Phase analysis, a novel SPECT technique for left ventricular dyssynchrony: Are degrees and milliseconds interchangeable?

BACKGROUND: Phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy provides a measure of left ventricular dyssynchrony and may have applications for identifying patients suitable for cardiac resynchronisation therapy. Phase analysis is typically described in degrees of cardiac cycle, less intuitive to cardiologists familiar with ECGs. We assessed the relationship between time and degrees, to determine whether they are interchangeable. METHODS AND RESULTS: 399 patients underwent normal stress-only SPECT myocardial perfusion imaging using Technetium-99m-tetrofosmin. Data analysis used QGS software (Cedars Sinai) calculating bandwidth and standard deviation. Heart rate, age, gender, stress modality, and ejection fraction were analyzed for their relation to phase variables. 13 patients were excluded for conduction abnormalities including right and left bundle branch block and ventricular pacing. Heart rate was strongly correlated to bandwidth and standard deviation measured in time, but unrelated when measured in degrees. Although bandwidth measured by time and degrees were strongly correlated with each other this relationship was not perfect (correlation coefficient 0.87, P < .001). The addition of heart rate to the model explained most of the residual variation between the two. The results for standard deviation were similar. CONCLUSION: In patients with normal myocardial perfusion and QRS duration bandwidth measured by degrees is not directly interchangeable with time in milliseconds. However most of the variation is explainable by heart rate, which predominantly affects measures of time rather than degrees. We would propose that although the values are less intuitive to cardiologists, normal ranges for phase measured in degrees are potentially more robust.

Physiology of oxygen uptake kinetics: Insights from incremental cardiopulmonary exercise testing in the Study of Health in Pomerania.

BACKGROUND: Cardiopulmonary exercise testing allows for assessment of cardiac and respiratory limitation, but is often affected by patient effort. Indices of oxygen kinetics, including the oxygen uptake efficiency slope (OUES), oxygen uptake-work-rate slope (VO2-WR slope) and the heart rate-oxygen uptake slope (HR-VO2 slope) are relatively effort independent but may be affected by patient characteristics. The objective of this study is to identify the impact of factors, such as age, gender, body size, respiratory function, smoking and beta-blockade on these parameters, as well as generate predictive equations. METHODS: 1708 volunteers from the population-based Study of Health in Pomerania underwent an incremental bicycle exercise protocol. Markers of oxygen kinetics were calculated. Participants with structural heart disease, echocardiographic or lung function pathology were excluded, leaving 577 males and 625 females. Age, height, weight, smoking, forced expiratory volume in 1 s (FEV1) and beta-blockers were analysed for their influencing power by gender. Quantile regression analysis determined the reference equations for each parameter. RESULTS: Age, gender, height, weight and FEV1 (but not percent predicted FEV1) are strongly related to OUES. Participants using beta-blockers and male smokers had significantly lower OUES values. VO2-WR slope was minimally affected by age, gender, weight and FEV1. Gender, height, weight and beta-blocker use, but not FEV1 and smoking status, were related to the HR-VO2 slope whilst age was only related in females. CONCLUSIONS: Markers of oxygen kinetics are differentially affected by patient characteristics. This study provides normal reference values for these variables thereby facilitating interpretation of oxygen uptake kinetics in health and disease.

The effect of duration of follow-up and presence of competing risk on lifespan-gain from implantable cardioverter defibrillator therapy: who benefits the most?

BACKGROUND: In at-risk patients with left ventricular dysfunction, implantable cardioverter defibrillators (ICDs) prolong life. Implantable cardioverter defibrillators are increasingly implanted for primary prevention and therefore into lower risk patients. Trial data have demonstrated the benefit of these devices but does not provide an estimate of potential lifespan-gain over longer time periods, e.g. a patient's lifespan. METHODS: Using data from landmark ICD trials, lifespan-gain was plotted against baseline annual mortality in the individual trials. Lifespan-gain was then extrapolated to a time-horizon of >20 years while adjusting for increasing 'competing' risk from ageing and non-sudden cardiac death (pump failure). RESULTS: At 3 years, directly observed lifespan-gain was strongly dependent on baseline event rate (r = 0.94, P < 0.001). However, projecting beyond the duration of the trial, lifespan-gain increases rapidly and non-linearly with time. At 3 years, it averages 1.7 months, but by 10 years up to 9-fold more. Lifespan-gain over time horizons >20 years were greatest in lower risk patients (∼5 life-years for 5% baseline mortality, ∼2 life-years for 15% baseline mortality). Increased competing risks significantly reduce lifespan-gain from ICD implantation. CONCLUSION: While high-risk patients may show the greatest short-term gain, the dramatic growth of lifespan-gain over time means that it is the lower risk patients, e.g. primary prevention ICD implantation, who gain the most life-years over their lifetime. Benefit is underestimated when only trial data are assessed as trials can only maintain randomization over limited periods. Lifespan-gain may be further increased through advances in ICD device programming.

A regulatory governance perspective on health technology assessment (HTA) in France: the contextual mediation of common functional pressures.

The new regulatory governance perspective has introduced several insights to the study of health technology assessment (HTA): it has broadened the scope for the analysis of HTA; it has provided a more sophisticated account of national diversity and the potential for cross-border policy learning; and, it has dissolved the distinction between HTA assessment and appraisal processes. In this paper, we undertake a qualitative study of the French process for HTA with a view to introducing a fourth insight: that the emergence and continuing function of national agencies for HTA follows a broadly evolutionary pattern in which contextual factors play an important mediating role. We demonstrate that the French process for HTA is characterised by distinctive institutions, processes and evidential requirements. Consistent with the mediating role of this divergent policy context, we argue that even initiatives for the harmonisation of national approaches to HTA are likely to meet with divergent national policy responses.

"Triple therapy" of heart failure with angiotensin-converting enzyme inhibitor, beta-blocker, and aldosterone antagonist may triple survival time: shouldn't we tell patients?

Prescription and adherence to medical therapy for heart failure are disappointing despite convincing randomized controlled trial (RCT) evidence for angiotensin-converting enzyme inhibition, beta-blockade, and aldosterone antagonism. In this study, we report an imbalanced approach amongst clinicians, who describe focusing during patient consultations on perceived risks of therapy rather than survival benefits. Only one-half of clinicians mention increased lifespan, and very few suggest to the patient how large this gain might be. We calculate from the available RCT data that, for patients whose lifespan is limited by heart failure, triple therapy triples lifespan.

What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice.

OBJECTIVE: Discussions about statin efficacy in cardiovascular prevention are always based on data from blinded randomized controlled trials (RCTs) comparing statin to placebo; however, discussion of side effects is not. Clinicians often assume symptoms occurring with statins are caused by statins, encouraging discontinuation. We test this assumption and calculate an evidence-based estimate of the probability of a symptom being genuinely attributable to the statin itself. METHODS: We identified RCTs comparing statin to placebo for cardiovascular prevention that reported side effects separately in the two arms. RESULTS: Among 14 primary prevention trials (46,262 participants), statin therapy increased diabetes by absolute risk of 0.5% (95% CI 0.1-1%, p = 0.012), meanwhile reducing death by a similar extent: -0.5% (-0.9 to -0.2%, p = 0.003). In the 15 secondary prevention RCTs (37,618 participants), statins decreased death by 1.4% (-2.1 to -0.7%, p < 0.001). There were no other statin-attributable symptoms, although asymptomatic liver transaminase elevation was 0.4% more frequent with statins across all trials. Serious adverse events and withdrawals were similar in both arms. CONCLUSIONS: Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo; nevertheless only 1 in 5 of new cases were actually caused by statins. Higher statin doses produce a detectable effect, but even still the proportion attributable to statins is variable: for asymptomatic liver enzyme elevation, the majority are attributable to the higher dose; in contrast for muscle aches, the majority are not.

Long-term antihypertensive treatment fails to improve E/e' despite regression of left ventricular mass: an Anglo-Scandinavian cardiac outcomes trial substudy.

Antihypertensive treatment can improve tissue Doppler indices of left ventricular diastolic function in the short term, but little is known about the longer-term effect of different antihypertensive treatments on progression of left ventricular diastolic function and left ventricular hypertrophy. We hypothesized that long-term treatment of hypertension will lead to improvements in left ventricular hypertrophy and diastolic function. We collected detailed cardiovascular phenotypic data on 1006 participants from a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Patients randomized to either an amlodipine±perindopril-based or an atenolol±bendroflumethiazide-based regimen underwent conventional and tissue Doppler echocardiography at time of control of blood pressure after randomization (≈1.5 years; phase 1) and after a further 2 years of antihypertensive treatment (phase 2). There were no prerandomization data. Five hundred thirty-six patients had complete data collection at both phases. Left ventricular mass index regressed from phase 1 to 2 with no significant difference between treatment groups (amlodipine: 119.5-116.8; atenolol: 122.9-117.5; P<0.001 for both). Conversely, tissue Doppler diastolic indices did not change in the amlodipine±perindopril-based regimen (E/e', 7.5-7.6 cm/s; P=not significant), but deteriorated in the atenolol±bendroflumethiazide-based regimen (E/e', 8.0-8.5 cm/s; P<0.01). Despite regression of left ventricular hypertrophy, there was no associated improvement in diastolic function. In fact, long-term treatment with atenolol±bendroflumethiazide resulted in a progressive deterioration in E/e'. This may be a factor contributing to the previously described worse clinical outcome in patients treated with atenolol±bendroflumethiazide compared with amlodipine±perindopril.

Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.

BACKGROUND: Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. METHODS: We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological". RESULTS: 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01). CONCLUSIONS: Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

Regulatory space and the contextual mediation of common functional pressures: analyzing the factors that led to the German Efficiency Frontier approach.

There are no automatic links between the functional advantages and pressures associated with delegation to independent agencies for Health Technology Assessment (HTA) and their emergence in national regulatory spaces. We argue that the rise of these organizations is mediated by contextual factors, which must be explained. Accordingly, we analyze the German 'regulatory space' for health policy decision-making, identifying contextual factors relevant to the adoption of the Efficiency Frontier approach. Based on qualitative interviews with key stakeholders, we argue that the development of the Efficiency Frontier can be associated with cultural reluctance to frame healthcare prioritization decisions around cost based valuations of human health and related doubts about the validity of metrics for human health gain. Based on this finding, we conclude that the delegation of authority to independent HTA agencies follows a broadly evolutionary pattern, in which contextual factors allow for significant variation in institutional and methodological responses to the functional pressures and advantages leading to their establishment.

First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study.

BACKGROUND: Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD: 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS: No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic -7.1 ± 6.9 mmHg, p=0.35; Δdiastolic -0.6 ± 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine -5.7 ± 8.4 µmol/l, p=0.52 and Δurea -1.0 ± 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ=27.1 ± 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS: This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700

The role for cardiopulmonary exercise testing in patients with atrial septal defects: a review.

Secundum atrial septal defects (ASD) are the commonest congenital cardiac abnormality. They are often identified incidentally, or in conjunction with an acquired cardiac abnormality. Untreated they may lead to significant morbidity and mortality, with consequences including right ventricular overload and right heart failure, pulmonary arterial hypertension, shunt reversal and cyanosis, and arrhythmias. Deciding whether to close an ASD can consume as much clinical time as finding them or indeed closing them. In the past when surgical closure was the only option, the morbidity of the procedure, including the need for sternotomy or thoracotomy, limited its use to large defects considered likely to result in shunt reversal or heart failure. Smaller defects were often managed conservatively. However within the past 2 decades percutaneous closure has come to the fore and is now considered first line when morphology allows. With lower morbidity, this has "lowered the bar" in terms of who is considered for closure, although the absolute mortality risk of either procedure is low. However, even though mortality is low, morbidity is still significant after percutaneous closure. Despite this, the utilisation of ASD closure has dramatically increased in the last decade with a sudden rise from 2001, owing largely to growth in percutaneous closures. Instead of looking for symptoms, which are subjective, or evidence of large shunt/RV failure, an objective measure of exercise capacity might help identify other patients who would benefit from closure. This review will look at the current evidence of cardiopulmonary exercise testing (CPET) in ASD closure.

Reduced confounding by impaired ventilatory function with oxygen uptake efficiency slope and VE/VCO2 slope rather than peak oxygen consumption to assess exercise physiology in suspected heart failure.

Heart failure and ventilatory disease often coexist; both create abnormalities in cardiopulmonary exercise test measurements. The authors evaluated the relative dependency of a well-recognized index of heart failure, peak oxygen consumption (VO(2)), and 2 newer indices, the minute ventilation (VE)/carbon dioxide production (VCO(2)) slope and oxygen uptake efficiency slope (OUES), on standard markers of impaired cardiac and ventilatory function. One hundred twenty-four patients (median age, 65.8; range, 22.6-84.9), with functional limitation from clinical heart failure were exercised. Peak VO(2) was 17.14 ± 7.58 mL/kg/min, VE/VCO(2) slope 50.1 ± 20.1, OUES 1.46 ± 0.68 L/min, and forced expiratory volume in 1 second (FEV(1) ) 1.88 ± 0.75 L. Peak VO(2) is substantially more sensitive to FEV(1) than ejection fraction (4.0 mL/kg/min difference between above- and below-median FEV(1) and 1.5 mL/kg/min between above- and below-median ejection fraction). OUES does not share this peculiar excess sensitivity to FEV(1) (0.12 L/min difference between above- and below-median FEV(1) and 0.01 L/min between above- and below-median ejection fraction). VE/VCO(2) slope has a borderline effect by FEV(1) (7.07 difference between above- and below-median FEV(1) and 2.07 between above- and below-median ejection fraction). Although widely used as a marker of heart failure severity, peak VO(2) is very sensitive to spirometry status and is indeed more affected by FEV(1) than by ejection fraction. OUES in contrast does not show this preferential sensitivity to impaired FEV(1).

Chronic activation of extracellular-signal-regulated protein kinases by phenylephrine is required to elicit a hypertrophic response in cardiac myocytes.

Extracellular-signal-regulated protein kinases (ERKs) are activated rapidly and transiently in response to phenylephrine (PE) and endothelin-1 (ET-1) in cardiac myocytes, but whether this is linked to the subsequent development of the hypertrophic phenotype remains equivocal. To investigate this, we examined the dependence of the hypertrophic response on the length of exposure to PE in neonatal myocyte cultures. In addition to the initial transient activation of ERKs (maximum at 5-10 min), PE (10 microM) induced a second, more prolonged peak of activity several hours later. The activity of a transfected atrial natriuretic factor-luciferase reporter gene was increased 10- to 24-fold by PE. This response was inhibited by the alpha(1)-antagonist prazosin (100 nM) and by U0126 (10 microM) and PD184352 (1 microM), inhibitors of ERK activation, irrespective of whether these were added before or up to 24 h after the addition of PE. Prazosin had no effect on ET-1 (50 nM)-stimulated atrial natriuretic factor-luciferase activity. Protein synthesis was enhanced by 35+/-6% by PE, and this was blocked by prazosin added 1 h after the addition of PE, but decreased only by half when added 8 h after PE. Similarly, PE (48 h) increased myocyte area by 49% and this was prevented by prazosin added 1 h after PE, but decreased only by half when added at 24 h. These results demonstrate that prolonged exposure to PE is required to elicit alterations in gene expression, protein synthesis and cell size, characteristic of hypertrophied myocytes, and they confirm that the initial peak of ERK activity is insufficient to trigger hypertrophic responses.