness, concurrent assessments of titin, calcium handling, energetics and extracellular matrix, their interaction and molecular drivers, are required.Machine learning techniques, such as those used by Shah et al, applied to large, deeply phenotyped (biological and clinical) datasets in conjunction with well-defined outcomes may help to further resolve the heterogeneity of HFpEF, improve our understanding of how biological mechanisms integrate (‘biological phenogroups’) and how biological phenotypes integrate with clinical phenotypes. From this, specific interventions can follow, targeting individuals identified on the basis of their biological phenotypes. Biological heterogeneity has potentially compromised HFpEF trials previously PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaXR0PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (12-14); HFpEF now needs ‘to get personal’.This involves multiple challenges, not least the translation of cardiovascular molecular biology into clinical diagnostics that are acceptable and scalable. CMR ECM volume quantification has its limitations, but is an example of a technique that non-invasively interrogates a pathophysiological mechanism, which can be used to identify patients and measure the effect of interventions. A specific preclinical HFpEF model is lacking, although this reflects the heterogeneity of the condition and our lack of understanding of the integrated pathophysiology. Nevertheless, the ‘epidemic’ status of HF means the potential gains are large. Understanding the relationship between HFpEF and aging may help with understanding the biology of HFpEF more generally. In the study by Shah et al, older patients had more severe electrical and myocardial remodelling, more abnormal ventricular-arterial coupling, worse RV function and higher PA pressures in comparison to younger patients, despite a similar duration of HF. The mechanisms responsible for these age-related phenotypic differences are not clear, but it does not appear to simply reflect accumulation of comorbidities; whilst CKD was more common in older patients, obesity, diabetes and obstructive sleep apnea were not. Diastolic dysfunction is common in older patients without HF and is generally considered a benign manifestation of aging. However, it may reflect changes in myocardial and vascular structure that confer vulnerability PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFoPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj
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Biological phenotypes in heart failure with preserved ejection fraction (HFpEF). HFpEF is a systemic disease with multiple biological phenotypes contributing to a heterogeneous clinical syndrome, including cardiomyocyte, extracellular matrix, vascular and co-morbidity-related pathophysiological mechanisms.Figure 2. Morphological and functional heterogeneity in HFpEF clinical trials. The prevalence of left ventricular hypertrophy (A), left atrial dilatation (B) and diastolic dysfunction (C) is highly variable, demonstrated in major HFpEF randomised trials (I-PRESERVE, CHARM-Preserve, and TOPCAT). Figure 3. Cardiomyocyte-specific biological phenotypes in HFpEF. Titin phosphorylation and isoform expression (N2B/N2BA) alter cardiomyocyte stiffness. Mitochondrial dysfunction leads to abnormal phosphocreatinine (PCr) to adenosine triphosphate (ATP) ratio. Abnormal calcium handling may result from calcium leak and reduced expression of the sarcoendoplasmic reticulum calcium-transport ATPase (SERCA) pump. ADP, adenosine triphosphate; CaMKII, Ca2+/calmodulin-dependent protein kinase-II; cAMP, cyclic adenosine monophosphate; Cr, creatinine; ERK2, extracellular signal-regulated kinase-2; GMP, guanosine monophosphate; GTP, guanosine triphosphase; pGC, particulate guanylyl cyclase; PKA, protein kinase A; PKCα, protein kinase Cα; PKG, protein kinase G; sGC, soluble-guanylyl cyclase. Figure 4. Outcomes in patients with HFpEF or at risk of HFpEF according to extracellular volume (ECV). ECV measurement of myocardial fibrosis provides robust risk stratification for the combined end point of death or hospitalisation for heart failure (HHF). CMR, cardiac magnetic resonance imaging. Reproduced with permission from Schelbert et al PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hlbGJlcnQ8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA (57). ................
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