Physiology of Angina and Its Alleviation With Nitroglycerin: Insights From Invasive Catheter Laboratory Measurements During Exercise.

BACKGROUND: The mechanisms governing exercise-induced angina and its alleviation by the most commonly used antianginal drug, nitroglycerin, are incompletely understood. The purpose of this study was to develop a method by which the effects of antianginal drugs could be evaluated invasively during physiological exercise to gain further understanding of the clinical impact of angina and nitroglycerin. METHODS: Forty patients (mean age, 65.2±7.6 years) with exertional angina and coronary artery disease underwent cardiac catheterization via radial access and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual nitroglycerin was administered to half the patients, and all patients continued to exercise for 2 minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity and central aortic pressure were recorded with sensor wires. RESULTS: Patients continued to exercise after nitroglycerin administration with less ST-segment depression (P=0.003) and therefore myocardial ischemia. Significant reductions in afterload (aortic pressure, P=0.030) and myocardial oxygen demand were seen (tension-time index, P=0.024; rate-pressure product, P=0.046), as well as an increase in myocardial oxygen supply (Buckberg index, P=0.017). Exercise reduced peripheral arterial wave reflection (P<0.05), which was not further augmented by the administration of nitroglycerin (P=0.648). The observed increases in coronary pressure gradient, stenosis resistance, and flow velocity did not reach statistical significance; however, the diastolic velocity-pressure gradient relation was consistent with a significant increase in relative stenosis severity (k coefficient, P<0.0001), in keeping with exercise-induced vasoconstriction of stenosed epicardial segments and dilatation of normal segments, with trends toward reversal with nitroglycerin. CONCLUSIONS: The catheterization laboratory protocol provides a model to study myocardial ischemia and the actions of novel and established antianginal drugs. Administration of nitroglycerin causes changes in the systemic and coronary circulation that combine to reduce myocardial oxygen demand and to increase supply, thereby attenuating exercise-induced ischemia. Designing antianginal therapies that exploit these mechanisms may provide new therapeutic strategies.

Use of the Lotus Transcatheter Valve to Treat Severe Native Aortic Regurgitation.

Transcatheter aortic valve implantation (TAVI) has become the standard treatment for aortic stenosis in high-risk patients. TAVI for native valve aortic regurgitation is technically more demanding because of a lack of anchoring calcification, a lower index incidence, heterogeneous causes, and larger anatomy. We present 3 cases in which the Lotus TAV was used to treat severe native aortic regurgitation (AR) successfully.

Meta-analysis of the impact of mitral regurgitation on outcomes after transcatheter aortic valve implantation.

Significant mitral regurgitation (MR) constitutes an important co-existing valvular heart disease burden in the setting of aortic valve stenosis. There are conflicting reports on the impact of significant MR on outcomes after transcatheter aortic valve implantation (TAVI). We evaluated the impact of MR on outcomes after TAVI by performing a meta-analysis of 8 studies involving 8,927 patients reporting TAVI outcomes based on the presence or absence of moderate-severe MR. Risk ratios (RRs) were calculated using the inverse variance random-effects model. None-mild MR was present in 77.8% and moderate-severe MR in 22.2% of the patients. The presence of moderate-severe MR at baseline was associated with increased mortality at 30 days (RR 1.35, 95% confidence interval [CI] 1.14 to 1.59, p = 0.003) and 1 year (RR 1.24, 95% CI 1.13 to 1.37, p <0.0001). The increased mortality associated with moderate-severe MR was not influenced by the cause of MR (functional or degenerative MR; RR 0.90, 95% CI 0.62 to 1.30, p = 0.56). The severity of MR improved in 61 ± 6.0% of patients after TAVI. Moderate-severe residual MR, compared with none-mild residual MR after TAVI, was associated with significantly increased 1-year mortality (RR 1.48, 95% CI 1.31 to 1.68, p <0.00001). In conclusion, baseline moderate-severe MR and significant residual MR after TAVI are associated with an increase in mortality after TAVI and represent an important group to target with medical or transcatheter therapies in the future.

The effect of coronary artery disease defined by quantitative coronary angiography and SYNTAX score upon outcome after transcatheter aortic valve implantation (TAVI) using the Edwards bioprosthesis.

AIMS: We sought to evaluate the effects of significant coronary artery disease (CAD) upon outcome after transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: We performed a retrospective study of 271 consecutive patients undergoing TAVI using either the Edwards SAPIEN or Edwards SAPIEN XT valve. Pre-procedural coronary angiograms were analysed by quantitative coronary angiography (defining significant CAD as a stenosis of ≥70% or ≥50% if in the left main stem or a vein graft). Ninety-three out of 271 patients had significant CAD. There was no difference in mortality at 30 days or 12 months between the two groups (6.7% vs. 7.5% and 21.5% vs. 23.7%; log-rank p=0.805). A secondary analysis using the SYNTAX algorithm of coronary anatomy complexity was performed on 189 patients. Those in the high SYNTAX score (>33) group had higher mortality at 30 days and 12 months (14.3% and 57.1%) than the low (5.2% and 23.3%) and intermediate-risk groups (11.1% and 22.2%; log-rank p=0.007). ROC analysis identified a SYNTAX score of >9 at the time of TAVI as the optimal cut-off, with an independent association with mortality (HR 1.95 [95% CI: 1.21-3.13]; p=0.006). Patients with a SYNTAX score >9 had greater 30-day, 12-month and overall mortalities than those with a SYNTAX score <9 (3.7% vs. 11.3% and 20.7% vs. 34.3%; log-rank p=0.005). CONCLUSIONS: Significant CAD, as defined using "real-world" QCA margins, did not have a significant effect upon mortality after TAVI for severe aortic stenosis. However, higher-risk SYNTAX groups, including those with a score >9, had increased mortality.

Early and late changes in quality of life following transcatheter aortic valve implantation using the transfemoral and transapical approaches.

AIMS: To evaluate the effects of access route upon clinical results and quality of life (QoL) in patients undergoing either transfemoral (TF-TAVI) or transapical balloon-expandable transcatheter aortic valve implantation (TA-TAVI) in the real world. METHODS AND RESULTS: A prospective analysis was performed upon 264 consecutive patients receiving TF-TAVI or TA-TAVI. QoL was assessed using the EQ-5D questionnaire. At baseline, TA-TAVI patients reported significantly more problems in mobility, self-care, usual activities and lower overall health status domains (p<0.01 for all). At 30 days, the TF-TAVI group reported fewer problems with usual activity (p=0.01) and pain/discomfort (p<0.01), and higher EQ-5D index and visual analogue scale (VAS) (p=0.01 and p<0.01, respectively) than the TA-TAVI group. Nevertheless, the absolute improvements (ΔEQ-5D index and ΔEQ-5D VAS) were larger in the TA-TAVI group, with most dramatically marked QoL absolute improvements (p<0.01 and p=0.02, respectively). By one year, notwithstanding higher all-cause mortality in the sicker TA-TAVI group, there were no differences between groups in any EQ-5D domain. Indeed, surviving TA-TAVI group's greater absolute improvements remained (p<0.01). CONCLUSIONS: QoL is greater at the earlier time point of 30 days in the TF-TAVI cohort but equatable by one year. However, the magnitude of improvement in QoL is greater in the TA-TAVI patients at both 30 days and one year.

Coronary artery disease in patients undergoing TAVI--why not to treat.

The management of coronary artery disease in the context of severe aortic stenosis in patients at increased surgical risk is an increasingly relevant problem in the transcatheter aortic valve implantation (TAVI) era. We review the current data on percutaneous coronary intervention (PCI) in TAVI patients and discuss how it has impacted upon our decision making, advocating that pre-TAVI revascularisation is not necessarily required.

The percutaneous coronary intervention prior to transcatheter aortic valve implantation (ACTIVATION) trial: study protocol for a randomized controlled trial.

BACKGROUND: Current guidelines recommend treatment of significant coronary artery disease by concomitant coronary artery bypass grafting (CABG) in patients undergoing surgical aortic valve replacement. However there is no consensus as to how best to treat coronary disease in high-risk patients requiring transcatheter aortic valve implantation (TAVI). METHODS/DESIGN: The percutaneous coronary intervention prior to transcatheter aortic valve implantation (ACTIVATION) trial is a randomized, controlled open-label trial of 310 patients randomized to treatment of significant coronary artery disease by percutaneous coronary intervention (PCI - test arm) or no PCI (control arm). Significant coronary disease is defined as ≥1 lesion of ≥70% severity in a major epicardial vessel or 50% in a vein graft or protected left main stem lesion. The trial tests the hypothesis that the strategy of performing pre-TAVI PCI is non-inferior to not treating such coronary stenoses with PCI prior to TAVI, with a composite primary outcome of 12-month mortality and rehospitalization. Secondary outcomes include efficacy end-points such as 30-day mortality, safety endpoints including bleeding, burden of symptoms, and quality of life (assessed using the Seattle Angina Questionnaire and the Kansas City Cardiomyopathy Questionnaire). In conclusion, we hope that using a definition of coronary artery disease severity closer to that used in everyday practice by interventional cardiologists - rather than the 50% severity used in surgical guidelines - will provide robust evidence to direct guidelines regarding TAVI therapy and improve its safety and efficacy profile of this developing technique. TRIAL REGISTRATION: ISRCTN75836930, http://www.controlled-trials.com/ISRCTN75836930 (registered 19 November 2011).

Hemodynamic response to intravenous adenosine and its effect on fractional flow reserve assessment: results of the Adenosine for the Functional Evaluation of Coronary Stenosis Severity (AFFECTS) study.

BACKGROUND: We studied the hemodynamic response to intravenous adenosine on calculation of fractional flow reserve (FFR). Intravenous adenosine is widely used to achieve conditions of stable hyperemia for measurement of FFR. However, intravenous adenosine affects both systemic and coronary vascular beds differentially. METHODS AND RESULTS: A total of 283 patients (310 coronary stenoses) underwent coronary angiography with FFR using intravenous adenosine 140 mcg/kg per minute via a central femoral vein. Offline analysis was performed to calculate aortic (Pa), distal intracoronary (Pd), and reservoir (Pr) pressure at baseline, peak, and stable hyperemia. Seven different hemodynamic patterns were observed according to Pa and Pd change at peak and stable hyperemia. The average time from baseline to stable hyperemia was 68.2±38.5 seconds, when both ΔPa and ΔPd were decreased (ΔPa, -10.2±10.5 mm Hg; ΔPd, -18.2±10.8 mm Hg; P<0.001 for both). The fall in Pa closely correlated with the reduction in peripheral Pr (ΔPr, -12.9±15.7 mm Hg; P<0.001; r=0.9; P<0.001). ΔPa and ΔPd were closely related under conditions of peak (r=0.75; P<0.001) and stable hyperemia (r=0.83; P<0.001). On average, 56% (10.2 mm Hg) of the reduction in Pd was because of fall in Pa. FFR lesion classification changed in 9% using an FFR threshold of ≤0.80 and 5.2% with FFR threshold <0.75 when comparing Pd/Pa at peak and stable hyperemia. CONCLUSIONS: Intravenous adenosine results in variable changes in systemic blood pressure, which can lead to alterations in FFR lesion classification. Attention is required to ensure FFR is measured under conditions of stable hyperemia, although the FFR value at this point may be numerically higher.

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.

Standalone balloon aortic valvuloplasty: indications and outcomes from the UK in the transcatheter valve era.

OBJECTIVES: We sought to characterize UK-wide balloon aortic valvuloplasty (BAV) experience in the TAVI era. BACKGROUND: BAV for acquired calcific aortic stenosis is in a phase of renaissance, largely due to the development of transcatheter aortic valve implantation (TAVI). METHODS: Data from 423 patients at 14 centers across the UK were analyzed. RESULTS: Patients were aged 80.9 ± 9.5 years; 52.5% were male. Mean logistic EuroScore was 27.3% ± 16.8%. Mean peak transaortic gradient fell from 62.0 ± 26.3 to 28.3 ± 16.2 mm Hg. Aortic valve area increased from 0.58 ± 0.19 to 0.80 ± 0.25 cm(2) echocardiographically. Procedural complication rate was 6.3%, comprising death (2.4%), blood transfusion ≥ 2 U (1.2%), cardiac tamponade (1.0%), stroke (1.0%), vascular surgical repair (1.0%), coronary embolism (0.5%), and permanent pacemaker (0.2%). Mortality was 13.8% at 30 days and 36.3% at 12 months. Subsequently, 18.3% of patients underwent TAVI and 7.0% sAVR, with improved survival compared to those who had no further intervention (logrank < 0.0001). Multivariate Cox proportional hazard analysis demonstrated that survival was adversely effected by the presence of coronary artery disease (HR 1.53, 95%CI 1.08-2.17, P = 0.018), poor LV function (HR 1.54, 95%CI 1.09-2.16, P = 0.014), and either urgent (HR 1.70, 95%CI 1.18-2.45; P = 0.004) or emergent presentation (HR 3.72, 95%CI 2.27-6.08; P < 0.0001). CONCLUSION: Balloon aortic valvuloplasty offers good immediate hemodynamic efficacy at an acceptable risk of major complications. Medium-term prognosis is poor in the absence of definitive therapy.

Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry.

AIMS: To evaluate the classification agreement between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) in patients with angiographic intermediate coronary stenoses. METHODS AND RESULTS: Three hundred and twelve patients (339 stenoses) with angiographically intermediate stenoses were included in this international clinical registry. The iFR was calculated using fully automated algorithms. The receiver operating characteristic (ROC) curve was used to identify the iFR optimal cut-point corresponding to FFR 0.8. The classification agreement of coronary stenoses as significant or non-significant was established between iFR and FFR and between repeated FFR measurements for each 0.05 quantile of FFR values, from 0.2 to 1. Close agreement was observed between iFR and FFR (area under ROC curve= 86%). The optimal iFR cut-off (for an FFR of 0.80) was 0.89. After adjustment for the intrinsic variability of FFR, the classification agreement (accuracy) between iFR and FFR was 94%. Amongst the stenoses classified as non-significant by iFR (>0.89) and as significant by FFR (≤0.8), 81% had associated FFR values located within the FFR "grey-zone" (0.75-0.8) and 41% within the 0.79-0.80 FFR range. CONCLUSIONS: In a population of intermediate coronary stenoses, the classification agreement between iFR and FFR is excellent and similar to that of repeated FFR measurements in the same sample. Vasodilator-independent assessment of intermediate stenosis seems applicable and may foster adoption of coronary physiology in the catheterisation laboratory.

The effects of VARC-defined acute kidney injury after transcatheter aortic valve implantation (TAVI) using the Edwards bioprosthesis.

AIMS: The aim of this study was to identify the incidence and risk factors for acute kidney injury (AKI) after TAVI, a potentially serious complication of transcatheter aortic valve implantation (TAVI) that has been redefined by the Valve Academic Research Consortium (VARC). METHODS AND RESULTS: We performed a retrospective analysis of 248 patients undergoing TAVI. AKI was defined as a VARC-modified Risk, Injury, Failure, Loss, and End-stage (RIFLE) kidney disease score ≥ 2. Eighty-nine patients suffered AKI (35.9%) and demonstrated increased mortality at 30 days (13.5% vs. 3.8%) and one year (31.5% vs. 15.0%) (p<0.001). Multivariate regression analysis identified diabetes mellitus (p<0.001), peripheral vascular disease (p=0.007), chronic kidney disease stage (p=0.010) as independently associated risk factors for AKI. CONCLUSIONS: More than one third of patients sustain AKI after TAVI using the Edwards bioprosthesis, as defined by the VARC-modified RIFLE score. AKI increased the mortality at both 30 days and at one year. A history of diabetes mellitus, peripheral vascular disease and higher chronic kidney disease stage had the strongest independent associations with post-TAVI AKI.

Transaortic Transcatheter Aortic valve implantation using Edwards Sapien valve: a novel approach.

OBJECTIVES: To evaluate feasibility and outcome of Transoartic Transcatheter Sapien valve implantation. BACKGROUND: Transcatheter Aortic valve implantation (TAVI) using the Edwards SAPIEN device (Edwards LifeScience, Irvine, CA) is usually performed via the transfemoral (TF) or transapical (TA) routes. Some patients are not suitable for these approaches. We report our experience with the novel transaortic (TAo) approach via a partial upper sternotomy and discuss the advantages and future applications. METHODS: Between January 2008 to March 2011 193 patients with severe aortic stenosis underwent TAVI with the Edwards SAPIEN bioprosthesis at the St. Thomas' Hospital, London. 108 patients were unable to undergo a TF-TAVI and of those 17 were accepted for a TAo-TAVI on the basis of anatomy, risk, LV function, and significant respiratory disease. RESULTS: The TAo-TAVI group (n = 17) had more prevalent respiratory disease than the TA-TAVI group (47.0% vs. 18.7%, P = 0.011). Otherwise the groups were similar in demographics and history. Despite this the 30 day mortalities were not significantly different between the groups (TAo-TAVI 4.3% at 30 days versus TA-TAVI 7.7%, P = 0.670). There were no significant differences in procedural complications. CONCLUSIONS: The TA-TAVI approach may not be desirable in patients with severe chest deformity, poor lung function or poor left ventricular function. TAo-TAVI via a partial sternotomy is safe and feasible in these patients.

Successful treatment of a late presentation exercise-induced spontaneous left anterior descending artery dissection.

Spontaneous coronary artery dissection is an unusual condition that mainly happens in fit and healthy women in the peripartum period. Strenuous exercise is a rare cause of dissection in angiographically normal coronary arteries. There is no definitive consensus on the etiology, prognosis and treatment of SCAD. We report a case of successful treatment of a late presentation of a coronary artery dissection secondary to intense physical activity in a 48 year old cyclist who continued to cycle for 3 months post event.

Redo patent foramen ovale closure for persistent residual right-to-left shunting.

AIMS: The success rate in eliminating a right-left-shunting following percutaneous patent foramen ovale closure is estimated to be > 90%. However up to 10% of patients may have residual shunting following initial closure. Little is known as to the optimum treatment strategy for these patients. We report four cases in which to redo patent foramen ovale closure was possible with a second device. METHODS AND RESULTS: At our institution during 2008-2009, 101 patients underwent PFO closure: 81 patients (80%) underwent PFO closure for cerebrovascular events, 12 patients (12%) for migraine with aura, eight patients for systemic embolisation (8%), three patients (3%) for decompression illness and one patient underwent PFO closure for platypnea-orthodexia syndrome. Irrespective of the initial device, redo closure was technically feasible in all cases. All patients had at least a moderate residual shunt evident on echocardiographic evaluation at > 6-month follow-up. The patients in the current study were offered a redo procedure based on the presence of persistent disabling symptoms, as well as increased risk of neurological events, despite adequate antiplatelet therapy and anticoagulation. CONCLUSIONS: A second percutaneous interatrial septal occluder is feasible in those patients with significant residual shunting following initial closure.