Howard Ellis

Physiology of Angina and its Alleviation with Nitroglycerine- 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.

Doppler Versus Thermodilution-Derived Coronary Microvascular Resistance to Predict Coronary Microvascular Dysfunction in Patients With Acute Myocardial Infarction or Stable Angina Pectoris

Coronary microvascular resistance is increasingly measured as a predictor of clinical outcomes, but there is no accepted gold-standard measurement. We compared the diagnostic accuracy of 2 invasive indices of microvascular resistance, Doppler-derived hyperemic microvascular resistance (hMR) and thermodilution-derived index of microcirculatory resistance (IMR), at predicting microvascular dysfunction. A total of 54 patients (61 ± 10 years) who underwent cardiac catheterization for stable coronary artery disease (n = 10) or acute myocardial infarction (n = 44) had simultaneous intracoronary pressure, Doppler flow velocity and thermodilution flow data acquired from 74 unobstructed vessels, at rest and during hyperemia. Three independent measurements of microvascular function were assessed, using predefined dichotomous thresholds: (1) coronary flow reserve (CFR), the average value of Doppler- and thermodilution-derived CFR; (2) cardiovascular magnetic resonance (CMR) derived myocardial perfusion reserve index; and (3) CMR-derived microvascular obstruction. hMR correlated with IMR (rho = 0.41, p <0.0001). hMR had better diagnostic accuracy than IMR to predict CFR (area under curve [AUC] 0.82 vs 0.58, p <0.001, sensitivity and specificity 77% and 77% vs 51% and 71%) and myocardial perfusion reserve index (AUC 0.85 vs 0.72, p = 0.19, sensitivity and specificity 82% and 80% vs 64% and 75%). In patients with acute myocardial infarction, the AUCs of hMR and IMR at predicting extensive microvascular obstruction were 0.83 and 0.72, respectively (p = 0.22, sensitivity and specificity 78% and 74% vs 44% and 91%). We conclude that these 2 invasive indices of coronary microvascular resistance only correlate modestly and so cannot be considered equivalent. In our study, the correlation between independent invasive and noninvasive measurements of microvascular function was better with hMR than with IMR.

A lead to the culprit

A 45-year-old woman presented with persistent chest pain. She had no past medical history and was otherwise fit and well. A 12-lead ECG (Figure 1) recorded by the ambulance team triggered the primary percutaneous intervention pathway. On transit to the primary percutaneous intervention center, the patient suffered a ventricular fibrillation arrest, and sinus rhythm was successfully restored after 3 minutes of resuscitation protocol. What is the likely angiographic finding that would explain the 12-lead ECG pattern? Please turn the page to read the diagnosis. Haseeb Rahman, BMBCh Bhavik Modi, MBBS Howard Ellis, BSc Satpal Arri, MBBS Divaka Perera, MD A Lead to the Culprit

DOPPLER INDICES OF RESISTANCE ARE SUPERIOR TO THERMODILUTION INDICES AT PREDICTING CORONARY MICROVASCULAR DYSFUNCTION

methods: 27-patients (64±11 yrs) were recruited, 48% following an acute coronary syndrome. Simultaneous pressure, Doppler flow velocity and cold-bolus transit time were measured in 40 unobstructed coronary arteries, using a Volcano Combowire and St Jude Pressure Wire, at rest and during intravenous adenosine hyperemia. The following were calculated using standard definitions: coronary flow reserve (CFR) by thermodilution and Doppler, hMR and IMR. 3T cardiac MRI scans were carried out and Myocardial Perfusion Reserve Index (MPRI) calculated in the corresponding segments as previously described.

A Unravelling the Mechanisms of Exercise Induced Ischaemia, its Optimal Assessment, and Alleviation with Nitroglycerine

Introduction The mechanisms governing exercise-induced angina, its alleviation by the most common anti-anginal drug, nitroglycerine (GTN), and the best techniques to elucidate whether a stenosis causes sufficient ischaemia to warrant revascularisation are incompletely understood. In this multifaceted investigation we aimed to investigate these processes. Methods A porcine model of coronary stenosis was developed for invasive assessment of coronary haemodynamics and perfusion MRI. Coronary lesions were created using an external balloon constrictor to investigate the optimal method of assessing stenosis severity, using an invasive standard for coronary ischaemia of Hyperemic Stenosis Resistance (HSR) and a non-invasive standard of adenosine stress perfusion cardiac MRI. In the human translation, 21 Patients with exertional angina and documented coronary artery disease underwent cardiac catheterisation via radial access and performed incremental exercise using a supine cycle ergometer. As they developed limiting angina, sublingual GTN was administered and exercise continued for two minutes at the same workload. Throughout exercise, distal coronary pressure and flow velocity, and central aortic pressure were recorded using sensor wires. After a period of rest, intravenous adenosine was administered to assess lesion severity using conventional catheter methods. Results 64 lesions of varying severity were created in the porcine model showing that Fractional Flow Reserve (FFR) provided the best test of stenosis severity, which was significantly better than instantaneous wave-free ratio (iFR), Basal Stenosis Resistance (BSR), and resting Pd/Pa ratio. In the human translation, indices measured at peak exercise (HSR, FFR) performed significantly better than adenosine-based indices, which were superior to measurements at rest. Compared to peak exercise, patients continued to exercise post-GTN administration with less ischemia (P = 0.003). Coronary pressure and flow were maintained (P=NS), in the face of significant reduction in left ventricular afterload (0.01). On wave intensity analysis, significant increases were seen in both the energy of the diastolic microcirculatory backward expansion wave, and the systolic backward compression wave related to myocardial contractility (0.05). Conclusions Coronary ischaemia can be studied using a porcine model in the catheter laboratory as well as MRI environment. This model showed that the adenosine based indices, HSR and FFR, performed significantly better than those measured at rest, suggesting that these should be used in the assessment of lesion severity. The human exercise protocol provides a new paradigm with which the physiology of ischemia as well as the performance of novel and established anti-anginals can be studied. Administration of GTN causes harmonious changes in the systemic and coronary circulation that combine to reduce afterload while maintaining coronary perfusion. The study also demonstrates, for the first time, a coronary derived index with potential to measure myocardial contractility.

18 Baseline coronary flow varies with normal cardiac catheter laboratory stimuli

Introduction Fractional Flow Reserve (FFR) is a pressure-derived estimate of coronary flow impairment during maximal and constant hyperaemia provided by an adenosine infusion, when flow and pressure approximate linearly. The need for adenosine-induced hyperaemia has led to development of a stenosis severity index measured at rest, Instantaneous Wave Free Ratio (iFR). Its use and proposed applicability to serial/diffuse disease has relied on assumptions that coronary flow at rest is maintained at constant levels. This study aimed to assess variability of resting coronary flow with normal Catheter laboratory stimuli. Methods Forty-Seven elective patients were recruited with a variety of coronary artery disease severity (mean FFR: 0.883; SD: 0.938). Simultaneous intracoronary pressure (Pd) and Doppler Average Peak Flow Velocity, APV(U), recordings were made. These were made both at rest and just prior to supine bicycle exercise or intravenous adenosine infusion. Results Average peak flow velocity varied significantly between measurements at rest and just prior to commencement of adenosine or supine bicycle exercise (18.1765cm/s vs. 19.4689cm/s, p 0.002). This was without significant change in haemodynamics (Table 1). Conclusion Resting coronary flow appears to vary significantly with normal Catheter Laboratory stimuli, such as simple warnings, irrespective of haemodynamic status. Abstract 18 Table 1 Table illustrating changes in Heart Rate, Systolic Blood Pressure (SBP), Ratio of distal coronary pressure to proximal aortic pressure (Pd/Pa) and Average Peak Coronary Flow Velocity (APV) Mean Std. Deviation Resting HR 80.149 14.7780 Pre Stress HR 82.468 (p: 0.227) 15.9208 Resting SBP 128.23 20.6944 Pre Stress SBP 128.88 (p: 0577) 22.9778 Resting Pd/Pa 0.9307 0.1106 Pre Stress Pd/Pa 0.9370 (p: 0.089) 0.1120 Resting APV (U) 18.1765 7.4892 Pre Stress APV (U) 19.4689 (p: 0.002) 7.7007

Resting coronary flow varies with normal cardiac catheter laboratory stimuli

BACKGROUND Growing evidence supports physiology-guided revascularization, with Fractional Flow Reserve (FFR) the most commonly used invasive measure of coronary blood flow impairment at the time of diagnostic angiography. Recently, there has been growing interest in stenosis severity indices measured at rest, such as Instantaneous Wave Free Ratio (iFR) and the ratio of distal coronary to aortic pressure at rest (resting Pd/Pa). Their reliability may, theoretically, be more susceptible to changes in microvascular tone and coronary flow. This study aimed to assess variability of resting coronary flow with normal catheter laboratory stimuli. METHODS Simultaneous intracoronary pressure (Pd) and Doppler Average Peak Flow Velocity (APV) recordings were made at rest and following the verbal warning preceding an intravenous adenosine infusion. RESULTS 72 patients undergoing elective angiography were recruited (mean age 62 years, 52.7% male) with a wide range of coronary artery disease severity (FFR 0.86 ± 0.09). Average peak flow velocity varied significantly between measurements at rest and just prior to commencement of adenosine, with a mean variation of 10.2% (17.82 ± 9.41 cm/s vs. 19.63 ± 10.44 cm/s, p < 0.001) with an accompanying significant drop in microvascular resistance (6.27 ± 2.73 mm Hg·cm-1·s-1 vs. 5.8 ± 2.92 mm Hg·cm-1·s-1, p < 0.001). These changes occurred without significant change in systemic hemodynamic measures. Whilst there was a trend for an associated change in the resting indices, Pd/Pa and iFR, this was statistically and clinically not significant (0.92 ± 0.08 vs. 0.92 ± 0.08, p = 0.110; and 0.90 ± 0.11 vs. 0.89 ± 0.12, p = 0.073). CONCLUSION Resting coronary flow and microvascular resistance vary significantly with normal catheter laboratory stimuli, such as simple warnings. The clinical impact of these observed changes on indices of stenosis severity, particularly those measured at rest, needs further assessment within larger cohorts.

Physiology of Angina and Its Alleviation With NitroglycerinClinical Perspective: 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.

Physiology of Angina and Its Alleviation With Nitroglycerin

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 novel intracoronary technology to investigate the effect of cold air inhalation during exercise on coronary microvascular resistance and blood flow in coronary artery disease: a cross-sectional study

Abstract Background Highest rates of exertion-related cardiac death occur during cold air inhalation (eg, shovelling snow), but the pathophysiological changes are unclear. Novel technology with intracoronary wires simultaneously and accurately measures coronary artery pressure and coronary blood flow, allowing physiological investigation of the effects of cold air during exercise. We explored the effects of exercise with and without cold air on coronary microvascular resistance and coronary blood flow in patients with coronary artery disease. Methods Patients with severe coronary artery stenoses undergoing coronary angiography were allocated to 5 min of cold air inhalation (–15°C), exercise (incremental supine ergometry), or exercise with cold air. We used two-way ANOVA to compare rest and peak measurements of coronary blood flow and microvascular resistance. We also used wave intensity analysis to identify waves that accelerate and decelerate coronary blood flow, and calculated the proportional contribution of accelerating waves as a coronary perfusion efficiency index. Findings We recruited 39 patients (mean 62 years [SD 9]), obtaining 51 datasets (14 cold air alone, 24 exercise, 13 exercise with cold air). 12 patients were in both the exercise and exercise with cold air groups, and for these patients the order was randomised. Microvascular resistance increased during cold air alone (558 mm Hg/cm per s [133] at rest vs 655 [221] at peak, p=0·04), and decreased during exercise (579 [192] vs 431 [166], p vs 495 [150]). The increase in coronary blood flow was similarly 34% less during exercise with cold air (19·3 cm/s [7·4] at rest vs 26·0 [10·7] at peak, p=0·04) than without (18·8 [7·3] vs 28·4 [11·3], p=0·04). An increase in coronary perfusion efficiency during exercise (69·8% [12·0] at rest vs 77·7 [9·2] at peak, p=0·05) was abolished with the addition of cold air during exercise (70·3 [10·7] vs 69·3 [10·0]). Interpretation We provide the first evidence, to our knowledge, that cold air substantially attenuates the reduction in microvascular resistance and the increase in coronary blood flow that normally occur during exercise. Moreover, although the heart has improved coronary perfusion efficiency during exercise, it can be reduced when combined with cold air. This finding suggests that cold air during exercise can impede coronary vasodilatation and ventricular relaxation, rendering the heart more susceptible to ischaemia. Funding British Heart Foundation, National Institute for Health Research.