Justin E. Davies

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

BACKGROUNDnSympathetic 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.nnnMETHODn7 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.nnnRESULTSnNo 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.nnnCONCLUSIONSnThis 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 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.

Wave intensity analysis and the development of the reservoir–wave approach

The parameters of wave intensity analysis are calculated from incremental changes in pressure and velocity. While it is clear that forward- and backward-traveling waves induce incremental changes in pressure, not all incremental changes in pressure are due to waves; changes in pressure may also be due to changes in the volume of a compliant structure. When the left ventricular ejects blood rapidly into the aorta, aortic pressure increases, in part, because of the increase in aortic volume: aortic inflow is momentarily greater than aortic outflow. Therefore, to properly quantify the effects of forward or backward waves on arterial pressure and velocity (flow), the component of the incremental change in arterial pressure that is due only to this increase in arterial volume—and not, fundamentally, due to waves—first must be excluded. This component is the pressure generated by the filling and emptying of the reservoir, Otto Frank’s Windkessel.

Fractional Flow Reserve–Guided Revascularization: Practical Implications of a Diagnostic Gray Zone and Measurement Variability on Clinical Decisions

OBJECTIVESnThis study sought to evaluate the effects of fractional flow reserve (FFR) measurement variability on FFR-guided treatment strategy.nnnBACKGROUNDnCurrent appropriateness guidelines recommend the utilization of FFR to guide coronary revascularization based on a fixed cut-off of 0.8. This rigid approach does not take into account the intrinsic biological variability of a single FFR result and the clinical judgment of experienced interventional cardiologists. [corrected].nnnMETHODSnFFR reproducibility data from the landmark Deferral Versus Performance of PTCA in Patients Without Documented Ischemia (DEFER) trial was analyzed (two repeated FFR measurements in the same lesion, 10 min apart) and the standard deviation of the difference (SDD) between repeated measurements was calculated. The measurement certainty (probability that the FFR-guided revascularization strategy will not change if the test is repeated 10 min later) was subsequently established across the whole range of FFR values, from 0.2 to 1.nnnRESULTSnOutside the [0.75 to 0.85] FFR range, measurement certainty of a single FFR result is >95%. However, closer to its cut-off, certainty falls to less than 80% within 0.77 to 0.83, reaching a nadir of 50% around 0.8. In clinical practice, that means that each time a single FFR value falls between 0.75 and 0.85, there is a chance that the FFR-derived revascularization recommendation will change if the measurement is repeated 10 min later, with this chance increasing the closer the FFR result is to 0.8.nnnCONCLUSIONSnA measurement FFR gray-zone is found between 0.75 and 0.85]. Therefore, clinicians should make revascularization decisions based on broadened clinical judgment when a single FFR result falls within this uncertainty zone, particularly between 0.77 and 0.83, when measurement certainty falls to less than 80%.

Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial

BACKGROUNDnPrevious randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure in the absence of antihypertensive medications.nnnMETHODSnSPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749.nnnFINDINGSnBetween June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP -5·5 mm Hg (95% CI -9·1 to -2·0; p=0·0031), 24-h DBP -4·8 mm Hg (-7·0 to -2·6; p<0·0001), office SBP -10·0 mm Hg (-15·1 to -4·9; p=0·0004), and office DBP -5·3 mm Hg (-7·8 to -2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP -0·5 mm Hg (95% CI -3·9 to 2·9; p=0·7644), 24-h DBP -0·4 mm Hg (-2·2 to 1·4; p=0·6448), office SBP -2·3 mm Hg (-6·1 to 1·6; p=0·2381), and office DBP -0·3 mm Hg (-2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP -5·0 mm Hg (95% CI -9·9 to -0·2; p=0·0414), 24-h DBP -4·4 mm Hg (-7·2 to -1·6; p=0·0024), office SBP -7·7 mm Hg (-14·0 to -1·5; p=0·0155), and office DBP -4·9 mm Hg (-8·5 to -1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group.nnnINTERPRETATIONnResults from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.nnnFUNDINGnMedtronic.

A Meta-Analysis of the Mechanism of Blood Pressure Change With Aging

OBJECTIVESnWe undertook a meta-analysis to determine whether changes in wave reflection substantiate the consensus explanation of why blood pressure (BP) changes with aging.nnnBACKGROUNDnConsensus documents attribute the aging changes in BP to wave reflection moving progressively from diastole into systole. However, the extensive quantitative data on this phenomenon have never been systematically reviewed. Individual studies have been small, and limited to a narrow age range.nnnMETHODSnUsing PubMed, Cochrane, and Web of Science databases, we identified 64 studies (including 13,770 subjects, age range 4 to 91 years) reporting the timing of wave reflection, defined as the time from the onset (foot) of the pressure waveform to the shoulder point (anachrotic notch).nnnRESULTSnIn subjects of all ages, reflection times were well within systole. There was a small tendency for younger subjects to have later reflection, but this was only 0.7 ms per year, whereas the weighted mean reflection time was 136 ms (99% confidence interval: 130 to 141 ms) and the mean duration of systole was 328 ms (99% confidence interval: 310 to 347 ms). At this rate of change with age, arrival of wave reflection would only be construed to be in diastole at an extrapolated age of -221 years.nnnCONCLUSIONSnThese findings challenge the current consensus view that a shift in timing of wave reflection significantly contributes to the changes in the BP waveform with aging. We should re-evaluate the mechanisms of BP elevation in aging.

Disturbed Coronary Hemodynamics in Vessels with Intermediate Stenoses Evaluated with Fractional Flow Reserve: A Combined Analysis of Epicardial and Microcirculatory Involvement in Ischemic Heart Disease

Background— In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown. Methods and Results— Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR>0.80 and CFR<2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75th percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR>0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR>0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4–31.8)] than those with FFR⩽0.80 [17.3 (95% confidence interval, 13.0–21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR (r=−0.207, P=0.055), and in vessels with FFR>0.80 and CFR<2 (n=28, 39%), IMR had a wide dispersion (7–72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR⩽0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation. Conclusions— A substantial number of coronary arteries with stenoses showing an FFR>0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.

Arterial Pulse Wave Dynamics After Percutaneous Aortic Valve Replacement Fall in Coronary Diastolic Suction With Increasing Heart Rate as a Basis for Angina Symptoms in Aortic Stenosis

Background— Aortic stenosis causes angina despite unobstructed arteries. Measurement of conventional coronary hemodynamic parameters in patients undergoing valvular surgery has failed to explain these symptoms. With the advent of percutaneous aortic valve replacement (PAVR) and developments in coronary pulse wave analysis, it is now possible to instantaneously abolish the valvular stenosis and to measure the resulting changes in waves that direct coronary flow. Methods and Results— Intracoronary pressure and flow velocity were measured immediately before and after PAVR in 11 patients with unobstructed coronary arteries. Using coronary pulse wave analysis, we calculated the intracoronary diastolic suction wave (the principal accelerator of coronary blood flow). To test physiological reserve to increased myocardial demand, we measured at resting heart rate and during pacing at 90 and 120 bpm. Before PAVR, the basal myocardial suction wave intensity was 1.9±0.3×10−5 W · m−2 · s−2, and this increased in magnitude with increasing severity of aortic stenosis (r=0.59, P=0.05). This wave decreased markedly with increasing heart rate (&bgr; coefficient=−0.16×10−4 W · m−2 · s−2; P<0.001). After PAVR, despite a fall in basal suction wave (1.9±0.3 versus 1.1±0.1×10−5 W · m−2 · s−2; P=0.02), there was an immediate improvement in coronary physiological reserve with increasing heart rate (&bgr; coefficient=0.9×10−3 W · m−2 · s−2; P=0.014). Conclusions— In aortic stenosis, the coronary physiological reserve is impaired. Instead of increasing when heart rate rises, the coronary diastolic suction wave decreases. Immediately after PAVR, physiological reserve returns to a normal positive pattern. This may explain how aortic stenosis can induce anginal symptoms and their prompt relief after PAVR. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01118442.Background— Aortic stenosis causes angina despite unobstructed arteries. Measurement of conventional coronary hemodynamic parameters in patients undergoing valvular surgery has failed to explain these symptoms. With the advent of percutaneous aortic valve replacement (PAVR) and developments in coronary pulse wave analysis, it is now possible to instantaneously abolish the valvular stenosis and to measure the resulting changes in waves that direct coronary flow.nnMethods and Results— Intracoronary pressure and flow velocity were measured immediately before and after PAVR in 11 patients with unobstructed coronary arteries. Using coronary pulse wave analysis, we calculated the intracoronary diastolic suction wave (the principal accelerator of coronary blood flow). To test physiological reserve to increased myocardial demand, we measured at resting heart rate and during pacing at 90 and 120 bpm. Before PAVR, the basal myocardial suction wave intensity was 1.9±0.3×10−5 W · m−2 · s−2, and this increased in magnitude with increasing severity of aortic stenosis ( r =0.59, P =0.05). This wave decreased markedly with increasing heart rate (β coefficient=−0.16×10−4 W · m−2 · s−2; P <0.001). After PAVR, despite a fall in basal suction wave (1.9±0.3 versus 1.1±0.1×10−5 W · m−2 · s−2; P =0.02), there was an immediate improvement in coronary physiological reserve with increasing heart rate (β coefficient=0.9×10−3 W · m−2 · s−2; P =0.014).nnConclusions— In aortic stenosis, the coronary physiological reserve is impaired. Instead of increasing when heart rate rises, the coronary diastolic suction wave decreases. Immediately after PAVR, physiological reserve returns to a normal positive pattern. This may explain how aortic stenosis can induce anginal symptoms and their prompt relief after PAVR.nnClinical Trial Registration— URL: . Unique identifier: [NCT01118442][1].nn# Clinical Perspective {#article-title-31}nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01118442&atom=%2Fcirculationaha%2F124%2F14%2F1565.atom

Association of masked hypertension and left ventricular remodeling with the hypertensive response to exercise

BACKGROUNDnA hypertensive response to exercise (HRE; defined as normal clinic blood pressure (BP) and exercise systolic BP (SBP) ≥210 mm Hg in men or ≥190 mm Hg in women, or diastolic BP (DBP) ≥105 mm Hg) independently predicts mortality. The mechanisms remain unclear but may be related to masked hypertension. This study aimed to assess the prevalence of masked hypertension and its association with cardiovascular risk factors, including left ventricular (LV) mass, in patients with a HRE.nnnMETHODSnComprehensive clinical and echocardiographic evaluation (including central BP, aortic pulse wave velocity by tonometry) and 24-h ambulatory BP monitoring (ABPM) were performed in 72 untreated patients with HRE (aged 54 ± 9 years; 60% male; free from coronary artery disease confirmed by exercise stress echocardiography). Masked hypertension was defined according to guidelines as daytime ABPM ≥135/85 mm Hg and clinic BP <140/90 mm Hg.nnnRESULTSnMasked hypertension was present in 42 patients (58%). These patients had higher LV mass index (41.5 ± 8.7 g/m(2.7) vs. 35.9 ± 8.5 g/m(2.7); P = 0.01), LV relative wall thickness (RWT; 0.42 ± 0.09 vs. 0.37 ± 0.06; P = 0.004) and exercise SBP (222 ± 17 mm Hg vs. 212 ± 14 mm Hg; P = 0.01), but no significant difference in aortic pulse wave velocity or central pulse pressure (P > 0.05 for both). The strongest independent determinant of LV mass index was the presence of masked hypertension (unstandardized β = 5.6; P = 0.007), which was also independently related to LV RWT (unstandardized β = 0.04; P = 0.03).nnnCONCLUSIONSnMasked hypertension is highly prevalent in HRE patients with a normal resting office BP and is associated with increased LV mass index and RWT. Clinicians should consider measuring ABPM or home BP in HRE patients.

Limitations of augmentation index in the assessment of wave reflection in normotensive healthy individuals.

Objectives Augmentation index (AIx) is widely used as a measure of wave reflection. We compared the relationship between AIx and age, height and sex with ‘gold standard’ measures of wave reflection derived from measurements of pressure and flow to establish how well AIx measures wave reflection. Materials and Methods Measurements of carotid pressure and flow velocity were made in the carotid artery of 65 healthy normotensive individuals (age 21–78 yr; 43 male) and pulse wave analysis, wave intensity analysis and wave separation was performed; waveforms were classified into type A, B or C. AIx, the time of the first shoulder (Ts), wave reflection index (WRI) and the ratio of backward to forward pressure (Pb/Pf) were calculated. Results AIx did not correlate with log WRI or Pb/Pf. When AIx was restricted to positive values AIx and log WRI were positively correlated (ru200a=u200a0.33; pu200a=u200a0.04). In contrast log WRI and Pb/Pf were closely correlated (ru200a=u200a0.66; p<0.001). There was no correlation between the Ts and the timing of Pb or the reflected wave identified by wave intensity analysis. Wave intensity analysis showed that the morphology of type C waveforms (negative AIx) was principally due to a forward travelling (re-reflected) decompression wave in mid-systole. AIx correlated positively with age, inversely with height and was higher in women. In contrast log WRI and Pb/Pf showed negative associations with age, were unrelated to height and did not differ significantly by gender. Conclusions AIx has serious limitations as a measure of wave reflection. Negative AIx values derived from Type C waves should not be used as estimates of wave reflection magnitude.