Jamil Mayet

Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study.

OBJECTIVES The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity. BACKGROUND Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and minimized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic efficiency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. METHODS A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measurements were made at baseline and under pharmacologic vasodilation with adenosine. RESULTS Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 ± 0.06 and 284 ± 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 ± 0.06 and 302 ± 315 mm Hg s/m; p = NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r = 0.9, p < 0.001) with excellent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR <0.8), specificity, sensitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively. CONCLUSIONS Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481).

Evidence of a Dominant Backward-Propagating “Suction” Wave Responsible for Diastolic Coronary Filling in Humans, Attenuated in Left Ventricular Hypertrophy

Background— Coronary blood flow peaks in diastole when aortic blood pressure has fallen. Current models fail to completely explain this phenomenon. We present a new approach—using wave intensity analysis—to explain this phenomenon in normal subjects and to evaluate the effects of left ventricular hypertrophy (LVH). Method and Results— We measured simultaneous pressure and Doppler velocity with intracoronary wires in the left main stem, left anterior descending, and circumflex arteries of 20 subjects after a normal coronary arteriogram. Wave intensity analysis was used to identify and quantify individual pressure and velocity waves within the coronary artery circulation. A consistent pattern of 6 predominating waves was identified. Ninety-four percent of wave energy, accelerating blood forward along the coronary artery, came from 2 waves: first a pushing wave caused by left ventricular ejection—the dominant forward-traveling pushing wave; and later a suction wave caused by relief of myocardial microcirculatory compression—the dominant backward-traveling suction wave. The dominant backward-traveling suction wave (18.2±13.7×103 W m−2 s−1, 30%) was larger than the dominant forward-traveling pushing wave (14.3±17.6×103 W m−2 s−1, 22.3%, P =0.001) and was associated with a substantially larger increment in coronary blood flow velocity (0.51 versus 0.14 m/s, P<0.001). In LVH, the dominant backward-traveling suction wave percentage was significantly decreased (33.1% versus 26.9%, P=0.01) and inversely correlated with left ventricular septal wall thickness (r=−0.52, P<0.02). Conclusions— Six waves predominantly drive human coronary blood flow. Coronary flow peaks in diastole because of the dominance of a “suction” wave generated by myocardial microcirculatory decompression. This is significantly reduced in LVH.

Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure

Background: Two ways to evaluate the symptoms of heart failure are the New York Heart Association (NYHA) classification and asking patients how far they can walk (walk distance). The NYHA system is commonly used, although it is not clear how individual clinicians apply it. Aim: To investigate how useful these measures are to assess heart failure and whether other questions might be more helpful. Methods: 30 cardiologists were asked what questions they used when assessing patients with heart failure. To assess interoperator variability, two cardiologists assessed a series of 50 patients in classes II and III using the NYHA classification. 45 patients who had undergone cardiopulmonary testing were interviewed using a specially formulated questionnaire. They were also asked how far they could walk before being stopped by symptoms, and then tested on their ability to estimate distance. Results: The survey of cardiologists showed no consistent method for assessing NYHA class and a literature survey showed that 99% of research papers do not reference or describe their methods for assigning NYHA classes. The interoperator variability study showed only 54% concordance between the two cardiologists. 70% of cardiologists asked patients for their walk distance; however, this walk distance correlated poorly with actual exercise capacity measured by cardiopulmonary testing (ρ = 0.04, p = 0.82). Conclusion: No consistent method of assessing NYHA class is in use and the interoperator study on class II and class III patients gave a result little better than chance. Some potential questions are offered for use in assessment. Walking distance, although frequently asked, does not correlate with formally measured exercise capacity, even after correction for patient perception of distance, and has never been found to have prognostic relevance. Its value is therefore doubtful.

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

Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery

Background Current European and American guidelines recommend the perioperative initiation of a course of β-blockers in those at risk of cardiac events undergoing high- or intermediate-risk surgery or vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) family of trials, the bedrock of evidence for this, are no longer secure. We therefore conducted a meta-analysis of randomised controlled trials of β-blockade on perioperative mortality, non-fatal myocardial infarction, stroke and hypotension in non-cardiac surgery using the secure data. Methods The randomised controlled trials of initiation of β-blockers before non-cardiac surgery were examined. Primary outcome was all-cause mortality at 30 days or at discharge. The DECREASE trials were separately analysed. Results Nine secure trials totalling 10 529 patients, 291 of whom died, met the criteria. Initiation of a course of β-blockers before surgery caused a 27% risk increase in 30-day all-cause mortality (p=0.04). The DECREASE family of studies substantially contradict the meta-analysis of the secure trials on the effect of mortality (p=0.05 for divergence). In the secure trials, β-blockade reduced non-fatal myocardial infarction (RR 0.73, p=0.001) but increased stroke (RR 1.73, p=0.05) and hypotension (RR 1.51, p<0.00001). These results were dominated by one large trial. Conclusions Guideline bodies should retract their recommendations based on fictitious data without further delay. This should not be blocked by dispute over allocation of blame. The well-conducted trials indicate a statistically significant 27% increase in mortality from the initiation of perioperative β-blockade that guidelines currently recommend. Any remaining enthusiasts might best channel their energy into a further randomised trial which should be designed carefully and conducted honestly.

Diagnostic classification of the instantaneous wave-free ratio is equivalent to fractional flow reserve and is not improved with adenosine administration. Results of CLARIFY (Classification Accuracy of Pressure-Only Ratios Against Indices Using Flow Study).

OBJECTIVES This study sought to determine if adenosine administration is required for the pressure-only assessment of coronary stenoses. BACKGROUND The instantaneous wave-free ratio (iFR) is a vasodilator-free pressure-only measure of the hemodynamic severity of a coronary stenosis comparable to fractional flow reserve (FFR) in diagnostic categorization. In this study, we used hyperemic stenosis resistance (HSR), a combined pressure-and-flow index, as an arbiter to determine when iFR and FFR disagree which index is most representative of the hemodynamic significance of the stenosis. We then test whether administering adenosine significantly improves diagnostic performance of iFR. METHODS In 51 vessels, intracoronary pressure and flow velocity was measured distal to the stenosis at rest and during adenosine-mediated hyperemia. The iFR (at rest and during adenosine administration [iFRa]), FFR, HSR, baseline, and hyperemic microvascular resistance were calculated using automated algorithms. RESULTS When iFR and FFR disagreed (4 cases, or 7.7% of the study population), HSR agreed with iFR in 50% of cases and with FFR in 50% of cases. Differences in magnitude of microvascular resistance did not influence diagnostic categorization; iFR, iFRa, and FFR had equally good diagnostic agreement with HSR (receiver-operating characteristic area under the curve 0.93 iFR vs. 0.94 iFRa and 0.96 FFR, p = 0.48). CONCLUSIONS iFR and FFR had equivalent agreement with classification of coronary stenosis severity by HSR. Further reduction in resistance by the administration of adenosine did not improve diagnostic categorization, indicating that iFR can be used as an adenosine-free alternative to FFR.

The arterial reservoir pressure increases with aging and is the major determinant of the aortic augmentation index

The augmentation index predicts cardiovascular mortality and is usually explained as a distally reflected wave adding to the forward wave generated by systole. We propose that the capacitative properties of the aorta (the arterial reservoir) also contribute significantly to the augmentation index and have calculated the contribution of the arterial reservoir, independently of wave reflection, and assessed how these contributions change with aging. In 15 subjects (aged 53 ± 10 yr), we measured pressure and Doppler velocity simultaneously in the proximal aorta using intra-arterial wires. We calculated the components of augmentation pressure in two ways: 1) into forward and backward (reflected) components by established separation methods, and 2) using an approach that accounts for an additional reservoir component. When the reservoir was ignored, augmentation pressure (22.7 ± 13.9 mmHg) comprised a small forward wave (peak pressure = 6.5 ± 9.4 mmHg) and a larger backward wave (peak pressure = 16.2 ± 7.6 mmHg). After we took account of the reservoir, the contribution to augmentation pressure of the backward wave was reduced by 64% to 5.8 ± 4.4 mmHg (P < 0.001), forward pressure was negligible, and reservoir pressure was the largest component (peak pressure = 19.8 ± 9.3 mmHg). With age, reservoir pressure increased progressively (9.9 mmHg/decade, r = 0.69, P < 0.001). In conclusion, the augmentation index is principally determined by aortic reservoir function and other elastic arteries and only to a minor extent by reflected waves. Reservoir function rather than wave reflection changes markedly with aging, which accounts for the age-related changes in the aortic pressure waveform.

Haemodynamic effects of changes in atrioventricular and interventricular delay in cardiac resynchronisation therapy show a consistent pattern: analysis of shape, magnitude and relative importance of atrioventricular and interventricular delay

Objective: To assess the haemodynamic effect of simultaneously adjusting atrioventricular (AV) and interventricular (VV) delays. Method: 35 different combinations of AV and VV delay were tested by using digital photoplethysmography (Finometer) with repeated alternations to measure relative change in systolic blood pressure (SBPrel) in 15 patients with cardiac resynchronisation devices for heart failure. Results: Changing AV delay had a larger effect than changing VV delay (range of SBPrel 21 v 4.2 mm Hg, p < 0.001). Each had a curvilinear effect. The curve of response to AV delay fitted extremely closely to a parabola (average R2  =  0.99, average residual variance 0.8 mm Hg2). The response to VV delay was significantly less curved (quadratic coefficient 67 v 1194 mm Hg/s2, p  =  0.003) and therefore, although the residual variance was equally small (0.8 mm Hg2), the R2 value was 0.7. Reproducibility at two months was good, with the SD of the difference between two measurements of SBPrel being 2.5 mm Hg for AV delay (2% of mean systolic blood pressure) and 1.5 mm Hg for VV delay (1% of mean systolic blood pressure). Conclusions: Changing AV and VV delays results in a curvilinear acute blood pressure response. This shape fits very closely to a parabola, which may be valuable information in developing a streamlined clinical protocol. VV delay adjustment provides an additional, albeit smaller, haemodynamic benefit to AV optimisation.

Cardiac and vascular pathophysiology in hypertension

Hypertension is one the earliest recorded medical conditions (Nei Jin by Huang Ti around 2600BC); it has shaped the course of modern history1 and the consequences of hypertension (myocardial infarction, strokes, and heart failure) will soon be the leading global cause of death. Nevertheless, despite intensive research, the aetiology of hypertension remains obscure; only around 5% of cases have an identifiable cause.2 Indeed, primary or essential hypertension is perhaps better not considered a disease at all,w1 rather (as suggested by Sir Geoffrey Rose) a level of blood pressure above which treatment does more good than harm. An individual’s blood pressure depends on the complex interplay of heart and blood vessels and understanding this relation is the key to understanding the pathophysiology of hypertension. ### Relation between mean pressure and mean flow in the human circulation The role of the circulation is to deliver blood to the tissues and flow occurs because of the pressure difference established by the pumping action of the heart. The relation between the pressure difference and flow can be described by a relation that is analogous to Ohm’s Law for electrical current (box 1) and sometimes termed Darcy’s Law. \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[{\Delta}P\ =\ Q\ {\times}\ R\] \end{document} (where ΔP = pressure difference. Q = bulk flow, R = resistance) This relation can be restated for the whole circulation in terms of mean arterial pressure, cardiac output, and peripheral resistance (box 2). \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \[MAP\ =\ CO\ {\times}\ PVR\] \end{document} (where MAP = mean arterial pressure, CO = cardiac output (= stroke volume × heart rate), PVR = total peripheral vascular resistance) Although a simplification, this emphasises that an elevation of mean blood pressure can only come about as a result of an increase in cardiac output (CO), an increase in total peripheral vascular resistance (PVR), or a combination of both. CO is a consequence of left ventricular pump function, which in turn depends on a number of factors (fig 1) including …

Quantifying the paradoxical effect of higher systolic blood pressure on mortality in chronic heart failure

Background: Although higher blood pressures are generally recognised to be an adverse prognostic marker in risk assessment of cardiology patients, its relationship to risk in chronic heart failure (CHF) may be different. Objective: To examine systematically published reports on the relationship between blood pressure and mortality in CHF. Methods: Medline and Embase were used to identify studies that gave a hazard or relative risk ratio for systolic blood pressure in a stable population with CHF. Included studies were analysed to obtain a unified hazard ratio and quantify the degree of confidence. Results: 10 studies met the inclusion criteria, giving a total population of 8088, with 29 222 person-years of follow-up. All studies showed that a higher systolic blood pressure (SBP) was a favourable prognostic marker in CHF, in contrast to the general population where it is an indicator of poorer prognosis. The decrease in mortality rates associated with a 10 mm Hg higher SBP was 13.0% (95% CI 10.6% to 15.4%) in the heart failure population. This was not related to aetiology, ACE inhibitor or β blocker use. Conclusion: SBP is an easily measured, continuous variable that has a remarkably consistent relationship with mortality within the CHF population. The potential of this simple variable in outpatient assessment of patients with CHF should not be neglected. One possible application of this information is in the optimisation of cardiac resynchronisation devices.