Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.

OBJECTIVES: Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). METHODS: We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. RESULTS: Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. CONCLUSIONS: Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.

Are non-invasive estimations of plasma volume an accurate measure of congestion in patients with chronic heart failure?

AIMS: We report associations between different formulae for estimating plasma volume status (PVS) and clinical and ultrasound markers of congestion in patients with chronic heart failure (CHF) enrolled in the Hull Lifelab registry. METHODS AND RESULTS: Cohort 1 comprised patients with data on signs and symptoms at initial evaluation (n = 3505). Cohort 2 included patients with ultrasound assessment of congestion [lung B-line count, inferior vena cava (IVC) diameter, jugular vein distensibility (JVD) ratio] (N = 341). Two formulae for PVS were used: (a) Hakim (HPVS) and (b) Duarte (DPVS). Results were compared with clinical and ultrasound markers of congestion. Outcomes assessed were mortality and the composite of heart failure (HF) hospitalisation and all-cause mortality. In cohort 1, HPVS was associated with mortality [hazard ratio (HR) per unitary increase = 1.02 (1.01-1.03); P < 0.001]. In cohort 2, HPVS was associated with B-line count (HR) = 1.05 [95% confidence interval (CI) (1.01-1.08); P = 0.02] and DPVS with the composite outcome [HR = 1.26 (1.01-1.58); P = 0.04]. HPVS and DPVS were strongly related to haemoglobin concentration and HPVS to weight. After multivariable analysis, there were no strong or consistent associations between PVS and measures of congestion, severity of symptoms, or outcome. By contrast, log[NTproBNP] was strongly associated with all three. CONCLUSION: Amongst patients with CHF, HPVS and DPVS are not strongly or consistently associated with clinical or ultrasound evidence of congestion, nor clinical outcomes after multivariable adjustment. They appear only to be surrogates of the variables from which they are calculated with no intrinsic clinical utility.

Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise-CISCO-21.

BACKGROUND: Coronavirus disease-19 (COVID-19) infection causes persistent health problems such as breathlessness, chest pain and fatigue, and therapies for the prevention and early treatment of post-COVID-19 syndromes are needed. Accordingly, we are investigating the effect of a resistance exercise intervention on exercise capacity and health status following COVID-19 infection. METHODS: A two-arm randomised, controlled clinical trial including 220 adults with a diagnosis of COVID-19 in the preceding 6 months. Participants will be classified according to clinical presentation: Group A, not hospitalised due to COVID but persisting symptoms for at least 4 weeks leading to medical review; Group B, discharged after an admission for COVID and with persistent symptoms for at least 4 weeks; or Group C, convalescing in hospital after an admission for COVID. Participants will be randomised to usual care or usual care plus a personalised and pragmatic resistance exercise intervention for 12 weeks. The primary outcome is the incremental shuttle walks test (ISWT) 3 months after randomisation with secondary outcomes including spirometry, grip strength, short performance physical battery (SPPB), frailty status, contacts with healthcare professionals, hospitalisation and questionnaires assessing health-related quality of life, physical activity, fatigue and dyspnoea. DISCUSSION: Ethical approval has been granted by the National Health Service (NHS) West of Scotland Research Ethics Committee (REC) (reference: GN20CA537) and recruitment is ongoing. Trial findings will be disseminated through patient and public forums, scientific conferences and journals. TRIAL REGISTRATION: ClinicialTrials.gov NCT04900961 . Prospectively registered on 25 May 2021.

Hypochloraemia following admission to hospital with heart failure is common and associated with an increased risk of readmission or death: a report from OPERA-HF.

AIMS: Hypochloraemia is common in patients hospitalized with heart failure (HF) and associated with a high risk of adverse outcomes during admission and following discharge. We assessed the significance of changes in serum chloride concentrations in relation to serum sodium and bicarbonate concentrations during admission in a cohort of 1002 consecutive patients admitted with HF and enrolled into an observational study based at a single tertiary centre in the UK. METHODS AND RESULTS: Hypochloraemia (<96 mmol/L), hyponatraemia (<135 mmol/L), and metabolic alkalosis (bicarbonate >32 mmol/L) were defined by local laboratory reference ranges. Outcomes assessed were all-cause mortality, all-cause mortality or all-cause readmission, and all-cause mortality or HF readmission. Cox regression and Kaplan-Meier curves were used to investigate associations with outcome. During a median follow-up of 856 days (interquartile range 272-1416), discharge hypochloraemia, regardless of serum sodium, or bicarbonate levels was associated with greater all-cause mortality [hazard ratio (HR) 1.44, 95% confidence interval (CI) 1.15-1.79; P = 0.001], all-cause mortality or all-cause readmission (HR 1.26, 95% CI 1.04-1.53; P = 0.02), and all-cause mortality or HF readmission (HR 1.41, 95% CI 1.14-1.74; P = 0.002) after multivariable adjustment. Patients with concurrent hypochloraemia and natraemia had lower haemoglobin and haematocrit, suggesting congestion; those with hypochloraemia and normal sodium levels had more metabolic alkalosis, suggesting decongestion. CONCLUSION: Hypochloraemia is common at discharge after a hospitalization for HF and is associated with worse outcome subsequently. It is an easily measured clinical variables that is associated with morbidity or mortality of any cause.

Mode of presentation and mortality amongst patients hospitalized with heart failure? A report from the First Euro Heart Failure Survey.

BACKGROUND: Heart failure is heterogeneous in aetiology, pathophysiology, and presentation. Despite this diversity, clinical trials of patients hospitalized for HF deal with this problem as a single entity, which may be one reason for repeated failures. METHODS: The first EuroHeart Failure Survey screened consecutive deaths and discharges of patients with suspected heart failure during 2000-2001. Patients were sorted into seven mutually exclusive hierarchical presentations: (1) with cardiac arrest/ventricular arrhythmia; (2) with acute coronary syndrome; (3) with rapid atrial fibrillation; (4) with acute breathlessness; (5) with other symptoms/signs such as peripheral oedema; (6) with stable symptoms; and (7) others in whom the contribution of HF to admission was not clear. RESULTS: The 10,701 patients enrolled were classified into the above seven presentations as follows: 260 (2%), 560 (5%), 799 (8%), 2479 (24%), 1040 (10%), 703 (7%), and 4691 (45%) for which index-admission mortality was 26%, 20%, 10%, 8%, 6%, 6%, and 4%, respectively. Compared to those in group 7, the hazard ratios for death during the index admission were 4.9 (p ≤ 0.001), 4.0 (p < 0.001), 2.2 (p < 0.001), 2.1 (p < 0.001), 1.4 (p < 0.04) and 1.4 (p = 0.04), respectively. These differences were no longer statistically significant by 12 weeks. CONCLUSION: There is great diversity in the presentation of heart failure that is associated with very different short-term outcomes. Only a minority of hospitalizations associated with suspected heart failure are associated with acute breathlessness. This should be taken into account in the design of future clinical trials.

Dynamic risk stratification using serial measurements of plasma concentrations of natriuretic peptides in patients with heart failure.

BACKGROUND: Prognostic models for patients with chronic heart failure are generally based on a single assessment but treatment is often given with the intention of changing risk; re- evaluation of risk is an important aspect of care. The prognostic value of serial measurements of natriuretic peptides for the assessment of changes in risk is uncertain. AIMS: To evaluate the prognostic value of serial measurements of plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP) during follow-up of out-patients with chronic heart failure (CHF). METHODS: Patients diagnosed with CHF between 2001 and 2014 at a single out-patient clinic serving a local community were included in this analysis. NT-proBNP was measured at the initial visit and serially during follow-up. Only patients who had one or more measurements of NT-proBNP after baseline, at 4, 12 and/or 24 months were included. RESULTS: At baseline, amongst 1998 patients enrolled, the median age was 73 (IQR: 64-79) years, 70% were men, 31% were in NYHA class III/IV, and 77% had NT-proBNP >400 pg/mL. Median follow-up was 4.8 (IQR: 2.5-8.6) years. Serial measurements of NT-proBNP improved prediction of all-cause mortality at 3 years (c- statistic = 0.71) compared with using baseline data only (c-statistic = 0.67; p < 0.001) but a model using only the most recent NT-proBNP had an even higher c-statistic (0.72; p < 0.001). Similar results were obtained based on long-term prediction of mortality using all available follow-up data. CONCLUSIONS: Serial measurement of NT-proBNP in patients with CHF improves prediction of all-cause mortality. However, using the most recent value of NT-proBNP has similar predictive power as using serial measurements.

Estimated peak functional capacity: an accurate method for assessing change in peak oxygen consumption after cardiac rehabilitation?

OBJECTIVE: Cardiopulmonary exercise testing (CPET) is the 'gold standard' method of determining VO2peak . When CPET is unavailable, VO2peak may be estimated from treadmill or cycle ergometer workloads and expressed as estimated metabolic equivalents (METs). Cardiac rehabilitation (CR) programmes use estimated VO2peak (METs) to report changes in cardiorespiratory fitness (CRF). However, the accuracy of determining changes in VO2peak based on estimated functional capacity is not known. METHODS: A total of 27 patients with coronary heart disease (88·9% male; age 59·5 ± 10·0 years, body mass index 29·6 ± 3·8 kg m-2 ) performed maximal CPET before and after an exercise-based CR intervention. VO2peak was directly determined using ventilatory gas exchange data and was also estimated using the American College of Sports Medicine (ACSM) leg cycling equation. Agreement between changes in directly determined VO2peak and estimated VO2peak was evaluated using Bland-Altman limits of agreement (LoA) and intraclass correlation coefficients. RESULTS: Directly determined VO2peak did not increase following CR (0·5 ml kg-1 min-1 (2·7%); P = 0·332). Estimated VO2peak increased significantly (0·4 METs; 1·4 ml kg-1  min-1 ; 6·7%; P = 0·006). The mean bias for estimated VO2peak versus directly determined VO2peak was 0·7 ml kg-1  min-1 (LoA -4·7 to 5·9 ml  kg-1  min-1 ). Aerobic efficiency (ΔVO2 /ΔWR slope) was significantly associated with estimated VO2peak measurement error. CONCLUSION: Change in estimated VO2peak derived from the ACSM leg cycling equation is not an accurate surrogate for directly determined changes in VO2peak . Our findings show poor agreement between estimates of VO2peak and directly determined VO2peak . Applying estimates of VO2peak to determine CRF change may over-estimate the efficacy of CR and lead to a different interpretation of study findings.

Cardiac resynchronization therapy update: evolving indications, expanding benefit?

Cardiac resynchronisation therapy (CRT) is an effective intervention for appropriately selected patients with heart failure, but exactly how it works is uncertain. Recent data suggest that much, or perhaps most, of the benefits of CRT are not delivered by re-coordinating left ventricular dyssynchrony. Atrio-ventricular resynchronization, reduction in mitral regurgitation and prevention of bradycardia are other potential mechanisms of benefit that will vary from one patient to the next and over time. Because there is no single therapeutic target, it is unlikely that any single measure will accurately predict benefit. The only clinical characteristic that appears to be a useful predictor of the benefits of CRT is a QRS duration of >140 ms. Many new approaches are being developed to try to improve the effectiveness of and extend the indications for CRT. These include smart pacing algorithms, better pacing-site targeting, new sensors, multipoint pacing, remote device monitoring and leadless endocardial pacing. Whether CRT is effective in patients with atrial fibrillation or whether adding a defibrillator function to CRT improves prognosis awaits further evidence.

The effect of carvedilol on B-type natriuretic peptide and cardiac function in patients with heart failure and persistent atrial fibrillation.

OBJECTIVES: We sought to determine the relationship between changes in natriuretic peptides and symptoms as a consequence of introducing beta-blocker therapy, in patients with chronic heart failure (CHF) and persistent atrial fibrillation (AF). METHODS: In a randomised, double-blind, placebo-controlled study involving 47 patients with CHF and persistent AF (mean age 68 years and 62% men), we analysed the individual change (Δ) in B-type natriuretic peptide (BNP) level to the introduction of carvedilol (titrated to a target dose of 25 mg twice daily, group A) or placebo (group B) in addition to background treatment with digoxin. Symptoms score, 6-min walk distance, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), heart rate (24-hour ECG) and BNP were measured at baseline and at 4 months. RESULTS: LVEF (Δ median +5 vs. +0.4, p = 0.048), symptoms score (Δ median -4 vs. 0, p = 0.04), NYHA class (Δ median -33% vs. +3% in NYHA class 3-4, p = 0.046) and heart rate [Δ median 24-hour ventricular rate (VR) -19 vs. -2, p < 0.0001] improved with combination therapy of digoxin and carvedilol compared to digoxin alone, but BNP (Δ median +28 vs. -6 , p = 0.11) trended in the opposite direction. There was no relationship between the degree of symptomatic improvement or VR control and BNP response. CONCLUSION: After the introduction of carvedilol, clinical outcome appears unrelated to BNP changes in patients with CHF and AF. Changes in BNP cannot be used as a marker of clinical response in terms of symptoms or cardiac function in this setting.

Telemonitoring in heart failure: Big Brother watching over you.

Heart failure (HF) is a leading cause of hospitalisations in older people. Several strategies, supported by novel technologies, are now available to monitor patients' health from a distance. Although studies have suggested that remote monitoring may reduce HF hospitalisations and mortality, the study of different patient populations, the use of different monitoring technologies and the use of different endpoints limit the generalisability of the results of the clinical trials reported, so far. In this review, we discuss the existing home monitoring modalities, relevant trials and focus on future directions for telemonitoring.

Medical management of stable coronary atherosclerosis.

Revascularisation strategies involving coronary artery bypass grafting or percutaneous interventions are the main treatments for stable coronary artery disease, particularly for patients with ongoing symptoms despite medical therapy and/or extensive ischaemia as demonstrated by either non-invasive or invasive means. Irrespective of whether revascularisation is being undertaken, all patients with stable coronary disease require optimal medical therapy in order to reduce the risk of subsequent adverse cardiac events, particularly acute myocardial infarction. The role of medical management has been very actively investigated and reported, particularly because of the global disease burden and the associated high morbidity and mortality. In this review, the current available medical management for the treatment of coronary atherosclerosis is described together with the role and prospects of the newer classes of drugs that are coming into use, and future perspectives in this field.

Derivation and validation of a simple clinical risk-model in heart failure based on 6 minute walk test performance and NT-proBNP status--do we need specificity for sex and beta-blockers?

BACKGROUND: It is unclear whether risk prediction strategies in chronic heart failure (CHF) need to be specific for sex or beta-blockers. We examined this problem and developed and validated the consequent risk models based on 6-minute-walk-test and NT-proBNP. METHODS: The derivation cohort comprised 636 German patients with systolic dysfunction. They were validated against 676 British patients with similar aetiology. ROC-curves for 1-year mortality identified cut-off values separately for specificity (none, sex, beta-blocker, both). Patients were grouped according to number of cut-offs met (group I/II/III - 0/1/2 cut-offs). RESULTS: Widest separation between groups was achieved with sex- and beta-blocker-specific cut offs. In the derivation population, 1-year mortality was 0%, 8%, 31% for group I, II and III, respectively. In the validation population, 1-year rates in the three risk groups were 2%, 7%, 14%, respectively, after application of the same cut-offs. CONCLUSION: Risk stratification for CHF should perhaps take sex and beta-blocker usage into account. We derived and independently validated relevant risk models based on 6-minute-walk-tests and NT-proBNP. Specifying sex and use of beta-blockers identified three distinct sub-groups with widely differing prognosis. In clinical practice, it may be appropriate to tailor the intensity of follow-up and/or the treatment strategy according to the risk-group.

Unmasking the truth.

In the emergency setting, shortness of breath is a frequent presenting complaint to physicians worldwide. The differential diagnosis is often broad and requires careful analysis of investigations to reach the correct diagnosis. The authors present a case of acute heart failure with a number of unusual presenting features that suggested an uncommon aetiology.

A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFE-II Study).

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) often coexist. The aim was to investigate whether restoring sinus rhythm (SR) could improve cardiac function, symptoms, exercise capacity and quality of life (QoL) in patients with chronic heart failure. METHODS: Patients with HF and persistent AF receiving guideline-recommended treatments, including anticoagulants, were eligible for the study. Patients were randomised to either rhythm (treated with amiodarone for at least 3 months prior to attempting biphasic external cardioversion and continued amiodarone long-term if SR was restored) or rate control. Anticoagulants were continued throughout the study regardless of rhythm, unless contraindications developed. Both groups were treated with beta blockers and/or digoxin to reduce the heart rate to <80 bpm at rest and <110 bpm after walking. Symptoms, walk distance (6-minute corridor walk test, 6MWT), QoL and cardiac function were assessed at baseline and 1 year. RESULTS: 61 patients with HF and persistent AF (median duration 14 months (IQR 5 to 32)) were randomly assigned to a rate or rhythm control strategy. Of patients assigned to rhythm control (n = 30), 66% were in SR at 1 year, and 90% of those assigned to rate control (n = 31) achieved the heart rate target. At 1 year, NYHA class (p = 0.424) and 6MWT distance (p = 0.342) were similar between groups but patients assigned to rhythm control had improved LV function (p = 0.014), NT-proBNP concentration (p = 0.046) and QoL (p = 0.019) compared with those assigned to rate control. Greatest improvement was seen in patients in whom SR was maintained. CONCLUSION: Restoring SR in patients with AF and heart failure may improve QoL and LV function when compared with a strategy of rate control.

Elevated glycated haemoglobin is a strong predictor of mortality in patients with left ventricular systolic dysfunction who are not receiving treatment for diabetes mellitus.

BACKGROUND: Glycated haemoglobin (HbA1c) is an indicator of average blood glucose concentrations over the preceding 3 months, is simpler to perform than either a fasting glucose or glucose tolerance test and is associated with a worse prognosis in some clinical settings. However, its relationship to survival in patients with suspected heart failure has not been studied. METHODS: Patients referred to a community-based heart failure clinic with suspected heart failure had a comprehensive assessment including the measurement of HbA1c. For this analysis, patients with DM or who started diabetic medication in the subsequent 12 months, which might influence HbA1c, were excluded. FINDINGS: Of 970 non-diabetic patients referred between 2001 and 2004, the median age was 72 years (range 25 to 96 years), 56% were men, 45% had left ventricular ejection fraction (LVEF) 6% (upper reference limit). Among patients with LVEF 6.7% (n = 68) compared with those with HbA1c 45% (HR 1.44, p = 0.36 after adjustment). INTERPRETATION: The abrupt increase in mortality with HbA1c may make it a useful risk stratification tool in non-diabetic patients with LVEF

The prognostic value of individual NT-proBNP values in chronic heart failure does not change with advancing age.

BACKGROUND: It is unclear whether age-related increases in N-terminal pro-brain natriuretic peptide (NT-proBNP) represent a normal physiological process-possibly affecting the prognostic power-of NT-proBNP-or reflect age-related subclinical pathological changes. OBJECTIVE: To determine the effect of age on the short-term prognostic value of NT-proBNP in patients with chronic heart failure (CHF). DESIGN: Prospective observational study with inclusion and matching of consecutive patients aged >65 years (mean (SD) 73.1 (6.0) years) to patients <65 years (53.7 (8.6) years) with respect to NT-proBNP, New York Heart Association stage, sex and aetiology of CHF (final n = 443). SETTING: University hospital outpatient departments in the UK and Germany. PATIENTS: Chronic stable heart failure due to systolic left ventricular dysfunction. INTERVENTION: None. OUTCOME MEASURE: All-cause mortality. RESULTS: In both age groups, NT-proBNP was a significant univariate predictor of mortality, and independent of age, sex and other established risk markers. The prognostic information given by NT-proBNP was comparable between the two groups, as reflected by the 1-year mortality of 9% in both groups. The prognostic accuracy of NT-proBNP as judged by the area under the receiver operating characteristics curve for the prediction of 1-year mortality was comparable for elderly and younger patients (0.67 vs 0.71; p = 0.09). CONCLUSION: NT-proBNP reflects disease severity in elderly and younger patients alike. In patients with chronic stable heart failure, the NT-proBNP value carries the same 1-year prognostic information regardless of the age of the patient.

[Heart failure in men and women: important differences in the diagnostic workup and treatment]. / Hartfalen bij mannen en vrouwen: belangrijke verschillen in diagnostiek en behandeling.

OBJECTIVE: To determine gender differences in diagnostic workup and treatment of patients with heart failure. DESIGN: Retrospective. METHOD: The data of 8914 patients (of whom 4166 women; 47%) with confirmed heart failure, who participated in the Euro Heart Survey on Heart Failure (EHS-HF) were analysed. RESULTS: On average, the women in the study were older than the men (75 versus 68 years) and less often suffered from a coronary heart disease (56 versus 66%). Women were more likely to have hypertension (59 versus 49%), diabetes mellitus (29 versus 26%), or valvular heart disease (42 versus 36%). Fewer women had an ultrasonographic evaluation of ventricular function (59 versus 74%) and, among those investigated, fewer had left ventricular systolic dysfunction (44 versus 72%). These observed results remained stable after adjustment for age and other possible confounding variables. Medication with a documented positive impact on survival, i.e. angiotensin converting enzyme (ACE) inhibitors, beta-blocking drugs and the diuretic spironolactone, was prescribed less often to women than men. Women, however, received symptomatic medication such as other diuretics and digoxin more often than men. CONCLUSION: Men and women with heart failure differed with respect to a number of relevant clinical characteristics. Clinicians should take good note of this and take measures to prevent differences in patient care.

Perception of symptoms is out of proportion to cardiac pathology in patients with "diastolic heart failure".

BACKGROUND: Epidemiological studies suggest that "diastolic heart failure" (DHF) is common and has a prognosis similar to that of systolic heart failure (SHF). We wanted to assess whether patients with breathlessness who were being treated for DHF had objective evidence of cardiac impairment and exercise limitation. METHODS: Consecutive patients with a clinical diagnosis of chronic heart failure completed a standardised 6-minute walk test (6-MWT) and underwent an echocardiographic examination to determine the presence of major structural heart disease (MSHD). N-terminal pro-brain natriuretic peptide (NT-proBNP) was measured to determine degree of cardiac pathology. RESULTS: 568 patients were identified with SHF (75.7% males) and 104 with DHF (54.7% males). They were compared with 400 healthy controls (matched with DHF group for age, sex and body mass index (BMI)). Controls (median (interquartile range); 43 (20-62) pmol/l)) and DHF patients (27 (13-67) pmol/l) had significantly lower NT-proBNP levels compared to SHF patients (178 (82-422) pmol/l). There was no difference in NT-proBNP levels between controls and DHF patients (p = 0.348). There was no correlation between BMI and NT-proBNP in either DHF (r(2) = 0.03; p = 0.287) or SHF (r(2) = 0.02; p = 0.346) patients. Both SHF and DHF patients reported similar degrees of breathlessness. 6-MWT distance (p = 0.973) was similar between SHF and DHF patients. DHF patients had a higher BMI (p<0.0001). CONCLUSION: Patients being treated for a clinical diagnosis of DHF have the same self-reported symptoms and 6-MWT performance as patients with SHF, yet have normal NT-proBNP levels. Their perception of their symptoms is out of proportion to their evidence of cardiac pathology.