Cardiac resynchronization therapy: mechanisms of action and scope for further improvement in cardiac function.

Aims: Cardiac resynchronization therapy (CRT) may exert its beneficial haemodynamic effect by improving ventricular synchrony and improving atrioventricular (AV) timing. The aim of this study was to establish the relative importance of the mechanisms through which CRT improves cardiac function and explore the potential for additional improvements with improved ventricular resynchronization. Methods and Results: We performed simulations using the CircAdapt haemodynamic model and performed haemodynamic measurements while adjusting AV delay, at low and high heart rates, in 87 patients with CRT devices. We assessed QRS duration, presence of fusion, and haemodynamic response. The simulations suggest that intrinsic PR interval and the magnitude of reduction in ventricular activation determine the relative importance of the mechanisms of benefit. For example, if PR interval is 201 ms and LV activation time is reduced by 25 ms (typical for current CRT methods), then AV delay optimization is responsible for 69% of overall improvement. Reducing LV activation time by an additional 25 ms produced an additional 2.6 mmHg increase in blood pressure (30% of effect size observed with current CRT). In the clinical population, ventricular fusion significantly shortened QRS duration (Δ-27 ± 23 ms, P < 0.001) and improved systolic blood pressure (mean 2.5 mmHg increase). Ventricular fusion was present in 69% of patients, yet in 40% of patients with fusion, shortening AV delay (to a delay where fusion was not present) produced the optimal haemodynamic response. Conclusions: Improving LV preloading by shortening AV delay is an important mechanism through which cardiac function is improved with CRT. There is substantial scope for further improvement if methods for delivering more efficient ventricular resynchronization can be developed. Clinical Trial Registration: Our clinical data were obtained from a subpopulation of the British Randomised Controlled Trial of AV and VV Optimisation (BRAVO), which is a registered clinical trial with unique identifier: NCT01258829, https://clinicaltrials.gov

Automated aortic Doppler flow tracing for reproducible research and clinical measurements

In clinical practice, echocardiographers are often unkeen to make the significant time investment to make additional multiple measurements of Doppler velocity. Main hurdle to obtaining multiple measurements is the time required to manually trace a series of Doppler traces. To make it easier to analyze more beats, we present the description of an application system for automated aortic Doppler envelope quantification, compatible with a range of hardware platforms. It analyses long Doppler strips, spanning many heartbeats, and does not require electrocardiogram to separate individual beats. We tested its measurement of velocity-time-integral and peak-velocity against the reference standard defined as the average of three experts who each made three separate measurements. The automated measurements of velocity-time-integral showed strong correspondence (R2 = 0.94) and good Bland-Altman agreement (SD = 1.39 cm) with the reference consensus expert values, and indeed performed as well as the individual experts ( R2 = 0.90 to 0.96, SD = 1.05 to 1.53 cm). The same performance was observed for peak-velocities; ( R2 = 0.98, SD = 3.07 cm/s) and ( R2 = 0.93 to 0.98, SD = 2.96 to 5.18 cm/s). This automated technology allows > 10 times as many beats to be analyzed compared to the conventional manual approach. This would make clinical and research protocols more precise for the same operator effort

Renal artery sympathetic denervation:observations from the UK experience

Background: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN. Methods: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. Results: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p &lt; 0.001 for trend). Use of aldosterone antagonist did not predict response (p &lt; 0.2). Conclusion: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response

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

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 &gt;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 &lt; 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 &gt;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

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 &gt;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 &lt; 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 &gt;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