The link among heart failure, chronic kidney disease, and cancer: new light shed on the complex patient

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies contains a State of the Art Review entitled ‘Prevention of cardiorenal damage: importance of albuminuria’ by Luis M. Ruilope from the Hospital Universitario in Madrid, Spain, and colleagues.1 The authors note that chronic kidney disease (CKD) is projected to become a leading global cause of death by 2040, and its early detection is critical for effective and timely management.2–6 The current definition of CKD identifies only advanced stages, when kidney injury has already destroyed >50% of functioning kidney mass as reflected by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urinary albumin/creatinine ratio more than six-fold higher than physiological levels (i.e. >30 mg/g). An elevated urinary albumin excretion rate is a known early predictor of future cardiovascular events. There is thus a ‘blind spot’ in the detection of CKD, when kidney injury is present, but it is undetectable by current diagnostic criteria, and no intervention is made before renal and cardiovascular damage occurs. The present review discusses the CKD ‘blind spot’ concept and how it may facilitate a holistic approach to CKD and cardiovascular disease prevention, and implement the call for albuminuria screening implicit in current guidelines. Cardiorenal risk associated with albuminuria in the high-normal range, novel genetic and biochemical markers of elevated cardiorenal risk, and the role of heart and kidney protective drugs evaluated in recent clinical trials are also discussed. As albuminuria is a major risk factor for cardiovascular and renal disease, starting from levels not yet considered in the definition of CKD, the implementation of opportunistic or systematic albuminuria screening and therapy, possibly complemented with novel early biomarkers, has the potential to improve cardiorenal outcomes and mitigate the dismal 2040 projections for CKD and related cardiovascular burden. Cancer and heart failure (HF) share risk factors, pathophysiological mechanisms, and possibly genetics.7–10 Improved HF survival may increase the risk of cancer being a competing risk. In a Clinical Research article entitled ‘Temporal trends in the incidence of malignancy in heart failure: a nationwide Danish study’, Jonas Bruhn from the Herlev and Gentofte University Hospital in Copenhagen, Denmark, and colleagues note that whether the incidence of cancer has increased over time in patients with HF as survival has improved is unclear.11 Therefore, temporal trends of new-onset cancer in HF patients between 1997 and 2016 were investigated. Using Danish nationwide registers, >103 000 individuals alive, free of cancer, and aged 30–80 years at 1 year after HF diagnosis (index date) were included between 1 January 1997 and 31 December 2016. A 5-year incidence rate of cancer for each year after the index date was calculated. The median age and proportion of women on the index date decreased with advancing calendar time. The 5-year incidence rate of cancer was 20.9 and 20.2 per 1000 person-years in 1997 and 2016, respectively. In a multivariable Cox regression model, the hazard rates between index years 1997 (reference) and 2016 were not significantly different. The five-year absolute risk of cancer did not change with advancing calendar year, going from 9.0% (1997–2001) to 9.0% (2012–2016). The 5-year cumulative incidence of survival for HF patients significantly increased with advancing calendar year, going from 55.9% (1997–2001) to 74.3% (2012–2016). The authors conclude that although cancer rates during 1997–2016 have remained stable within 1–6 years after the HF diagnosis, long-term survival following a HF diagnosis has increased significantly. The contribution is accompanied by an Editorial by Pietro Ameri from the University of Genova, Italy, and colleagues.12 The authors note that the article by Bruhn et al. leaves the clinician with the confirmation that cancer is a comorbidity of HF to be aware of. According to the Danish registers, the 5-year risk of ischaemic stroke, transient ischaemic attack, or systemic thrombo-embolism in men aged 70 years with atrial fibrillation (AF) is 6.8%, and in those with one risk factor in addition to AF it is 8.7%. In women of the same age, the corresponding risks are 8.2% and 9.1%, respectively. The 5-year risk of incident cancer in the HF cohort examined by Bruhn et al. was 9.0%. In pragmatic terms, therefore, the practitioner should be concerned about cancer in HF as much as about ischaemic complications of AF. Nevertheless, it remains to be established whether the management of HF should be modified when cancer is diagnosed, and this is the most clinically relevant task to be accomplished in the field of cardio-oncology focusing on cancer in HF. The upper part of the figure describes the calculation of each of the anthropometric measures. The lower part of the figure shows the risk of outcomes according to continuous body mass index (left panel) and waist-to-height ratio (right panel). The solid line represents the hazard ratio and the shaded area the 95% confidence interval. The blue spline is adjusted for treatment and region. The red spline is adjusted for treatment, age, sex, region, systolic blood pressure, heart rate, estimated glomerular filtration rate, left ventricular ejection fraction, log of n-terminal pro-B-type natriuretic peptide, body mass index (only in the waist-to-height ratio analyses), New York Heart Association functional class, heart failure aetiology, duration of heart failure, prior heart failure hospitalization, a history of diabetes, and atrial fibrillation. BMI, body mass index; BRI, body roundness index; BSA, body surface area; BSI, body shape index; CI, confidence interval; HF, heart failure; HR, hazard ratio; RFM, relative fat mass; WHR, waist-to-hip ratio; WHtR, waist-to-height ratio; WWI, weight-adjusted-waist index.16 Obesity is a pandemic of growing relevance.13–15 In a Clinical Research article entitled ‘Anthropometric measures and adverse outcomes in heart failure with reduced ejection fraction: revisiting the obesity paradox’, John J.J.V. McMurray from the Western Infirmary in Glasgow, UK, and colleagues indicate that although body mass index (BMI) is the most commonly used anthropometric measure, newer indices such as the waist-to-height ratio better reflect the location and amount of ectopic fat, as well as the weight of the skeleton, and may be more useful.16 In their contribution, the prognostic value of several newer anthropometric indices was compared with that of BMI in patients with HF and reduced ejection fraction (HFrEF) enrolled in PARADIGM-HF. The primary outcome was HF hospitalization or cardiovascular death. The association between anthropometric indices and outcomes was comprehensively adjusted for other prognostic variables, including natriuretic peptides. An ‘obesity–survival paradox’ related to lower mortality risk in those with BMI ≥25 kg/m2 (compared with normal weight) was identified but this was eliminated by adjustment for other prognostic variables. This paradox was less evident for waist-to-height ratio (as an exemplar of indices not incorporating weight) and eliminated by adjustment: the adjusted hazard ratio (aHR) for all-cause mortality, for quintile 5 vs. quintile 1, was 1.10. Notably, both BMI and waist-to-height ratio showed that greater adiposity was associated with a higher risk of HF hospitalization; this was more evident for waist-to-height ratio and persisted after adjustment, e.g. the aHR for HF hospitalization for quintile 5 vs. quintile 1 of waist-to-height ratio was 1.39 (1.06–1.81) (Figure 1). McMurray et al. conclude that in patients with HFrEF, alternative anthropometric measurements show no evidence for an ‘obesity–survival paradox’. Newer indices that do not incorporate weight show that greater adiposity is clearly associated with a higher risk of HF hospitalization. The contribution is linked to an Editorial by Stephan von Haehling from the Charité Campus Virchow-Klinikum in Berlin, and Ryosuke Sato from the University Medical Center Göttingen in Germany.17 von Haehling and Sato conclude that the present findings raise the alarm over the term ‘obesity paradox’, which has been claimed to be based on BMI. We should also revisit the obesity paradox in patients with HF with preserved ejection fraction (HFpEF) and in lean HF patients by waist-to-height ratio, since this better reflects pathophysiological processes of obesity. Additionally, further tests are warranted to validate the effect of weight loss in ‘truly’ obese HF patients with a high waist-to-height ratio. CKD increases the risk of cardiovascular disease (CVD).2–5 In a Clinical Research article entitled ‘Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study’, Patrick Mark from the University of Glasgow, UK, and colleagues point out that less is known regarding how CVD associates with future risk of kidney failure with replacement therapy (KFRT).18 The study included about 26 000 000 individuals from the CKD Prognosis Consortium with known baseline eGFR and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, HF, and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes, and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were >269 000 CHD, >311 000 stroke, >712 000 HF, and >605 000 AF incident events; 101 044 patients (0.4%) experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with aHRs of 3.1, 4.5, and 2.8 after incident CHD, stroke, HF, and AF, respectively. HRs were highest in the first 3 months post-CVD, declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT (HR 46 within 3 months) after adjustment for the incidence of other CVD subtypes. The authors conclude that incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed. This manuscript is accompanied by an Editorial by Carmine Zoccali and Francesca Mallamaci from the Grande Ospedale Metropolitano in Reggio Calabria, Italy.19 The authors note that the findings by Mark et al. suggest that policies preventing HF, CHD, AF, and stroke, together with early, timely treatment of the same diseases will protect not only the cardiovascular system but also the kidney. Appropriate cardiovascular interventions targeting these diseases may avert a not trivial proportion of CKD cases reaching the end-stage phase of this disease, thereby contributing to mitigating the human and financial costs of kidney failure. Well beyond the critical cardio-renal connection, preventing the epidemic of chronic diseases, i.e. a set of highly interconnected diseases, remains an absolute public health priority in the years to come. Our analyses reveal substantial variation in mitochondrial dysfunction in patients with hypertrophic cardiomyopathy. At the cellular level, this was strongly linked to mitochondrial disorganization. In patients with no known causative sarcomere mutation, mitochondrial dysfunction was associated with septal thickening. Mitochondria were responsive to treatments aimed at boosting NADH-driven respiration, indicating therapeutic potential of the mitochondria despite severe cardiac remodelling.22 Genetic hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein-encoding genes (i.e. genotype-positive HCM).20,21 In an increasing number of patients, HCM occurs in the absence of a mutation (i.e. genotype-negative HCM). In a Translational Research article entitled ‘Mitochondrial dysfunction in human hypertrophic cardiomyopathy is linked to cardiomyocyte architecture disruption and corrected by improving NADH-driven mitochondrial respiration’, Edgar Nollet from Amsterdam UMC in the Netherlands, and colleagues report that mitochondrial dysfunction might be a key driver of pathological remodelling in genotype-negative HCM.22 Respirometry was performed on septal myectomy tissue from patients with HCM (n = 59) to evaluate oxidative phosphorylation and fatty acid oxidation. Mitochondrial dysfunction was most notably reflected by impaired NADH-linked respiration. In genotype-negative patients, but not genotype-positive patients, NADH-linked respiration was markedly depressed in patients with an indexed septal thickness ≥10 compared with <10 mm. Mitochondrial dysfunction was not explained by reduced abundance or fragmentation of mitochondria, as evaluated by transmission electron microscopy. Rather, improper organization of mitochondria relative to myofibrils (expressed as a percentage of disorganized mitochondria) was strongly associated with mitochondrial dysfunction. Pre-incubation with the cardiolipin-stabilizing drug elamipretide and raising mitochondrial NAD+ levels both boosted NADH-linked respiration (1.06–1.81) (Figure 2). The authors conclude that in genotype-negative HCM, mitochondrial dysfunction associated with improper organization of mitochondria relative to myofibrils is linked to septal hypertrophy. Despite severe myocardial remodelling, mitochondria are responsive to treatments aimed at restoring respiratory function, eliciting the mitochondria as a drug target to prevent and ameliorate cardiac disease in this subset of HCM. The contribution is accompanied by an Editorial by Christoph Maack, Angelika Batzner, and Vasco Sequeira from the Universitätsklinikum Würzburg in Germany.23 The authors note that the current study provides convincing evidence that respiratory defects of cardiac mitochondria may contribute to energy depletion and the pathophysiology of HCM, in particular when left ventricular hypertrophy progresses. Improving the provision of reducing equivalents in the Krebs cycle with the delivery of NAD+, modifying cardiac substrate metabolism (as has been performed previously in HCM with perhexilline), or improving respiratory chain function with elamipretide could be valuable treatment options that may further improve the course of the disease beyond the currently available approaches. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.