Early Initiation of Sacubitril/Valsartan in Patients With Acute Heart Failure and Renal Dysfunction: An Analysis of the TRANSITION Study.

BACKGROUND: Treatment of patients with heart failure with reduced ejection fraction (HFrEF) and renal dysfunction (RD) is challenging owing to the risk of further deterioration in renal function, especially after acute decompensated HF (ADHF). METHODS AND RESULTS: We assessed the effect of RD (estimated glomerular filtration rate of ≥30 to <60 mL/min/1.73 m2) on initiation, up-titration, and tolerability of sacubitril/valsartan in hemodynamically stabilized patients with HFrEF admitted for ADHF (RD, n = 476; non-RD, n = 483). At week 10, the target dose of sacubitril/valsartan (97/103 mg twice daily) was achieved by 42% patients in RD subgroup vs 54% in non-RD patients (P < .001). Sacubitril/valsartan was associated with greater estimated glomerular filtration rate improvements in RD subgroup than non-RD (change from baseline least squares mean 4.1 mL/min/1.73 m2, 95% confidence interval 2.2-6.1, P < .001). Cardiac biomarkers improved significantly in both subgroups; however, compared with the RD subgroup, the improvement was greater in those without RD (N-terminal pro-brain natriuretic peptide, -28.6% vs -44.8%, high-sensitivity troponin T -20.3% vs -33.9%) (P < .001). Patients in the RD subgroup compared with those without RD experienced higher rates of hyperkalemia (16.3% vs 6.5%, P < .001), investigator-reported cardiac failure (9.7% vs 5.6%, P = .029), and renal impairment (6.4% vs 2.1%, P = .002). CONCLUSIONS: Most patients with HFrEF and concomitant RD hospitalized for ADHF tolerated early initiation of sacubitril/valsartan and showed significant improvements in estimated glomerular filtration rate and cardiac biomarkers. CLINICAL TRIAL REGISTRATION: NCT02661217.

Development and validation of a model to predict ceiling of care in COVID-19 hospitalized patients.

BACKGROUND: Therapeutic ceiling of care is the maximum level of care deemed appropiate to offer to a patient based on their clinical profile and therefore their potential to derive benefit, within the context of the availability of resources. To our knowledge, there are no models to predict ceiling of care decisions in COVID-19 patients or other acute illnesses. We aimed to develop and validate a clinical prediction model to predict ceiling of care decisions using information readily available at the point of hospital admission. METHODS: We studied a cohort of adult COVID-19 patients who were hospitalized in 5 centres of Catalonia between 2020 and 2021. All patients had microbiologically proven SARS-CoV-2 infection at the time of hospitalization. Their therapeutic ceiling of care was assessed at hospital admission. Comorbidities collected at hospital admission, age and sex were considered as potential factors for predicting ceiling of care. A logistic regression model was used to predict the ceiling of care. The final model was validated internally and externally using a cohort obtained from the Leeds Teaching Hospitals NHS Trust. The TRIPOD Checklist for Prediction Model Development and Validation from the EQUATOR Network has been followed to report the model. RESULTS: A total of 5813 patients were included in the development cohort, of whom 31.5% were assigned a ceiling of care at the point of hospital admission. A model including age, COVID-19 wave, chronic kidney disease, dementia, dyslipidaemia, heart failure, metastasis, peripheral vascular disease, chronic obstructive pulmonary disease, and stroke or transient ischaemic attack had excellent discrimination and calibration. Subgroup analysis by sex, age group, and relevant comorbidities showed excellent figures for calibration and discrimination. External validation on the Leeds Teaching Hospitals cohort also showed good performance. CONCLUSIONS: Ceiling of care can be predicted with great accuracy from a patient's clinical information available at the point of hospital admission. Cohorts without information on ceiling of care could use our model to estimate the probability of ceiling of care. In future pandemics, during emergency situations or when dealing with frail patients, where time-sensitive decisions about the use of life-prolonging treatments are required, this model, combined with clinical expertise, could be valuable. However, future work is needed to evaluate the use of this prediction tool outside COVID-19.

The role of cardiopulmonary exercise testing and echocardiography prior to elective endovascular aneurysm repair.

INTRODUCTION: Cardiopulmonary exercise testing (CPET) and transthoracic echocardiography (TTE) are common preparative investigations prior to elective endovascular aneurysm repair (EVAR). Whether these investigations can predict survival following EVAR and contribute to shared decision making is unknown. METHODS: Patients who underwent EVAR at a tertiary centre between June 2007 and December 2014 were identified from the National Vascular Registry. Variables obtained from preoperative investigations were assessed for their association with survival at three years. Regression analysis was used to determine variables that independently predicted survival at three years. RESULTS: A total of 199 patients underwent EVAR during the study period. Of these, 120 had preoperative CPET and 123 had TTE. Lower forced expiratory ventilation (FEV1), ratio of FEV1 to forced vital capacity, work at peak oxygen consumption and higher ventilatory equivalent for carbon dioxide were associated with increased mortality. Variables obtained from TTE were not associated with survival at three years although there was a low incidence of left ventricular systolic dysfunction and significant valvular disease in this cohort. CONCLUSIONS: CPET might be a useful adjunct to assist in shared decision making in patients undergoing elective EVAR and may influence anaesthetic technique. TTE does not appear to be able to discriminate between high and low risk individuals. However, a low rate of significant ventricular dysfunction and valvular disease in patients undergoing elective EVAR may account for these findings.

Chronic heart failure and micronutrients.

Heart failure (HF) is associated with weight loss, and cachexia is a well-recognized complication. Patients have an increased risk of osteoporosis and lose muscle bulk early in the course of the disease. Basal metabolic rate is increased in HF, but general malnutrition may play a part in the development of cachexia, particularly in an elderly population. There is evidence for a possible role for micronutrient deficiency in HF. Selective deficiency of selenium, calcium and thiamine can directly lead to the HF syndrome. Other nutrients, particularly vitamins C and E and beta-carotene, are antioxidants and may have a protective effect on the vasculature. Vitamins B6, B12 and folate all tend to reduce levels of homocysteine, which is associated with increased oxidative stress. Carnitine, co-enzyme Q10 and creatine supplementation have resulted in improved exercise capacity in patients with HF in some studies. In this article, we review the relation between micronutrients and HF. Chronic HF is characterized by high mortality and morbidity, and research effort has centered on pharmacological management, with the successful introduction of angiotensin-converting enzyme inhibitors and beta-adrenergic antagonists into routine practice. There is sufficient evidence to support a large-scale trial of dietary micronutrient supplementation in HF.

Clinical trials update: highlights of the scientific sessions of the American Heart Association year 2000: Val HeFT, COPERNICUS, MERIT, CIBIS-II, BEST, AMIOVIRT, V-MAC, BREATHE, HEAT, MIRACL, FLORIDA, VIVA and the first human cardiac skeletal muscle myoblast transfer for heart failure.

This article continues a series of reports summarising recent research developments pertinent to the topic of heart failure. This is a summary of presentations made at scientific sessions of the American Heart Association in November 2000. Clinical studies of particular interest to people caring for patients with heart failure include Val-HeFT, AMIOVIRT and V-MAC. New data from beta-blockers trials are reviewed, highlights from some important developments in post-infarction care, including MIRACL and FLORIDA, discussed and results of some early studies of gene therapy reported.

Prospective development and validation of a model to predict heart failure hospitalisation.

OBJECTIVE: Acute heart failure syndrome (AHFS) is a major cause of hospitalisation and imparts a substantial burden on patients and healthcare systems. Tools to define risk of AHFS hospitalisation are lacking. METHODS: A prospective cohort study (n=628) of patients with stable chronic heart failure (CHF) secondary to left ventricular systolic dysfunction was used to derive an AHFS prediction model which was then assessed in a prospectively recruited validation cohort (n=462). RESULTS: Within the derivation cohort, 44 (7%) patients were hospitalised as a result of AHFS during 1 year of follow-up. Predictors of AHFS hospitalisation included furosemide equivalent dose, the presence of type 2 diabetes mellitus, AHFS hospitalisation within the previous year and pulmonary congestion on chest radiograph, all assessed at baseline. A multivariable model containing these four variables exhibited good calibration (Hosmer-Lemeshow p=0.38) and discrimination (C-statistic 0.77; 95% CI 0.71 to 0.84). Using a 2.5% risk cut-off for predicted AHFS, the model defined 38.5% of patients as low risk, with negative predictive value of 99.1%; this low risk cohort exhibited <1% excess all-cause mortality per annum when compared with contemporaneous actuarial data. Within the validation cohort, an identically applied model derived comparable performance parameters (C-statistic 0.81 (95% CI 0.74 to 0.87), Hosmer-Lemeshow p=0.15, negative predictive value 100%). CONCLUSIONS: A prospectively derived and validated model using simply obtained clinical data can identify patients with CHF at low risk of hospitalisation due to AHFS in the year following assessment. This may guide the design of future strategies allocating resources to the management of CHF.

Excessive breathlessness in patients with diastolic heart failure.

OBJECTIVES: To establish the prevalence of preserved left ventricular (LV) systolic function (PSF) in 435 consecutive symptomatic patients referred to a heart failure clinic and to examine their ventilatory response to exercise when compared with 134 control volunteers. METHODS: 216 (50%) patients had systolic heart failure (SHF) (ejection fraction < 45%). 51 (11%) had an immediately apparent alternative causes of breathlessness and 168 (39%), with no obvious other cause of breathlessness, were divided into those with PSF and diastolic dysfunction (DD) (PSF(DD); n = 113 or 26% of referrals) and those without DD (PSF(N); n = 55 or 13% of referrals). The controls were divided into those with (C(DD); n = 32) and those without (C(N); n = 102) echocardiographic evidence of DD. RESULTS: Patients with SHF had lower peak oxygen consumption (pVo(2)), steeper slope of minute ventilation (Ve) to carbon dioxide production, lower exercise time and shorter 6 min walk test than PSF patients and controls. PSF(DD) patients had lower pVo(2), exercise time and 6 min walk test than C(DD), although their echocardiograms were not different. Exercise capacity did not differ between PSF(DD) and PSF(N) patients. The slope relating Ve to symptoms (Borg/Ve slope) was less steep in those with SHF than in PSF(DD) (0.17 (0.04) v 0.20 (0.08), p < 0.05) and in PSF(N) (0.19 (0.10), p < 0.05), implying greater symptoms of breathlessness for a given level of Ve. Both PSF groups had a steeper slope than C(DD) (0.14 (0.09), p < 0.05 for both comparisons). CONCLUSIONS: Patients with PSF have exercise tolerance intermediate between that of patients with SHF and controls. Exercise tolerance is similar in PSF(DD) and PSF(N). Both groups have worse exercise tolerance than C(DD). PSF(DD) and PSF(N) patients seem to experience a greater awareness of Ve than C(DD) and patients with SHF.

Chronic heart failure, chronotropic incompetence, and the effects of beta blockade.

OBJECTIVE: To establish the prevalence of chronotropic incompetence in a cohort of patients with chronic heart failure (CHF) taking modern medications for heart failure, and whether this affected exercise capacity and predicted prognosis. METHODS: Heart rate response to exercise was examined in 237 patients with CHF in sinus rhythm, who were compared with 118 control volunteers. The percentage of maximum age predicted peak heart rate (%Max-PPHR) and percentage heart rate reserve (%HRR) were calculated, with a cut off of < 80% as the definition of chronotropic incompetence for both. Patients were followed up for an average (SD) of 2.8 (9) years. Mortality was related to peak oxygen consumption (pVo2), and the presence or absence of chronotropic incompetence. RESULTS: %Max-PPHR < 80% identified 103 (43%) and %HRR < 80% identified 170 patients (72%) as having chronotropic incompetence. Chronotropic incompetence was more common in patients taking beta blockers than in those not taking beta blockers as assessed by both methods (80 (49%) v 23 (32%) by %Max-PPHR and 123 (75%) v 47 (64%) by %HRR, respectively). Patients with chronotropic incompetence by either method had a lower pVo2 than those without. These differences remained significant for both patients taking and not taking a beta blocker. %HRR, Max-PPHR%, and HRR were related to New York Heart Association class and correlated with pVo2. There was no difference in the slopes relating heart rate to pVo2 between patients with and those without chronotropic incompetence (6.1 (1.7) v 5.1 (1.8), p = 0.34). During an average 2.8 year follow up 40 patients (17%) died. In Cox proportional hazard models, pVo2 was the most powerful predictor of survival and neither measure of chronotropic incompetence independently predicted outcome. CONCLUSIONS: pVo2 is a powerful marker of prognosis for patients with CHF whether they are taking beta blockers or not. A low heart rate response to exercise in patients with CHF correlates with worse exercise tolerance but is unlikely to contribute to exercise impairment.

Exercise capacity and cardiac function assessed by tissue Doppler imaging in chronic heart failure.

OBJECTIVE: To examine the relation between longitudinal left ventricular function assessed by tissue Doppler imaging (TDi) and exercise capacity in heart failure. SUBJECTS: 153 patients with chronic heart failure from left ventricular systolic dysfunction (ejection fraction < 45%) and 87 age and sex matched controls. METHODS: Echocardiography was used to measure conventional indices of left ventricular systolic function. TDi was used to assess left and right ventricular longitudinal function by measuring mitral and lateral tricuspid annular velocities during the cardiac cycle. Velocities measured at each point were the systolic peak (S(m)) and the diastolic troughs (E(m) and A(m)), corresponding to passive and active (atrial) left ventricular filling. Each patient also underwent treadmill exercise testing with metabolic gas exchange measurements. RESULTS: Left and right ventricular TDi velocities were greater in controls than in patients. Left ventricular ejection fraction (LVEF) correlated with S(m) (r = 0.30, p = 0.0005), but not with E(m), A(m), or the E(m)/A(m) ratio. There were no significant differences between New York Heart Association (NYHA) functional class for any of the TDi variables. Right ventricular indices were not related to exercise capacity. Systolic myocardial motion measured by TDi correlated more closely with peak oxygen consumption (pVO2) (r = 0.35, p < 0.0001) than LVEF (r = 0.21, p < 0.02). The E(m)/A(m) ratio was not correlated with pVO2. In multiple regression, S(m) was the only left ventricular TDi variable to predict exercise capacity independently (p < 0.05). CONCLUSIONS: Exercise capacity and symptoms are poorly related to conventional measures of cardiac function and more closely correlated with indices of longitudinal left ventricular function as assessed by TDi.

Pattern of ventilation during exercise in chronic heart failure.

OBJECTIVE: To determine the pattern of the abnormal ventilatory response in heart failure and how it relates to symptoms by looking at tidal volume (VT) and frequency (f) during exercise. METHODS: 45 patients with heart failure and 21 controls underwent maximal treadmill based exercise testing with metabolic gas exchange analysis. The relation of ventilation (VE) to VT was plotted to look for an inflection point where VT failed to increase further. The slope of the relation before this inflection point was documented. Time to the inflection point, VT, and f at the inflection point were recorded. The relation of symptom scores to f and E was also examined. RESULTS: Peak oxygen consumption (PVO2) (mean (SD)) was lower (19.7 (4.5) v 37.9 (8.6) ml/kg/min; p < 0001) and the ventilation to carbon dioxide production (VE/VCO2) slope was steeper (40.0 (6.5) v 26.0 (1.6); p < 0.0001) in patients with heart failure than in the control group. The patients reached the inflection point of the VE/VT slope sooner during exercise than the controls (271 (110) v 502 (196) seconds; p < 0.0001). Patients had a higher f and a smaller VT at that point and throughout exercise until the peak where f was the same for patients and controls. VT at the inflection point correlated with PVO2 (r = 0.67; p < 0.0001). Despite having an increased sensation of breathlessness for a given E, patients were less symptomatic of f than controls. CONCLUSIONS: Patients with heart failure breathe at a higher f throughout exercise, reaching an apparent maximal VT earlier. The VT at an inflection point on the VE/VT slope predicts PVO2.

The effects of alpha and beta blockade on ventilatory responses to exercise in chronic heart failure.

OBJECTIVE: To assess the influence of acute alpha and beta blockade on ventilation and symptoms of breathlessness during exercise in patients with chronic heart failure and in controls. METHODS: 11 patients with chronic heart failure and 11 control subjects underwent repeated exercise testing with metabolic gas exchange after random, double blind administration of either an alpha blocker and placebo, a beta blocker and a placebo, both an alpha blocker and a beta blocker, or double placebo. RESULTS: Patients had a lower peak oxygen consumption (mean (SD) 20.7 (4.9) v 37.6 (9.6) ml/kg/min, p < 0.0001) and a steeper slope relating ventilation to carbon dioxide production (VE/CO2 slope) (26.5 (4.1) v 37.1 (8.2), p = 0.0011), than controls. Blood pressure was lower following alpha and beta blockade (p < 0.05) and the gradients of the slopes relating heart rate to oxygen consumption following the beta blocker were reduced (p < 0.05). Exercise time and peak ventilatory variables following beta or alpha blockers were unchanged. Ventilation was reduced during submaximal exercise following the active medications. Combined alpha and beta blockade produced the greatest difference (p < 0.005), but the alpha and beta blockers alone also reduced ventilation (p < 0.05). There was no difference in perceived exertion during exercise with any of the treatments. CONCLUSION: Acute sympathetic inhibition can reduce submaximal ventilation during exercise in patients with heart failure and control subjects, suggesting that autonomic nervous system activation has an important role in the abnormal ventilatory response to exercise in chronic heart failure.

Effect of age and sex on left atrial morphology and function.

AIMS: Left atrial function is abnormal in a wide range of cardiac diseases. This study was designed to assess the effects of normal ageing and sex on left atrial morphology and function. METHODS AND RESULTS: Echocardiography was performed in 123 subjects (age 57 +/- 19 years, range 22 to 89 years, 59 women) with no evidence of cardiovascular disease. M-mode derived left atrial size, B-mode derived left atrial maximal and minimal volumes, and the volume at onset of atrial systole (P-volume) were measured. Left atrial filling, active and passive emptying volumes and ejections fractions, and expansion index were calculated. Subjects were divided into four groups according to age. Left atrial diameter increased with age, with significantly smaller left atrial size in younger subjects. The oldest subjects had significantly higher (P<0.05) left atrial minimal, maximal and P-volume indices. Filling volume index was highest in the oldest subjects (21.9 +/- 5.6 ml/m(2)). Passive emptying volume index was the lowest in those of middle age (10.5 +/- 2.8 ml/m(2)). Active emptying volume index progressively increased with age (P<0.001). Left atrial expansion index and active emptying fraction were not different between the age groups. There was significant difference in passive emptying fraction (P<0.001) with highest values in the youngest (44.7 +/- 7.3%) and lowest values in the oldest subjects (33.6+/-5.4%). CONCLUSIONS: Age- and sex-related reference values of echocardiographic indices of left atrial morphology and function are reported. Ageing is associated with left atrial dilatation. Left atrial conduit function deteriorates with age while reservoir and pump function are maintained. Left atrial anteroposterior diameter is smaller in women than in men, but overall left atrial function is not influenced by sex.