Comparative prognostic importance of measures of left atrial structure and function in non-ischaemic dilated cardiomyopathy.

AIMS: To compare the association between measures of left atrial (LA) structure and function, derived from cardiovascular magnetic resonance (CMR), with cardiovascular (CV) death or non-fatal heart failure (HF) events in patients with non-ischaemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: CMR studies of 580 prospectively recruited patients with DCM in sinus rhythm (median age 54 [interquartile range 44-64] years, 61% men, median LVEF 42% [30-51%]) were analysed for measures of LA structure (left atrial maximum volume index [LAVImax], left atrial minimum volume index [LAVImin]) and function (left atrial emptying fraction [LAEF], left atrial reservoir strain [LARS], left atrial conduit strain [LACS] and left atrial booster strain [LABS]). Over median follow-up of 7.4 years, 103 patients (18%) met the primary endpoint. Apart from LACS, each measure of LA structure and function was associated with the primary endpoint after adjusting for other important prognostic variables. The addition of each LA metric to a baseline model containing the same important prognostic covariates improved model discrimination, with LAVImin providing the greatest improvement (C-statistic improvement: 0.702 to 0.738; χ2 test comparing likelihood ratio p < 0.0001; categorical net reclassification index: 0.210 (95% CI 0.023-0.392)). Patients in the highest tercile of LAVImin had similar event rates to those with persistent atrial fibrillation. Measures of LA strain did not enhance model discrimination above LA volumetric measures. CONCLUSION: Measure of left atrial structure and function offer important prognostic information in patients with DCM and enhance prediction of adverse outcomes. LA strain was not incremental to volumetric analysis for risk prediction.

Arrhythmic Risk Stratification by Cardiovascular Magnetic Resonance Imaging in Patients With Nonischemic Cardiomyopathy.

BACKGROUND: Myocardial fibrosis (MF) forms part of the arrhythmic substrate for ventricular arrhythmias (VAs). OBJECTIVES: This study sought to determine whether total myocardial fibrosis (TF) and gray zone fibrosis (GZF), assessed using cardiovascular magnetic resonance, are better than left ventricular ejection fraction (LVEF) in predicting ventricular arrhythmias in patients with nonischemic cardiomyopathy (NICM). METHODS: Patients with NICM in a derivation cohort (n = 866) and a validation cohort (n = 848) underwent quantification of TF and GZF. The primary composite endpoint was sudden cardiac death or VAs (ventricular fibrillation or ventricular tachycardia). RESULTS: The primary endpoint was met by 52 of 866 (6.0%) patients in the derivation cohort (median follow-up: 7.5 years; Q1-Q3: 5.2-9.3 years). In competing-risks analyses, MF on visual assessment (MFVA) predicted the primary endpoint (HR: 5.83; 95% CI: 3.15-10.8). Quantified MF measures permitted categorization into 3 risk groups: a TF of >0 g and ≤10 g was associated with an intermediate risk (HR: 4.03; 95% CI: 1.99-8.16), and a TF of >10 g was associated with the highest risk (HR: 9.17; 95% CI: 4.64-18.1) compared to patients with no MFVA (lowest risk). Similar trends were observed in the validation cohort. Categorization into these 3 risk groups was achievable using TF or GZF in combination or in isolation. In contrast, LVEF of <35% was a poor predictor of the primary endpoint (validation cohort HR: 1.99; 95% CI: 0.99-4.01). CONCLUSIONS: MFVA is a strong predictor of sudden cardiac death and VAs in NICM. TF and GZF mass added incremental value to MFVA. In contrast, LVEF was a poor discriminator of arrhythmic risk.

Sex Differences in the Clinical Presentation and Natural History of Dilated Cardiomyopathy.

BACKGROUND: Biological sex has a diverse impact on the cardiovascular system. Its influence on dilated cardiomyopathy (DCM) remains unresolved. OBJECTIVES: This study aims to investigate sex-specific differences in DCM presentation, natural history, and prognostic factors. METHODS: The authors conducted a prospective observational cohort study of DCM patients assessing baseline characteristics, cardiac magnetic resonance imaging, biomarkers, and genotype. The composite outcome was cardiovascular mortality or major heart failure (HF) events. RESULTS: Overall, 206 females and 398 males with DCM were followed for a median of 3.9 years. At baseline, female patients had higher left ventricular ejection fraction, smaller left ventricular volumes, less prevalent mid-wall myocardial fibrosis (23% vs 42%), and lower high-sensitivity cardiac troponin I than males (all P < 0.05) with no difference in time from diagnosis, age at enrollment, N-terminal pro-B-type natriuretic peptide levels, pathogenic DCM genetic variants, myocardial fibrosis extent, or medications used for HF. Despite a more favorable profile, the risk of the primary outcome at 2 years was higher in females than males (8.6% vs 4.4%, adjusted HR: 3.14; 95% CI: 1.55-6.35; P = 0.001). Between 2 and 5 years, the effect of sex as a prognostic modifier attenuated. Age, mid-wall myocardial fibrosis, left ventricular ejection fraction, left atrial volume, N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponin I, left bundle branch block, and NYHA functional class were not sex-specific prognostic factors. CONCLUSIONS: The authors identified a novel paradox in prognosis for females with DCM. Female DCM patients have a paradoxical early increase in major HF events despite less prevalent myocardial fibrosis and a milder phenotype at presentation. Future studies should interrogate the mechanistic basis for these sex differences.

Precision prediction of heart failure events in patients with dilated cardiomyopathy and mildly reduced ejection fraction using multi-parametric cardiovascular magnetic resonance.

AIMS: To assess whether left ventricular (LV) global longitudinal strain (GLS), derived from cardiovascular magnetic resonance (CMR), is associated with (i) progressive heart failure (HF), and (ii) sudden cardiac death (SCD) in patients with dilated cardiomyopathy with mildly reduced ejection fraction (DCMmrEF). METHODS AND RESULTS: We conducted a prospective observational cohort study of patients with DCM and LV ejection fraction (LVEF) ≥40% assessed by CMR, including feature-tracking to assess LV GLS and late gadolinium enhancement (LGE). Long-term adjudicated follow-up included (i) HF hospitalization, LV assist device implantation or HF death, and (ii) SCD or aborted SCD (aSCD). Of 355 patients with DCMmrEF (median age 54 years [interquartile range 43-64], 216 men [60.8%], median LVEF 49% [46-54]) followed up for a median 7.8 years (5.2-9.4), 32 patients (9%) experienced HF events and 19 (5%) died suddenly or experienced aSCD. LV GLS was associated with HF events in a multivariable model when considered as either a continuous (per % hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.00-1.21, p = 0.045) or dichotomized variable (LV GLS > -15.4%: HR 2.70, 95% CI 1.30-5.94, p = 0.008). LGE presence was not associated with HF events (HR 1.49, 95% CI 0.73-3.01, p = 0.270). Conversely, LV GLS was not associated with SCD/aSCD (per % HR 1.07, 95% CI 0.95-1.22, p = 0.257), whereas LGE presence was (HR 3.58, 95% CI 1.39-9.23, p = 0.008). LVEF was neither associated with HF events nor SCD/aSCD. CONCLUSION: Multi-parametric CMR has utility for precision prognostic stratification of patients with DCMmrEF. LV GLS stratifies risk of progressive HF, while LGE stratifies SCD risk.

Culture, ethnicity, and socio-economic status as determinants of the management of patients with advanced heart failure who need palliative care: A clinical consensus statement from the Heart Failure Association (HFA) of the ESC, the ESC Patient Forum, and the European Association of Palliative Care.

The delivery of effective healthcare entails the configuration and resourcing of health economies to address the burden of disease, including acute and chronic heart failure, that affects local populations. Increasing migration is leading to more multicultural and ethnically diverse societies worldwide, with migration research suggesting that minority populations are often subject to discrimination, socio-economic disadvantage, and inequity of access to optimal clinical support. Within these contexts, the provision of person-centred care requires medical and nursing staff to be aware of and become adept in navigating the nuances of cultural diversity, and how that can impact some individuals and families entrusted to their care. This paper will examine current evidence, provide practical guidance, and signpost professionals on developing cultural competence within the setting of patients with advanced heart failure who may benefit from palliative care.

Phenotype, outcomes and natural history of early-stage non-ischaemic cardiomyopathy.

AIMS: To characterize the phenotype, clinical outcomes and rate of disease progression in patients with early-stage non-ischaemic cardiomyopathy (early-NICM). METHODS AND RESULTS: We conducted a prospective observational cohort study of patients with early-NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early-NICM H-/D+), non-dilated left ventricular cardiomyopathy (early-NICM H+/D-), or early dilated cardiomyopathy (early-NICM H+/D+). Clinical follow-up for major adverse cardiovascular events (MACE) included non-fatal life-threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early-NICM (median age 46 years [interquartile range 36-58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52-59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early-NICM H-/D+, higher in early-NICM H+/D- and highest in early-NICM H+/D+ (p = 0.03). Over a median follow-up of 7.9 (5.5-10.0) years, 28 patients (11%) experienced MACE. Non-sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36-11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73-8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73-15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early-NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11-34) months. CONCLUSION: Early-NICM is not benign. Fibrosis develops early in the phenotypic course. In-depth characterization enhances risk stratification and might aid clinical management.

Fully automatable, reproducible, noninvasive simple plethysmographic optimization: proof of concept and potential for implantability.

BACKGROUND: Hemodynamic optimization of cardiac resynchronization therapy (CRT) can be achieved reproducibly and--with bulky, nonimplantable equipment--noninvasively. We explored whether a simple photoplethysmogram signal might be used instead. METHOD: Twenty patients (age 65 ± 12) with CRT underwent automatic atrioventricular (AV) delay optimization, using a multiple-transitions protocol, at two atrially paced heart rates: just above sinus rate ("slow ApVp," 77 ± 11 beats per minute [bpm]) and 100 bpm ("fast ApVp"). We then retested to assess short-term reproducibility. RESULTS: All 80 optimizations identified an optimum (correctly oriented parabola). At 100 bpm, the simple photoplethysmogram had wider scatter between repeat optimizations than did Finometer: standard deviation of difference (SDD) 22 ms versus 14 ms, respectively, P = 0.028. The simple photoplethysmogram improved in reproducibility when slope (instead of peak) of its signal was used for optimization, becoming as reproducible as Finometer (SDD 14 ms vs 14 ms, P = 0.50). At slow heart rate, reproducibility of simple photoplethysmogram-based optimization worsened from 14 to 22 ms (P = 0.028), and Finometer-based optimization from 14 to 26 ms (P = 0.005). Increasing the number of replicates averaged improved reproducibility. For example, SDD of simple photoplethysmogram optimization (using peak) fell from 62 ms with two replicates to 22 ms with eight replicates (P < 0.0001). At 100 bpm, the eight-replicate protocol takes ∼12 minutes. CONCLUSIONS: A 12-minute protocol of simple photoplethysmographic AV optimization can be processed fully automatically. Blinded test-retest reproducibility of the optimum AV is good and improves with more replicates. If benefits to some patients are not to be neutralized by harm to others, endpoint studies should first test check narrowness of "within-patient error bars."

Moderate excess alcohol consumption and adverse cardiac remodelling in dilated cardiomyopathy.

OBJECTIVE: The effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM. METHODS: Prospective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited. RESULTS: DCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=<0.001). After adjustment for biological sex, moderate excess alcohol was not associated with adverse cardiac structure. There was no difference in midwall myocardial fibrosis between groups. Prior moderate excess alcohol consumption did not affect prognosis (HR 1.29, 95% CI 0.73 to 2.26, p=0.38) during median follow-up of 3.9 years. CONCLUSION: DCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.

Precision Phenotyping of Dilated Cardiomyopathy Using Multidimensional Data.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine.

Integration of a palliative approach into heart failure care: a European Society of Cardiology Heart Failure Association position paper.

The Heart Failure Association of the European Society of Cardiology has published a previous position paper and various guidelines over the past decade recognizing the value of palliative care for those affected by this burdensome condition. Integrating palliative care into evidence-based heart failure management remains challenging for many professionals, as it includes the identification of palliative care needs, symptom control, adjustment of drug and device therapy, advance care planning, family and informal caregiver support, and trying to ensure a 'good death'. This new position paper aims to provide day-to-day practical clinical guidance on these topics, supporting the coordinated provision of palliation strategies as goals of care fluctuate along the heart failure disease trajectory. The specific components of palliative care for symptom alleviation, spiritual and psychosocial support, and the appropriate modification of guideline-directed treatment protocols, including drug deprescription and device deactivation, are described for the chronic, crisis and terminal phases of heart failure.

Dynamic CO2 therapy in periodic breathing: a modeling study to determine optimal timing and dosage regimes.

We examine the potential to treat unstable ventilatory control (seen in periodic breathing, Cheyne-Stokes respiration, and central sleep apnea) with carefully controlled dynamic administration of supplementary CO(2), aiming to reduce ventilatory oscillations with minimum increment in mean CO(2). We used a standard mathematical model to explore the consequences of phasic CO(2) administration, with different timing and dosing algorithms. We found an optimal time window within the ventilation cycle (covering approximately 1/6 of the cycle) during which CO(2) delivery reduces ventilatory fluctuations by >95%. Outside that time, therapy is dramatically less effective: indeed, for more than two-thirds of the cycle, therapy increases ventilatory fluctuations >30%. Efficiency of stabilizing ventilation improved when the algorithm gave a graded increase in CO(2) dose (by controlling its duration or concentration) for more severe periodic breathing. Combining gradations of duration and concentration further increased efficiency of therapy by 22%. The (undesirable) increment in mean end-tidal CO(2) caused was 300 times smaller with dynamic therapy than with static therapy, to achieve the same degree of ventilatory stabilization (0.0005 vs. 0.1710 kPa). The increase in average ventilation was also much smaller with dynamic than static therapy (0.005 vs. 2.015 l/min). We conclude that, if administered dynamically, dramatically smaller quantities of CO(2) could be used to reduce periodic breathing, with minimal adverse effects. Algorithms adjusting both duration and concentration in real time would achieve this most efficiently. If developed clinically as a therapy for periodic breathing, this would minimize excess acidosis, hyperventilation, and sympathetic overactivation, compared with static treatment.

Phenotype and Clinical Outcomes of Titin Cardiomyopathy.

BACKGROUND: Improved understanding of dilated cardiomyopathy (DCM) due to titin truncation (TTNtv) may help guide patient stratification. OBJECTIVES: The purpose of this study was to establish relationships among TTNtv genotype, cardiac phenotype, and outcomes in DCM. METHODS: In this prospective, observational cohort study, DCM patients underwent clinical evaluation, late gadolinium enhancement cardiovascular magnetic resonance, TTN sequencing, and adjudicated follow-up blinded to genotype for the primary composite endpoint of cardiovascular death, and major arrhythmic and major heart failure events. RESULTS: Of 716 subjects recruited (mean age 53.5 ± 14.3 years; 469 men [65.5%]; 577 [80.6%] New York Heart Association function class I/II), 83 (11.6%) had TTNtv. Patients with TTNtv were younger at enrollment (49.0 years vs. 54.1 years; p = 0.002) and had lower indexed left ventricular mass (5.1 g/m2 reduction; padjusted = 0.03) compared with patients without TTNtv. There was no difference in biventricular ejection fraction between TTNtv+/- groups. Overall, 78 of 604 patients (12.9%) met the primary endpoint (median follow-up 3.9 years; interquartile range: 2.0 to 5.8 years), including 9 of 71 patients with TTNtv (12.7%) and 69 of 533 (12.9%) without. There was no difference in the composite primary outcome of cardiovascular death, heart failure, or arrhythmic events, for patients with or without TTNtv (hazard ratio adjusted for primary endpoint: 0.92 [95% confidence interval: 0.45 to 1.87]; p = 0.82). CONCLUSIONS: In this large, prospective, genotype-phenotype study of ambulatory DCM patients, we show that prognostic factors for all-cause DCM also predict outcome in TTNtv DCM, and that TTNtv DCM does not appear to be associated with worse medium-term prognosis.

Attenuation of reflected waves in man during retrograde propagation from femoral artery to proximal aorta.

BACKGROUND: Wave reflection may be an important influence on blood pressure, but the extent to which reflections undergo attenuation during retrograde propagation has not been studied. We quantified retrograde transmission of a reflected wave created by occlusion of the left femoral artery in man. METHODS: 20 subjects (age 31-83 years; 14 male) underwent invasive measurement of pressure and flow velocity with a sensor-tipped intra-arterial wire at multiple locations distal to the proximal aorta before, during and following occlusion of the left femoral artery by thigh cuff inflation. A numerical model of the circulation was also used to predict reflected wave transmission. Wave reflection was measured as the ratio of backward to forward wave energy (WRI) and the ratio of peak backward to forward pressure (Pb/Pf). RESULTS: Cuff inflation caused a marked reflection which was largest at 5-10 cm from the cuff (change (Δ) in WRI=0.50 (95% CI 0.38, 0.62); p<0.001, ΔPb/Pf=0.23 (0.18-0.29); p<0.001). The magnitude of the cuff-induced reflection decreased progressively at more proximal locations and was barely discernible at sites>40 cm from the cuff including in the proximal aorta. Numerical modelling gave similar predictions to those observed experimentally. CONCLUSIONS: Reflections due to femoral artery occlusion are markedly attenuated by the time they reach the proximal aorta. This is due to impedance mismatches of bifurcations traversed in the backward direction. This degree of attenuation is inconsistent with the idea of a large discrete reflected wave arising from the lower limb and propagating back into the aorta.

Do optimal prognostic thresholds in continuous physiological variables really exist? Analysis of origin of apparent thresholds, with systematic review for peak oxygen consumption, ejection fraction and BNP.

BACKGROUND: Clinicians are sometimes advised to make decisions using thresholds in measured variables, derived from prognostic studies. OBJECTIVES: We studied why there are conflicting apparently-optimal prognostic thresholds, for example in exercise peak oxygen uptake (pVO2), ejection fraction (EF), and Brain Natriuretic Peptide (BNP) in heart failure (HF). DATA SOURCES AND ELIGIBILITY CRITERIA: Studies testing pVO2, EF or BNP prognostic thresholds in heart failure, published between 1990 and 2010, listed on Pubmed. METHODS: First, we examined studies testing pVO2, EF or BNP prognostic thresholds. Second, we created repeated simulations of 1500 patients to identify whether an apparently-optimal prognostic threshold indicates step change in risk. RESULTS: 33 studies (8946 patients) tested a pVO2 threshold. 18 found it prognostically significant: the actual reported threshold ranged widely (10-18 ml/kg/min) but was overwhelmingly controlled by the individual study population's mean pVO2 (r = 0.86, p<0.00001). In contrast, the 15 negative publications were testing thresholds 199% further from their means (p = 0.0001). Likewise, of 35 EF studies (10220 patients), the thresholds in the 22 positive reports were strongly determined by study means (r = 0.90, p<0.0001). Similarly, in the 19 positives of 20 BNP studies (9725 patients): r = 0.86 (p<0.0001). Second, survival simulations always discovered a "most significant" threshold, even when there was definitely no step change in mortality. With linear increase in risk, the apparently-optimal threshold was always near the sample mean (r = 0.99, p<0.001). LIMITATIONS: This study cannot report the best threshold for any of these variables; instead it explains how common clinical research procedures routinely produce false thresholds. KEY FINDINGS: First, shifting (and/or disappearance) of an apparently-optimal prognostic threshold is strongly determined by studies' average pVO2, EF or BNP. Second, apparently-optimal thresholds always appear, even with no step in prognosis. CONCLUSIONS: Emphatic therapeutic guidance based on thresholds from observational studies may be ill-founded. We should not assume that optimal thresholds, or any thresholds, exist.

Novel cardiac pacemaker-based human model of periodic breathing to develop real-time, pre-emptive technology for carbon dioxide stabilisation.

BACKGROUND: Constant flow and concentration CO2 has previously been efficacious in attenuating ventilatory oscillations in periodic breathing (PB) where oscillations in CO2 drive ventilatory oscillations. However, it has the undesirable effect of increasing end-tidal CO2, and ventilation. We tested, in a model of PB, a dynamic CO2 therapy that aims to attenuate pacemaker-induced ventilatory oscillations while minimising CO2 dose. METHODS: First, pacemakers were manipulated in 12 pacemaker recipients, 6 with heart failure (ejection fraction (EF)=23.7±7.3%) and 6 without heart failure, to experimentally induce PB. Second, we applied a real-time algorithm of pre-emptive dynamic exogenous CO2 administration, and tested different timings. RESULTS: We found that cardiac output alternation using pacemakers successfully induced PB. Dynamic CO2 therapy, when delivered coincident with hyperventilation, attenuated 57% of the experimentally induced oscillations in end-tidal CO2: SD/mean 0.06±0.01 untreated versus 0.04±0.01 with treatment (p<0.0001) and 0.02±0.01 in baseline non-modified breathing. This translated to a 56% reduction in induced ventilatory oscillations: SD/mean 0.19±0.09 untreated versus 0.14±0.06 with treatment (p=0.001) and 0.10±0.03 at baseline. Of note, end-tidal CO2 did not significantly rise when dynamic CO2 was applied to the model (4.84±0.47 vs 4.91± 0.45 kPa, p=0.08). Furthermore, mean ventilation was also not significantly increased by dynamic CO2 compared with untreated (7.8±1.2 vs 8.4±1.2 L/min, p=0.17). CONCLUSIONS: Cardiac pacemaker manipulation can be used to induce PB experimentally. In this induced PB, delivering CO2 coincident with hyperventilation, ventilatory oscillations can be substantially attenuated without a significant increase in end-tidal CO2 or ventilation. Dynamic CO2 administration might be developed into a clinical treatment for PB. TRIAL REGISTRATION NUMBER: ISRCTN29344450.

Serum albumin changes and multivariate dynamic risk modelling in chronic heart failure.

BACKGROUND: We examined the prognostic utility of rate of change in serum albumin over time in chronic heart failure (CHF), as well as the utility of multivariate dynamic risk modelling. METHODS AND RESULTS: The survival implication of ∆albumin was analysed in 232 systolic CHF patients and validated in 212 patients. A multivariate dynamic risk score predicated on the rate of change in 6 simple indices including albumin was calculated and related to mortality. In derivation patients, 50 (22%) deaths occurred over 13 months. Greater rates of decline in albumin related to higher mortality (HR 0.55, 95% CI 0.41-0.73, P<0.0001) independently, incrementally and more accurately than other covariates including baseline albumin. A rate of attenuation >0.4 g/dL/month optimally forecasted death and was associated with a 5-fold escalated risk of mortality (HR 5.13, 95% CI 2.92-9.00, P<0.0001). Similar results were seen in the validation cohort. On multivariate dynamic risk modelling, survival at 1-year worsened with higher scores-a score ≥ 3 was associated with a 12-fold greater risk of death than a score of 0, a 6-fold higher risk of death than a score of 1, and a 4-fold enhanced risk of mortality than a score of 2. CONCLUSION: Attenuations in serum albumin over time relate to increased mortality in CHF, and a risk model predicated on the rate of change in 6 simple indices can identify patients at a 12-fold enhanced risk of death over the coming year.

Contrasting effect of different cardiothoracic operations on echocardiographic right ventricular long axis velocities, and implications for interpretation of post-operative values.

BACKGROUND: Patients undergoing coronary artery bypass grafting (CABG) experience a reduction in right ventricular long axis velocities post surgery. OBJECTIVES: We tested whether the phenomenon of right ventricular (RV) long axis velocity decline depends on the chest being opened fully by mid-line sternotomy, pericardial incision, or on the type of operation performed. METHOD: By intraoperative transoesophageal echocardiography (TEE) we recorded serial right ventricular (RV) systolic pulse-wave tissue Doppler velocities during 6 types of elective procedure: 53 CABG surgery, 15 robotic-assisted minimally-invasive CABG (RCABG), 28 aortic valve replacement (AVR), 8 minimally-invasive aortic valve replacement (mini-AVR), 5 mediastinal mass excision, and 1 left atrial myxoma excision. Pre and post operative transthoracic echocardiography (TTE) were also conducted. RESULTS: Surgery without substantial opening of the pericardium did not significantly reduce RV systolic velocities (RCABG 13 ± 1.8 versus 12.4 ± 2.7 cm/s post; mini-AVR 11.9 ± 2.3 versus 11.1 ± 2.3 cm/s; mediastinal mass excision 13.9 ± 3.1 versus 13.8 ± 4 cm/s). In contrast, within 5 min of pericardial incision those whose surgery involved full opening of the pericardium had large reductions in RV velocities: 54 ± 11% decline with CABG (11.3 ± 1.9 to 5.1 ± 1.6 cm/s, p<0.0001), 54 ± 5% with AVR (12.6 ± 1.4 to 5.7 ± 0.6 cm/s, p<0.001) and 49% with left atrial myxoma excision (11.3 to 15.8 cm/s). This persisted immediately after pericardial opening to the end of surgery (61 ± 11%, p<0.0001; 58 ± 7%, p<0.0001; 59% respectively). CONCLUSIONS: It is full opening of the pericardium, and not cardiac surgery in general, which causes RV long axis decline following cardiac surgery. The impact is immediate (within 5 min) and persistent.