October 2018 at a Glance: From Demographic Variables to Genotype–Phenotype Interactions

Prognostic assessment remains challenging. This time we move from very simple clinical and laboratory variables to genotype–phenotype interactions. It is still difficult how to better characterize patients with dilated cardiomyopathy.1, 2 Halliday et al.3 analysed the role of sex and age in 881 patients with dilated cardiomyopathy. Compared to men, women had more severe symptoms, smaller left ventricular (LV) end-diastolic volume, higher LV ejection fraction (EF) and were less likely to have mid-wall late gadolinium enhancement. Women had lower all-cause mortality during a median follow-up of 4.9 years. Age was another independent determinant of all-cause mortality and non-sudden cardiac death. Two articles show the high and independent prognostic value of hypochloraemia. Cuthbert et al.4 analysed a large cohort of patients with heart failure (HF) and reduced (HFrEF) or preserved EF (HFpEF). Patients in the first quartile of serum chloride values had more severe symptoms, were more likely to take loop diuretics and had a two-fold increased risk of death compared to patients in the fourth quartile. The association with increased mortality was independent of plasma brain natriuretic peptide (BNP) levels. Grodin et al.5 analysed 942 patients with high baseline BNP enrolled from the Americas in the Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist Trial (TOPCAT). Loop diuretic, but not spironolactone, administration was associated with lower serum chloride levels. Serum chloride had a continuous relation with outcomes with ∼50% increased risk of cardiovascular death and ∼30% increased risk of all-cause death for every standard deviation decrease in serum chloride. This relation persisted after multivariable adjustment. No association with the primary composite endpoint or with HF hospitalization alone was found.5 These data confirm and expand other recent studies showing that hypochloraemia is a powerful marker of poor outcomes.6-8 Lamin A/C mutations (LMNA) were investigated in three different affected families.9 A LMNA-p.Arg216Cys missense mutation was identified in a large family with 36 mutation carriers. These subjects had an unusually late onset and favourable prognosis of the cardiomyopathy. LMNA gene and protein expression was studied in eight of these carriers and they all showed the mutated lamin protein into the nuclear envelope with, however, a relatively low mutated to wild-type protein ratio (30:70). In contrast, two smaller families with severe disease expression and poor outcomes had different LMNA mutations with a higher mutated to wild-type protein ratio (50:50). This study shows that, differently than generally believed, LMNA mutations may be associated also with a benign clinical course and the amounts of mutated protein may be related with disease severity and outcomes.9 Transthyretin-related hereditary amyloidosis (ATTRm) can present with several phenotypes depending mainly on the specific mutation. Gagliardi et al.10 compared 67 patients with ATTRm and Ile68Leu mutation with patients with wild-type transthyretin amyloidosis (ATTRwt) and unaffected mutation carriers. Cumulative disease onset was 50% at age 71 with a predominant cardiac phenotype in most of the cases (84%). This was characterized by a normal LVEF, concentric LV hypertrophy, and low QRS voltage/mass ratio. Carpal tunnel syndrome was present in 43% of the patients. Compared with ATTRwt patients, those with the Ile68Leu mutation were younger and more likely to have a mild symptomatic neurological involvement. Age-adjusted survival was similar between groups.10 Anthracycline-based chemotherapy has improved survival in breast cancer but it is associated with cardiovascular morbidity and mortality.11 The long-term effects of anthracycline therapy are controversial and based on observational studies. Banke et al.12 report on the long-term effects of epirubicin administration in 980 women enrolled between 1990 and 1998 in the Danish Breast Cancer Cooperative Group (DBCG) 89D trial. During a median follow-up of 16.9 years, patients treated with epirubicin had a three-fold hazard ratio (HR) for HF vs. those not treated with epirubicin [HR 3.00, 95% confidence interval (CI) 1.39–6.49, P < 0.01] with, however, a relatively low overall risk of 3.7 per 1000 patient-years.12 There are no data comparing upgrade to CRT from a previous pacemaker (PM) or implantable cardioverter-defibrillator (ICD) with de novo implantations. Linde et al.13 have analysed the European Society of Cardiology (ESC) CRT Survey II and compared 2396 patients (23.2%) who had an upgrade to CRT from a previous PM (CRT-P) or ICD (CRT-D) with 7933 patients who had de novo CRT implantation. Compared with de novo implantations, patients with an upgrade were older, more often male, more frequently with ischaemic HF, atrial fibrillation, reduced renal function, worse symptoms, and had higher N-terminal pro-BNP levels. Despite older age and worse symptoms, total peri-procedural and in-hospital complications and length of hospital stay were similar.13 Using data from two randomized trials and one prospective observational research, Gasparini et al.14 compared the rate of ICD shocks and hospitalizations in patients with permanent atrial fibrillation undergoing CRT implantation and atrioventricular junction ablation (n = 262) compared with those who underwent CRT implantation and treatment with heart rate slowing drugs, if with atrial fibrillation (n = 402), or who were in sinus rhythm (n = 2694). Patients with permanent atrial fibrillation treated with CRT and atrioventricular junction ablation had a lower rate of all-cause ICD shocks (8.0 per 100 patient-years) than patients with atrial fibrillation and on rate slowing drugs (HR 0.18, 95% CI 010–0.32; P < 0.001) or those in sinus rhythm (HR 0.48, 95% CI 0.35–0.66; P < 0.001). Reductions were significant in both appropriate ICD shocks and inappropriate ICD shocks. Annual rate of all-cause and HF hospitalizations was also significantly lower in patients treated with atrioventricular junction ablation.14