Novel insights in HFpEF, cardiomyopathies, and myocarditis

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Heart failure is a clinical syndrome with many causes and presentations. One way of looking at it is the pump function of the heart. As outlined in the ‘The year in cardiology 2017: heart failure’ authored by Lars H. Lund and colleagues from the Karolinska Institutet in Stockholm, Sweden,1 the 2016 ESC Heart Failure Guidelines2 distinguish heart failure with a reduced ejection fraction <40% (HFrEF), those with mid-range ejection fraction between 40% and 49% (HFmrEF), and those with preserved ejection fraction of ≥50% (HFpEF). Although the limit of 40% as such is artificial and introduced by triallists to ensure a proper event rate, the introduction of HFmrEF has led to investigations on this neglected patient population.3 Indeed, a subanalysis of TopCat suggests that HFmrEF is essentially an early stage of HFrEF and not a clinical entity on its own.4 Furthermore, the authors summarize recent data on the implementation and utilization of existing proven therapy in HFrEF,5 additional neutral trials in HFpEF,6 but a more detailed characterization of its potential mechanisms.7 The latter aspects are discussed in detail in a research manuscript entitled ‘Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction’ by Viviany R. Taqueti and colleagues from the Brigham and Women’s Hospital in Boston, USA.8 The authors followed 201 patients undergoing myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting coronary artery disease or reduced left ventricular ejection fraction over 4 years. Interestingly, patients with impaired coronary flow reserve demonstrated linearly decreasing e' and increasing E/e' consistent with worsening diastolic function. Furthermore, detectable troponin was associated with diastolic dysfunction only in the presence of impaired coronary flow reserve. In adjusted analyses, impaired coronary flow reserve was independently associated with diastolic dysfunction and composite cardiovascular outcomes or HFpEF (Figure 1). Patients with both impaired coronary flow reserve and diastolic dysfunction demonstrated more than five-fold increased risk of hospitalization for HFpEF. The concept of microvascular dysfunction as a potential cause of diastolic dysfunction and HFpEF is critically discussed in an Editorial by Noel Bairey Merz from Cedar Sinai Medical Center in Los Angeles.9 Adjusted freedom from major adverse cardiovascular events (MACE)*, (A) and hospitalization for heart failure with preserved ejection fraction (HFpEF, (B) by coronary flow reserve (CFR). Event-free survival, adjusted for pretest clinical score, history of atrial fibrillation, estimated glomerular filtration rate <60 mL•min−1•1.73 m−2, detectable troponin, left ventricular ejection fraction and E/e′septal > 15. Freedom from events differed significantly among subgroups stratified by CFR such that patients with low CFR experienced higher rates of composite or HFpEF events (overall P < 0.001 in unadjusted and adjusted analyses) (from Taqueti VR, Solomon SD, Shah AM, Desai AS, Groarke JD, Osborne MT, Hainer J, Bibbo CF, Dorbala S, Blankstein R, Di Carli MF. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. See pages 840–849). Adjusted freedom from major adverse cardiovascular events (MACE)*, (A) and hospitalization for heart failure with preserved ejection fraction (HFpEF, (B) by coronary flow reserve (CFR). Event-free survival, adjusted for pretest clinical score, history of atrial fibrillation, estimated glomerular filtration rate <60 mL•min−1•1.73 m−2, detectable troponin, left ventricular ejection fraction and E/e′septal > 15. Freedom from events differed significantly among subgroups stratified by CFR such that patients with low CFR experienced higher rates of composite or HFpEF events (overall P < 0.001 in unadjusted and adjusted analyses) (from Taqueti VR, Solomon SD, Shah AM, Desai AS, Groarke JD, Osborne MT, Hainer J, Bibbo CF, Dorbala S, Blankstein R, Di Carli MF. Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction. See pages 840–849). Besides ischaemic cardiomyopathy due to coronary artery disease and infarctions, dilated cardiomyopathies are a less common, but important disease entity.10–12 Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy with frequent conduction blocks and arrhythmias. In their article ‘Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantations’, Kristina Hermann Haugaa and colleagues from the Oslo University Hospital in Norway explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among patients with familial dilated cardiomyopathy.13 Of 561 unrelated familial dilated cardiomyopathy probands, 6% had a LMNA mutation. Asymptomatic LMNA genotype-positive family members had a 9% annual incidence of newly documented cardiac phenotype and 61% cardiac penetrance during 4.4 years of follow-up. Ten had atrioventricular block, 7 atrial fibrillation/flutter, and 12 non-sustained ventricular tachycardia. Heart transplantation was performed in 19% of the LMNA patients during 7.8 years of follow-up. Thus, LMNA mutations account for 1 in 16 of patients with familial dilated cardiomyopathy in Norway, and nearly 1 in 5 required heart transplantation. These novel results are put into clinical context in an Editorial by Sabine Pankuweit from the Philipps-University Marburg in Germany.14 Truncating titin variants are the most prevalent genetic cause of dilated cardiomyopathy.15 In their paper entitled ‘Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis, and long-term life-threatening arrhythmia’, Stephane Heymans and colleagues from CARIM at Maastricht University Hospital in The Netherlands studied clinical parameters and long-term outcomes related to the genotype of truncating titin variants.16 A toal of 303 consecutive and extensively phenotyped dilated cardiomyopathy patients underwent DNA sequencing. At follow-up for up to 12 years, dilated cardiomyopathy patients with truncating titin variants had increased ventricular arrhythmias compared with other dilated cardiomyopathies, but surprisingly a similar survival. Arrhythmias were especially prominent in patients with truncating titin variants with a trigger such as a virus infection, cardiac inflammation, systemic disease, or exposure to toxin. Of note, all components of the mitochondrial electron transport chain were significantly up-regulated. Also, interstitial fibrosis was augmented at the histological and transcript level. Thus, truncating titin variants lead to pronounced alterations in mitochondrial function, with increased interstitial fibrosis, reduced hypertrophy, and ventricular arrhythmias, but with a similar survival and overall cardiac function. These somewhat puzzling results are further discussed in a comprehensive Editorial by Sanjay Prasad from the Royal Brompton Hospital in London, UK.17 Foxo3 is a transcription factor involved in cell metabolism, survival, and inflammatory disease. However, mechanistic insight into Foxo3 effects is still limited, although the transcription factor appears to be involved in cardiac senescence.18 In a Basic Science manuscript entitled ‘The forkhead transcription factor FOXO3 negatively regulates natural killer cell function and viral clearance in myocarditis’, Carsten Skurk and colleagues from the Charite Berlin in Germany investigated the role of Foxo3 on natural killer cell responses and its effects in Coxsackie virus B3 (CVB3) myocarditis.19 In Foxo3–/– mice, immune cell infiltration, viral titres, and pro-inflammatory cytokines in cardiac tissue were reduced at 7 days post-infection, while interferon-γ and NKp46 expression were up-regulated, suggesting early viral control by enhanced natural killer cell activity. CD69 expression of natural killer cells, frequencies of CD11b+CD27+ effector natural killer cells, and cytotoxicity of Foxo3–/– mice were enhanced compared with wild types (Figure 2). Moreover, microRNA-155 expression, essential in natural killer cell activation, was elevated in Foxo3–/– natural killer cells while its inhibition led to diminished interferon-γ production. Humans carrying the longevity-associated FOXO3 single nucleottide polymorphism (SNP) rs12212067 exhibited reduced interferon-γ and cytotoxic degranulation of natural killer cells (Figure 2). Viral cardiomyopathy patients with a FOXO3 SNP rs12212067 polymorphism showed a poorer outcome due to less efficient virus control. Thus, Foxo3 appears to play an important role in the antiviral innate immunity, and enhanced FOXO3 activity such as in the polymorphism rs12212067 may be protective in chronic inflammation, but disadvantageous to control acute viral infection. Schematic Summary—Foxo3 function in viral myocarditis. Effects of Foxo3 in viral myocarditis (left) and human viral cardiomyopathy (CMI, right) are summarized. In viral myocarditis, Foxo3 deficiency leads to cardiac accumulation of activated NK cells characterized by miR-155 dependent enhanced IFNγ expression, increased cytotoxic activity and differentiation into an effector natural killer (NK) cell type leading to early viral elimination and attenuated cardiac inflammation. Patients carrying the gain-of-function SNP rs12212067 are characterized by decreased NK cell activation, attenuated cytotoxic degranulation, and diminished IFNγ expression. Therefore, cardiac clearance of viral genomes is prolonged in viral CMI patients carrying the SNP associated with enhanced inflammation and attenuated improvement of cardiac function (i.e. LVEF, LVEDD) (from Loebel M, Holzhauser L, Hartwig JA, Shukla PC, Savvatis K, Jenke A, Gast M, Escher F, Becker SC, Bauer S, Stroux A, Beling A, Kespohl M, Pinkert S, Fechner H, Kuehl U, Lassner D, Poller W, Schultheiss H-P, Zeller T, Blankenberg S, Papageorgiou A-P, Heymans S, Landmesser U, Scheibenbogen C, Skurk C. The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis. See pages 876–887). Schematic Summary—Foxo3 function in viral myocarditis. Effects of Foxo3 in viral myocarditis (left) and human viral cardiomyopathy (CMI, right) are summarized. In viral myocarditis, Foxo3 deficiency leads to cardiac accumulation of activated NK cells characterized by miR-155 dependent enhanced IFNγ expression, increased cytotoxic activity and differentiation into an effector natural killer (NK) cell type leading to early viral elimination and attenuated cardiac inflammation. Patients carrying the gain-of-function SNP rs12212067 are characterized by decreased NK cell activation, attenuated cytotoxic degranulation, and diminished IFNγ expression. Therefore, cardiac clearance of viral genomes is prolonged in viral CMI patients carrying the SNP associated with enhanced inflammation and attenuated improvement of cardiac function (i.e. LVEF, LVEDD) (from Loebel M, Holzhauser L, Hartwig JA, Shukla PC, Savvatis K, Jenke A, Gast M, Escher F, Becker SC, Bauer S, Stroux A, Beling A, Kespohl M, Pinkert S, Fechner H, Kuehl U, Lassner D, Poller W, Schultheiss H-P, Zeller T, Blankenberg S, Papageorgiou A-P, Heymans S, Landmesser U, Scheibenbogen C, Skurk C. The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis. See pages 876–887). Human and mouse cardiac beta3-adrenergic receptors exert antipathetic effects to those of beta1- or beta2-adrenergic receptor stimulation. In a Basic Science manuscript entitled ‘Cardiac myocyte β3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signalling’, Jean-Luc Balligand and colleagues from UCL in Brussels, Belgium examined their role in modulating myocardial remodelling and fibrosis in response to haemodynamic stress.20 Mice with cardiac myocyte-specific expression of beta3-adrenergic receptors or tamoxifen-inducible homozygous deletion were submitted to transaortic constriction. Cardiac beta3-adrenergic receptors attenuated myocardial fibrosis in response to haemodynamic stress. Interstitial fibrosis and collagen content were reduced in beta3-adrenergic receptor transgenic mice, but augmented in beta3-adrenergic receptor knockout mice. Beta3-adrenergic receptors and collagen expression were inversely related in ventricular biopsies of patients with valve disease. Incubation of cardiac fibroblasts with media conditioned by hypertrophic myocytes induced fibroblast proliferation, myodifferentiation, and collagen production, which was abrogated upon beta3-adrenergic receptor expression in myocytes. Comparative shotgun proteomic analysis of the myocyte secretomes revealed reduced connective tissue growth factor which was similarly reduced in stressed hearts from beta3-adrenergic receptor transgenic mice, but increased in beta3-adrenergic receptor knockout mice. Connective tissue growth factor expression was mediated by reactive oxygen species production, which was reduced by beta3-adrenergic receptor expression. These antioxidant and antifibrotic effects involved coupling of beta3-adrenergic receptors to neuronal nitric oxide synthase. Thus, cardiac beta3-adrenergic receptors protect against fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress-dependent paracrine signalling to fibroblasts. Specific agonism at beta3-adrenergic receptors may offer a novel antifibrotic cardiac therapy. The editors hope that readers of this issue of the European Heart Journal will find it of interest.