Special issues in heart failure: pulmonary hypertension, deranged potassium levels, and haemodynamic profiles

Many, if not most cardiac diseases, regardless of whether or not they involve the coronary circulation or the myocardium, end up in heart failure. This can be heart failure with a preserved or a reduced ejection fraction.1 While heart failure with reduced ejection fraction (HFrEF) has declined due to modern management of acute coronary syndromes, heart failure with preserved ejection fraction (HFpEF) is increasing in ageing Western societies.2,3 A common consequence of both forms of heart failure is pulmonary congestion (assessed clinically or more recently with ultrasound4) and pulmonary hypertension,5 both important prognostic markers in these patients.6 In a Current Opinion article entitled ‘Pulmonary hypertension in heart failure with preserved ejection fraction:aplea for proper phenotyping and further research’,7 Marius Hoeper and colleagues from the Hannover Medical School in Germany address the uncertainties in proper phenotyping of patients with HFpEF and argue that a better classification, and outlines for future research on improvements in understanding its pathophysiology, and potential treatment strategies for pulmonary hypertension will be clinically useful. They hypothesize that proper phenotyping is key to identifying patients who may benefit from therapies targeting pulmonary hypertension. Hence, the two remaining controversial topics are the diastolic pressure gradient in distinguishing between isolated post-capillary pulmonary hypertension and combined pre- and post-capillary pulmonary hypertension, and the concept of ‘atypical’ pulmonary arterial hypertension. Adding to this discussion, Barry A. Borlaug and colleagues from the Mayo Clinic in Rochester, Minnesota provide a further perspective in a Viewpoint entitled ‘Is it time to recognize a new phenotype? Heartfailurewith preserved ejection fraction with pulmonary vascular disease’.8 Cardiac amyloidosisis is a rare but, thanks to better diagnostic tools,9 increasingly recognized cardiomyopathy leading to HFpEF. A specific form of often severe HFpEF is transthyretin cardiac amyloidosis.10 One in 20 patients with severe left ventricular hypertrophy have transthyretin cardiac amyloidosis as the underlying cause.11,12 It has recently been reported in patients with aortic stenosis, but its prevalence and phenotype are not known.13 In their article entitled ‘Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement’, Adam Castaño and colleagues from the New York University School of Medicine in the USA examined elderly patients with severe symptomatic aortic stenosis undergoing transcatheter aortic valve replacement or TAVI, and determined the prevalence and phenotype of transthyretin cardiac amyloidosis non-invasively.14 They prospectively performed 99m technetium pyrophosphate cardiac scintigraphy as well as transthoracic echocardiography and speckle-strain imaging on patients undergoing TAVI to screen for transthyretin cardiac amyloidosis. Among 151 patients with a mean age of 84 years, 24 (16%) screened positive for transthyretin cardiac amyloidosis based on 99m technetium pyrophosphate scintigraphy. Compared with patients without the condition, those with transthyretin cardiac amyloidosis had a thicker interventricular septum, a higher left ventricular mass index, lower stroke volume index, and advanced diastolic dysfunction with higher E/A ratios and lower deceleration time. Further, they exhibited a lower ejection fraction of 48% compared with 56% in those without amyloidosis, reduced myocardial contraction fraction, and a lower average lateral and septal mitral annular tissue Doppler S'. While global longitudinal strain was further reduced in amyloidosis patients compared with those without it, the relative apical longitudinal strain was the same regardless of the presence or absence of transthyretin cardiac amyloidosis. Average S' best predicted transthyretin cardiac amyloidosis in multivariable logistic regression, with an impressive odds ratio of 16.67 per 1 cm/s decrease and with an area under the curve in the receiver operating characteristic (ROC) analysis of 0.96, with a value <6 conferring 100% sensitivity for predicting a positive 99m technetium pyrophosphate scan (Figure 1). Thus, transthyretin cardiac amyloidosis is notable in 16% of patients with severe calcific aortic stenosis undergoing TAVI and is associated with a low-flow low-gradient phenotype with mildly reduced ejection fraction. An average tissue Doppler mitral annular S' of <6 cm/s may be a sensitive measure that should prompt a confirmatory 99m technetium pyrophosphate scan and subsequent testing for transthyretin cardiac amyloidosis. Prospective assessment of outcomes after transcatheter aortic valve replacement are now needed in patients with and without transthyretin cardiac amyloidosis. These clinically relevant findings are further discussed in an Editorial by Pasquale Perrone-Filardi from the Federico II University of Naples, in Italy.15 Predictors of ATTR-CA in elderly patients undergoing transcatheter aortic valve replacement. Quantitative assessment of technetium-99m pyrophosphate myocardial uptake (A) is shown in a patient with (bottom) and without ATTR-CA (top) with corresponding H/CL ratio. ROC curves for predictors of ATTR-CA (B) DT, deceleration time; H/CL, heart-to-contralateral ratio; MCF, myocardial contraction fraction; VMR, voltage-mass ratio; ATTR-CA, transthyretin cardiac amyloidosis (from Castãno A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, Rubin J, Chiuzan C, Nazif T, Vahl T, George I, Kodali S, Leon MB, Hahn R, Bokhari S, Maurer MS. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. See pages 2879–2887). Predictors of ATTR-CA in elderly patients undergoing transcatheter aortic valve replacement. Quantitative assessment of technetium-99m pyrophosphate myocardial uptake (A) is shown in a patient with (bottom) and without ATTR-CA (top) with corresponding H/CL ratio. ROC curves for predictors of ATTR-CA (B) DT, deceleration time; H/CL, heart-to-contralateral ratio; MCF, myocardial contraction fraction; VMR, voltage-mass ratio; ATTR-CA, transthyretin cardiac amyloidosis (from Castãno A, Narotsky DL, Hamid N, Khalique OK, Morgenstern R, DeLuca A, Rubin J, Chiuzan C, Nazif T, Vahl T, George I, Kodali S, Leon MB, Hahn R, Bokhari S, Maurer MS. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. See pages 2879–2887). Medication prescribed to patients suffering from chronic heart failure such as diuretics16 or inhibitors of the renin–angiotensin–aldosterone system17 carries an increased risk of impaired potassium homeostasis, a condition associated with potentially dangerous arrhythmias. While diuretics are used in all forms of heart failure for symptom relief, particularly in HFrEF and heart failure with mid-range ejection fraction (HFmrEF), mineralocorticoid antagonsist are prescribed to improve outcomes.18 In their article ‘Associations of serum potassium levels with mortality in chronic heart failure patients’,19 Mette Aldahl and colleagues from the Aalborg Universitetshospital in Denmark examined the relationship between different levels of serum potassium and mortality among 19 549 patients with chronic heart failure who had a measurement of potassium within 90 days after initiating loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, both altering potassium levels particularly at higher dosages.20 In multivariable adjusted analysis, patients with the following potassium levels had an increased risk of all-cause mortality: 2.8–3.4 mmol/L with a hazard ratio of 3.16, 3.5–3.8 mmol/L with a hazard ratio of 1.62, 3.9–4.1 mmol/L with a hazard ratio of 1.29, 4.8–5.0 mmol/L with a hazard ratio of 1.34, 5.1–5.5 mmol/L with a hazard ratio of 1.60, and 5.6–7.4 mmol/L with a hazard ratio of 3.31 (Figure 2). Thus, in chronic heart failure patients, potassium levels within both the lower and upper levels of the normal range were associated with a significantly increased short-term risk of death. Likewise, potassium below 3.5 mmol/L and above 5.0 mmol/L was also associated with increased mortality. These intriguing findings are further discussed in an educational Editorial by Bertram Pitt from the University of Michigan in Ann Arbor, USA.21 Restricted cubic spline curve showing the adjusted hazard ratios for all-cause mortality as a function of potassium concentration. Knots the 10th, 25th, 50th, 75th, and 90th percentiles of potassium. Model adjusted for sex, age, acute myocardial infarction, chronic obstructive pulmonary disease, diabetes, ICD, relevant concomitant pharmacotherapy (beta-blockers, mineralocorticoid receptor antagonists, thiazides, digoxin and potassium supplements) and a high serum creatinine level. At the figure, the frequency distribution of potassium is shown (from Aldahl M, Caroline Jensen A-S, Davidsen L, Eriksen MA, Møller Hansen S, Nielsen BJ, Krogager ML, Køber L, Torp-Pedersen C, Søgaard P. Associations of serumpotassiumlevels with mortality in chronic heart failure patients. See pages 2890–2896). Restricted cubic spline curve showing the adjusted hazard ratios for all-cause mortality as a function of potassium concentration. Knots the 10th, 25th, 50th, 75th, and 90th percentiles of potassium. Model adjusted for sex, age, acute myocardial infarction, chronic obstructive pulmonary disease, diabetes, ICD, relevant concomitant pharmacotherapy (beta-blockers, mineralocorticoid receptor antagonists, thiazides, digoxin and potassium supplements) and a high serum creatinine level. At the figure, the frequency distribution of potassium is shown (from Aldahl M, Caroline Jensen A-S, Davidsen L, Eriksen MA, Møller Hansen S, Nielsen BJ, Krogager ML, Køber L, Torp-Pedersen C, Søgaard P. Associations of serumpotassiumlevels with mortality in chronic heart failure patients. See pages 2890–2896). HFrEF is mainly caused by coronary artery disease and infarction, but a significant proportion of patients, particularly among the young, have cardiomyopathies of various origins as the underlying disease.22,23 In a further paper entitled ‘Haemodynamic profiles of children with end-stage heart failure’, Sharon Chen and colleagues from the Stanford University in Palo Alto, California evaluated associations between haemodynamic profiles and symptoms, end-organ function, and outcome in children listed for heart transplantation.24 As many as 1059 children younger than 18 with a median age of 7 years, half of them with dilated cardiomyopathy, listed for heart transplant with invasive haemodynamic data including pulmonary capillary wedge pressure, right atrial pressure, and cardiac index being available were analysed. Overall, 58% had congestion as reflected by a pulmonary capillary wedge pressure >15 mmHg, 28% had severe congestion with a wedge pressure >22 mmHg, and 22% had a low cardiac index <2.2 L/min/m2. Twenty-one per cent met the combined primary outcome of death or clinical deterioration. In multivariable analysis, worse NYHA class or Ross classification was associated with increased pulmonary capillary wedge pressure with an odds ratio of 1.03, renal dysfunction with increased right atrial pressure with an odds ratio of 1.04, and hepatic dysfunction with both increased pulmonary capillary wedge pressure with an odds ratio of 1.03 and increased right atrial pressure with an odds ratio of 1.09. There were no associations with low cardiac index. Death or clinical deterioration was strongly associated with severe congestion with an odds ratio of 1.6, but not with cardiac index alone. However, children with both low cardiac index and severe congestion were at the highest risk, with an odds ratio of 1.9. Thus, in children with end-stage heart failure, congestion is more common than low cardiac index and correlates with NYHA and Ross classification and end-organ dysfunction. Children with both congestion and a low cardiac index have the highest risk of death or clinical deterioration. These findings are put into context in an Editorial by Robert M. Blanton of the Tufts Medical Center in Boston, Massachusetts.25 The editors hope that readers of this issue of the European Heart Journal will find it of interest.