Risk factors for chronic heart failure: obesity, renal dysfunction, arteriovenous fistulas, and amyloid deposition

The prevalence and incidence of chronic heart failure have increased over the last decades due to increasing longevity of the population,1 chronic and not well controlled hypertension in many,2,3 increased survival after myocardial infarction,4 and recently the obesity epidemic.5 Besides the heart and its pump function, renal function is crucially involved in this syndrome and of relevance for its management.6 As pointed out in a clinical review entitled ‘Renal sodium avidity in heart failure: from pathophysiology to treatment strategies’ by Wilfried Mullens and colleagues from the Ziekenhuis Oost Limburg in Genk, Belgium, increased neurohumoral stimulation results in excessive sodium avidity and extracellular volume overload in decompensated heart failure.7 In the presence of renal dysfunction which often is present in such patients, the kidneys fail to provide effective natriuresis. Of note, serum creatinine—a surrogate for glomerular filtration—only represents part of the nephron’s function. Alterations in tubular sodium handling are equally important in the development of volume overload and congestion. Venous congestion and neurohumoral activation in advanced heart failure further promote renal sodium and water retention. Interestingly, even before clinical signs of heart failure are evident, intrinsic renal derangements already impair natriuresis. A better understanding of cardiorenal interactions which ultimately result in sodium avidity in heart failure might help to treat and prevent congestion in chronic and acute heart failure. A recently discussed risk factor for heart failure is obesity. The obesity epidemic is of great concern not only in adults, but also in children and adolescents.8 However, the impact of body weight in children and adolescents on the risk of developing heart failure in the long run is not known. In an article entitled ‘Body weight in adolescence and long-term risk of early heart failure in adulthood among men in Sweden’, Annika Rosengren from the Sahlgrenska University Hospital at Östra in Gothenburg, Sweden studied the relationship between body mass index and risk of early hospitalization due to heart failure in a prospective cohort of 1 610 437 young men 19 years of age followed for a median of 23 years.9 Overall, 5492 first hospitalizations for heart failure occurred at a mean age of 47 years. Compared with men with a body mass index of 18.5–20.0 kg/m2, men with a body mass index of 20.0–22.5 kg/m2 had an adjusted hazard ratio of 1.22. The risk rose incrementally with increasing body mass index such that men with a body mass index of 30–35 kg/m2 had an adjusted hazard ratio of 6.40 and those with a body mass index of ≥35 kg/m2 one of 9.53. The multiple-adjusted risk of heart failure per 1 unit increase in body mass index ranged from 1.06 in heart failure associated with valvular disease to 1.21 for cases associated with coronary heart disease, diabetes, or hypertension. There was a steeply rising risk of early heart failure detectable already at a normal body weight, increasing nearly 10-fold in the highest weight category. Given the current obesity epidemic, heart failure in the young may thus increase markedly in the future. The implications of these findings for weight management and prevention are reviewed in an Editorial by Pardeep Jhund from the University of Glasgow in Scotland.10 Heart failure may be due to ischaemia and infarction,11 valvular or congenital heart disease,12 as well as myocyte dysfunction13 or deposition of proteins and other molecules within the myocardial tissue. Infiltrative myocardial dysfunction is typical for different forms of amyloidosis.14 The diagnosis of amyloidosis is challenging, however; although typical echocardiographic findings may be leading to diagnosis, definitive confirmation requires detection of the protein in tissue. Although Congo red staining of an endomyocardial biopsy is the diagnostic gold standard in suspected cardiac amyloidosis, the procedure is invasive, and potentially associated with complications and sample bias. Thus, fat pad fine needle aspiration has been introduced for the work up of such patients. In an EHJ Brief Communication ‘Diagnostic sensitivity of abdominal fat aspiration in cardiac amyloidosis’, Julian Gillmore and colleagues from the University College London Medical School in London, UK note that although abdominal fat pad fine needle aspiration is a simple, safe, and well-established procedure in systemic amyloidosis, its diagnostic sensitivity in suspected cardiac amyloidosis has not been established.15 The authors therefore assessed the diagnostic sensitivity of fat pad fine needle aspiration in 600 consecutive patients diagnosed with cardiac amyloidosis, i.e. 216 amyloid light-chain, 113 hereditary transthyretin, and 271 wild-type transthyretin amyloidosis. Amyloid was detected on Congo red staining of fat pad fine needle aspirations in 84% patients with cardiac light-chain amyloidosis, including 100, 97, and 78% of those with a large, moderate, and small whole-body amyloid burden, respectively, as assessed by serum amyloid P component scintigraphy. The deposits were successfully typed as amyloid light-chain by immunohistochemistry in 47% of the cases. Amyloid was detected in fat pad fine needle aspirations of 45% with hereditary transthyretin cardiac amyloidosis, and in only 15% with wild-type transthyretin cardiac amyloidosis. The authors conclude that fat pad fine needle aspiration has reasonable diagnostic sensitivity in cardiac light-chain amyloidosis, particularly in patients with a large whole-body amyloid burden. The diagnostic sensitivity of fat pad fine needle aspiration is substantially lower in transthyretin cardiac amyloidosis, particularly wild-type transthyretin amyloidosis. The diagnostic implications of these findings are discussed in an Editorial by Frederick Ruberg from the Boston University School of Medicine in Massachusetts, USA.16 This issue is further discussed in an article entitled ‘Clinical characteristics of wild-type transthyretin cardiacamyloidosis: disproving myths’ by Pablo Garcia-Pavia and colleagues from the Hospital Universitario Puerta de Hierro in Majadahonda, in Madrid.17 They remind us that wild-type transthyretin amyloidosis is mostly considered a disease predominantly of elderly males, characterized by concentric left ventricular hypertrophy, preserved left ventricular ejection fraction, and low QRS voltages.14 They therefore sought to describe the characteristics of a large cohort of wild-type transthyretin amyloidosis patients to better define the disease. Wild-type transthyretin amyloidosis was diagnosed histologically or non-invasively based on left ventricular hypertrophy of ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy, and exclusion of amyloid light-chain amyloidosis. Mutations in transthyretin were excluded in all 108 cases. An asymmetric hypertrophy pattern was observed in 23% (Figure 1). Left ventricular ejection fraction was 52%, with 37% presenting with a value <50%. On ECG, 56% had atrial fibrillation and 63% had a pseudo-infarct pattern. Only 20% fulfilled QRS low-voltage criteria, while 9% showed left ventricular hypertrophy. Although heart failure was the leading symptom to diagnosis in 68%, 7% presented with atrioventricular block and 11% were diagnosed incidentally. Almost one-third were previously misdiagnosed. Thus, the clinical spectrum of wild-type transthyretin amyloidosis is heterogeneous and differs from the classic phenotype in that women are affected in a significant proportion, asymmetric left ventricular hypertrophy and impaired ejection fraction are not rare, and only a minority have low QRS voltages. Clinicians should therefore be aware of the broad clinical spectrum of wild-type transthyretin amyloidosis to identify correctly an entity for which several disease-modifying treatments are under investigation. The implications of these findings are further discussed in the Editorial by Frederick Ruberg cited above.16 Asymmetric left ventricular hypertrophy. Echocardiographic parasternal basal (A) and mid cavity (B) short axis views showing asymmetric left ventricular hypertrophy with anteroseptal predominance and a trace of posterior pericardial effusion. (From González-López E, Gagliardi C, Dominguez F, Quarta CC, de Haro-del Moral JF, Milandri A, Salas C, Cinelli M, Cobo-Marcos M, Lorenzini M, Lara-Pezzi E, Foffi S, Alonso-Pulpon L, Rapezzi C, Garcia-Pavia P. Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths. See pages: 1895–1904). The major haemodynamic mechanism of heart failure is pressure or volume overload.18 Of note, short-term studies have reported left ventricular dilatation following surgical creation of arteriovenous fistulas or arteriovenous grafts in renal patients, but chronic cardiac structural and functional changes have not been examined or related to clinical outcomes. In their article ‘Long-term cardiovascular changes following creation of arteriovenous fistulasin patients withend-stage renal disease’, Barry A. Borlaug and colleagues from the Mayo Clinic in Rochester, MN, USA characterized the long-term changes in cardiac structure and function in 137 renal patients undergoing shunt creation for haemodialysis.19 Following arteriovenous fistulas and dialysis initiation, there were reductions in blood pressure, body weight, and estimated plasma volume, coupled with modest reverse left ventricular remodelling. In contrast, arteriovenous fistula or arteriovenous graft creation was associated with significant right ventricular dilatation and deterioration in right ventricular function. Incident heart failure developed in 43% of patients in concordance with right ventricular remodelling. The development of right ventricular dilation following surgical arteriovenous fistulas or arteriovenous grafts was independently associated with increased risk of death, with a hazard ratio of 3.9. Thus, right ventricular remodelling and dysfunction develops following creation of arteriovenous fistulas or arteriovenous grafts and dialysis initiation, despite improved control of left ventricular pressure load through dialysis. The deleterious effects on right heart structure and function are coupled with the development of incident heart failure and increased risk of death. These findings may also have important implications for the evaluation of the recently introduced central arteriovenous fistula procedure for resistant hypertension.20 Further implications of these provocative findings are discussed to an Editorial by Peter A. McCullough from Baylor University Medical Center at Dallas in Texas.21 Morbidity and mortality from chronic heart failure has been substantially reduced over the last decades due to the introduction of inhibitors of the renin–angiotensin system, particularly if combined with a neprilysin inhibitor,22 beta-blockers, and aldosterone antagonists,23 as well as more recently cardiac resynchronization therapy.24 However, despite clear guidelines recommendations, most patients with heart failure and reduced ejection fraction do not attain guideline-recommended target dosages25 of live-saving drugs. In their research article ‘Determinants and clinical outcome of up-titration of ACE-inhibitorsand beta-blockersin patients with heart failure: a prospective European study’, Adriaan Voors and colleagues from the University Medical Center Groningen in The Netherlands report the results of BIOSTAT-CHF analysing 2516 heart failure patients from 69 centres in 11 European countries during 21 months. They investigated characteristics and treatment indication bias-corrected clinical outcome of patients with heart failure and reduced ejection fraction that did not reach recommended treatment doses of ACE inhibitors, angiotensin receptor blockers, and/or beta-blockers.26 Of the eventually 2100 patients with heart failure and reduced ejection fraction available, only 22% achieved the recommended treatment dosages for ACE inhibitors or angiotensin receptor antagonists and 12% for beta-blockers. Reaching <50% of the recommended ACE inhibitor, angiotensin receptor antagonist, and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50–99% of the recommended ACE inhibitor, angiotensin receptor antagonist, and/or beta-blocker dose had risk of death and/or heart failure hospitalization comparable with those reaching 100% (Figure 2). Patients not reaching recommended dosages because of symptoms, side effects, and non-cardiac organ dysfunction had the highest mortality rate, with a hazard ratio for an ACE inhibitor or angiotensin receptor antagonist of 1.72, and 1.70 for beta-blockers. The authors conclude that patients with heart failure and reduced ejection fraction who were treated with <50% of recommended dosages of ACE inhibitors or angiotensin receptor blockers and beta-blockers have a greater risk of death and/or heart failure hospitalization compared with those reaching target dosages. These clinically important findings are discussed in an Editorial by Luigi Tavazzi from the Maria Cecilia Hospital in Cotignola, Italy.27 Adjusted mortality rate for patients achieving or ≥ 100% for both ACE-inhibitor and angiotensin receptor blockers and beta-blocker recommended dose, ≥50% recommended ACE-inhibitor and beta-blocker dose, ≥50% of at least ACE-inhibitor and angiotensin receptor blockers or beta-blocker recommended dose, and for patients achieving <50% of recommended ACE-inhibitor/ARB and beta-blocker dose. (From Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, ter Maaten JM, Ng LL, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Metra M, Zwinderman AH. Determinants and clinical outcome of uptitration of ACE-inhibitor and beta-blocker in patients with heart failure: a prospective European study. See pages: 1883–1890). The editors hope that readers of this issue of the European Heart Journal will find it of interest to them.