David Lefroy

Reduced Coronary Vasodilator Function in Infarcted and Normal Myocardium after Myocardial Infarction

BACKGROUND The ability of the coronary vascular bed to dilate and thus increase blood flow to the myocardium may be impaired in coronary artery disease, even in regions of myocardium supplied by an angiographically normal coronary artery. If this kind of vasomotor dysfunction was present or accentuated after acute myocardial infarction, it might influence the extent of ischemia and necrosis in areas not directly injured by the infarction. METHODS We studied 13 patients (mean [+/- SD] age, 62 +/- 11 years) with single-vessel coronary artery disease after they had received thrombolytic therapy for myocardial infarction. Using positron-emission tomography (PET) with oxygen-15-labeled water, we measured regional myocardial blood flow under basal conditions and after the intravenous administration of dipyridamole (0.5 mg per kg of body weight over a period of four minutes) 8 +/- 3 days after infarction in all 13 patients (1-week study) and 6 +/- 2 months after infarction in 9 of the 13 (6-month study). On both occasions we measured blood flow both in the infarcted region and in a region of myocardium that was remote from the infarcted region and supplied by a normal artery. RESULTS At the one-week PET study, the coronary vasodilator response (the ratio of the myocardial blood flow after the administration of dipyridamole to basal blood flow) was 1.12 +/- 0.50 in the infarct-related artery and 1.53 +/- 0.36 in the remote region (P = 0.015). At the six-month study, the coronary vasodilator response was 1.42 +/- 0.37 in the infarcted region and 2.19 +/- 0.69 in the remote region (P = 0.004 for the comparison with the infarcted region; P = 0.011 for the comparison with the remote region at the one-week study). The value in remote myocardium remained lower than that in similar regions in 10 control patients, who had single-vessel coronary artery disease but no evidence of myocardial infarction (3.17 +/- 0.72; P = 0.009). CONCLUSIONS After acute myocardial infarction, there is a severe vasodilator abnormality involving not only resistance vessels in infarcted myocardium, but also those in myocardium perfused by normal coronary vessels. This dysfunction may affect the extent of myocardial ischemia and necrosis after coronary occlusion.

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).

Pulmonary venous isolation by antral ablation with a large cryoballoon for treatment of paroxysmal and persistent atrial fibrillation: medium-term outcomes and non-randomised comparison with pulmonary venous isolation by radiofrequency ablation

Background To prevent atrial fibrillation (AF) recurrence after catheter ablation, pulmonary venous isolation (PVI) at an antral level is more effective than segmental ostial ablation. Cryoablation around the pulmonary venous (PV) ostia for AF therapy is potentially safer compared to radiofrequency ablation (RFA). The aim of this study was to investigate the efficacy of a strategy using a large cryoablation balloon to perform antral cryoablation with ‘touch-up’ ostial cryoablation for PVI in patients with paroxysmal and persistent AF. Methods Paroxysmal and persistent AF patients undergoing their first left atrial ablation were recruited. After cryoballoon therapy, each PV was assessed for isolation and if necessary, treated with focal ostial cryoablation until PVI was achieved. Follow-up with Holter monitoring was performed. Clinical outcomes of the cryoablation protocol were compared, with consecutive patients undergoing PVI by RFA. Results 124 consecutive patients underwent cryoablation. 77% of paroxysmal and 48% of persistent AF subjects were free from AF at 12 months after a single procedure. Over the same time period, 53 consecutive paroxysmal AF subjects underwent PVI with RFA and at 12 months, 72% were free from AF at 12 months (p=NS). There were too few persistent AF subjects (n=8) undergoing solely PVI by RFA as a comparison group. Procedural and fluoroscopic times during cryoablation were significantly shorter than RFA. Conclusions PV isolation can be achieved in less than 2 h by a simple cryoablation protocol with excellent results after a single intervention, particularly for paroxysmal AF.

17-beta-estradiol therapy lessens angina in postmenopausal women with syndrome X

OBJECTIVES We sought to investigate the hypothesis that estrogen replacement therapy ameliorates symptoms in postmenopausal women with syndrome X. BACKGROUND Syndrome X (angina pectoris, positive findings on exercise electrocardiography and normal results on coronary angiography) frequently occurs in menopausal women. This observation, in conjunction with the known vasoactive properties of estrogens, suggests that estrogen depletion may contribute to the pathogenesis of syndrome X in some women. METHODS Twenty-five postmenopausal patients with syndrome X completed a double-blind, placebo-controlled study of the effect of 17-beta-estradiol cutaneous patches (100 micrograms/24 h) on the frequency of chest pain and on exercise tolerance. Patients were randomly assigned to receive either placebo or 17-beta-estradiol patches for 8 weeks and were then crossed over to the other treatment. RESULTS During the placebo phase, patients had a mean of 7.3 episodes of chest pain/10 days. A reduction to 3.7 episodes/10 days was observed during the 17-beta-estradiol phase (p < 0.05). No significant differences were observed between the effects of 17-beta-estradiol and placebo on exercise duration or the results of other cardiologic investigations. CONCLUSIONS Estrogen replacement reduces the frequency of chest pain and may be a useful new therapeutic option for treating postmenopausal women with syndrome X.

Diffuse reduction of myocardial beta-adrenoceptors in hypertrophic cardiomyopathy: A study with positron emission tomography

OBJECTIVES This study was conducted to determine the myocardial beta-adrenoceptor density as a marker of sympathetic function in patients with hypertrophic cardiomyopathy and normal control subjects. BACKGROUND Although some cases of hypertrophic cardiomyopathy are familial with an autosomal dominant pattern of inheritance, there remains a substantial proportion of cases in which neither a family history nor genetic abnormalities can be demonstrated. Additional abnormalities, both genetic and acquired, may be important in the phenotypic expression of this condition. Clinical features of the disease and metabolic studies suggest an increased activity of the sympathetic nervous system. METHODS Eleven patients with hypertrophic cardiomyopathy, none of whom had previously received beta-blocking drugs, and eight normal control subjects underwent positron emission tomography to evaluate regional left ventricular beta-adrenoceptor density and myocardial blood flow using carbon-11-labeled CGP 12177 and oxygen-15-labeled water as tracers. Plasma catecholamines were also measured. RESULTS Mean (+/- SD) myocardial beta-adrenoceptor density was significantly less in the hypertrophic cardiomyopathy group than in the control group (7.70 +/- 1.86 vs. 11.50 +/- 2.18 pmol/g tissue, p < 0.001). Myocardial blood flow was similar in both groups (0.91 +/- 0.22 vs. 0.91 +/- 0.21 ml/min per g, p = NS). The distribution of beta-adrenoceptor density was uniform throughout the left ventricle in both groups. In the hypertrophic cardiomyopathy group, there was no correlation between regional wall thickness and myocardial beta-adrenoceptor density. There were no significant differences in either plasma norepinephrine or epinephrine concentrations between the two groups. CONCLUSIONS There is a diffuse reduction in myocardial beta-adrenoceptor density in patients with hypertrophic cardiomyopathy in the absence of significantly elevated circulating catecholamine concentrations. This most likely reflects downregulation of myocardial beta-adrenoceptors secondary to increased myocardial concentrations of norepinephrine and is consistent with the hypothesis that cardiac sympathetic drive is increased in this condition.

Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation.

AIMS Adoption of fractional flow reserve (FFR) remains low (6-8%), partly because of the time, cost and potential inconvenience associated with vasodilator administration. The instantaneous wave-Free Ratio (iFR) is a pressure-only index of stenosis severity calculated without vasodilator drugs. Before outcome trials test iFR as a sole guide to revascularisation, we evaluate the merits of a hybrid iFR-FFR decision-making strategy for universal physiological assessment. METHODS AND RESULTS Coronary pressure traces from 577 stenoses were analysed. iFR was calculated as the ratio between Pd and Pa in the resting diastolic wave-free window. A hybrid iFR-FFR strategy was evaluated, by allowing iFR to defer some stenoses (where negative predictive value is high) and treat others (where positive predictive value is high), with adenosine being given only to patients with iFR in between those values. For the most recent fixed FFR cut-off (0.8), an iFR of <0.86 could be used to confirm treatment (PPV of 92%), whilst an iFR value of >0.93 could be used to defer revascularisation (NPV of 91%). Limiting vasodilator drugs to cases with iFR values between 0.86 to 0.93 would obviate the need for vasodilator drugs in 57% of patients, whilst maintaining 95% agreement with an FFR-only strategy. If the 0.75-0.8 FFR grey zone is accounted for, vasodilator drug requirement would decrease by 76%. CONCLUSION A hybrid iFR-FFR decision-making strategy for revascularisation could increase adoption of physiology-guided PCI, by more than halving the need for vasodilator administration, whilst maintaining high classification agreement with an FFR-only strategy.

Myocardial beta adrenoceptors and left ventricular function in hypertrophic cardiomyopathy.

OBJECTIVE--To assess the relation between left ventricular function and myocardial beta adrenoceptor density. METHODS--17 patients with hypertrophic cardiomyopathy, six with and 11 without heart failure, were studied. Left ventricular function was assessed by echocardiography, and myocardial beta adrenoceptors by positron emission tomography. Patient data were compared with those obtained in normal controls. RESULTS--Myocardial beta adrenoceptor density in the 17 patients was 7.00 (SD 1.90) pmol/g v 11.50 (2.18) pmol/g in normal controls (P < 0.01). beta Adrenoceptor density in the six patients with left ventricular failure was 5.61 (0.88) pmol/g v 7.71 (1.86) pmol/g in the 11 patients with normal ventricular function (P < 0.05), and there was a significant correlation (r = 0.52; P < 0.05) between left ventricular fractional shortening and myocardial beta adrenoceptor density. A positive correlation (r = 0.51; P < 0.05) was also found between myocardial beta adrenoceptor density and the E/A transmitral flow ratio, an index of left ventricular diastolic function. CONCLUSIONS--There is myocardial beta adrenoceptor downregulation in patients with hypertrophic cardiomyopathy with or without signs of heart failure.

Improvement in Coronary Blood Flow Velocity with Acute Biventricular Pacing is Predominantly Due to an Increase in a Diastolic Backward-Travelling Decompression (Suction) Wave

Background— Normal coronary blood flow is principally determined by a backward-traveling decompression (suction) wave in diastole. Dyssynchronous chronic heart failure may attenuate suction, because regional relaxation and contraction overlap in timing. We hypothesized that biventricular pacing, by restoring left ventricular (LV) synchronization and improving LV relaxation, might increase this suction wave, improving coronary flow. Method and Results— Ten patients with chronic heart failure (9 males; age 65±12; ejection fraction 26±7%) with left bundle-branch block (LBBB; QRS duration 174±18 ms) were atriobiventricularly paced at 100 bpm. LV pressure was measured and wave intensity calculated from invasive coronary flow velocity and pressure, with native conduction (LBBB) and during biventricular pacing at atrioventricular (AV) delays of 40 ms, 120 ms, and separately preidentified hemodynamically optimal AV delay. In comparison with LBBB, biventricular pacing at separately preidentified hemodynamically optimal AV delay (BiV-Opt) enhanced coronary flow velocity time integral by 15% (7%–25%) (P=0.007), LV dP/dtmax by 15% (10%–21%) (P=0.005), and negdP/dtmax by 17% (9%–22%) (P=0.005). The cumulative intensity of the diastolic backward decompression (suction) wave increased by 26% (18%–54%) (P=0.005). The majority of the increase in coronary flow velocity time integral occurred in diastole (69% [41%–84% ]; P=0.047). The systolic compression waves also increased: forward by 36% (6%–49%) (P=0.022) and backward by 38% (20%–55%) (P=0.022). Biventricular pacing at AV delays of 120 ms generated a smaller LV dP/dtmax (by 12% [5%–23% ], P=0.013) and negdP/dtmax (by 15% [8%–40% ]; P=0.009) increase than BiV-Opt, against LBBB as reference; BiV-Opt and biventricular pacing at AV delays of 120 ms were not significantly different in coronary flow velocity time integral or waves. Biventricular pacing at AV delays of 40 ms was no different from LBBB. Conclusions— When biventricular pacing improves LV contraction and relaxation, it increases coronary blood flow velocity, predominantly by increasing the dominant diastolic backward decompression (suction) wave.

Myocardial infarction in sickle-cell disease

A 50-year-old woman was admitted to our hospital in December, 2005, with a 5 h history of central chest pain of sudden onset. She described dull pain across her chest with radiation to the right arm accompanied by nausea and vomiting. The pain was worse on deep inspiration but not associated with dyspnoea, and it failed to improve after glyceryl trinitrate. She had a history of homozygous sicklecell disease with frequent painful episodes; she managed most of these episodes at home with diclofenac and dihydrocodeine phosphate, although intermittently needed exchange transfusion. The presenting chest pain was diff erent in character from her typical sickle-cell crises. She had no history of coronary heart disease, diabetes, hypertension, or dyslipidaemia, and was a non-smoker. She was apyrexial. Other than mild icterus, physical examination was unremarkable. Electrocardiography showed sinus rhythm with T-wave inversion in V1 to V3, and biphasic T-waves in V4 to V6. A chest radiograph was normal. Arterial blood gas analysis showed PaO2 of 10·6 kPa and SpO2 of 91·1% on room air. Haemoglobin concentration was similar to her steady state at 107 g/L. Serum biochemistry showed increased troponin I at 1·78 μg/L with normal creatinine and electrolytes. Acute coronary syndrome was suspected and enoxaparin sodium, aspirin, and clopidogrel bisulfate were started. Her troponin I peaked at 8·23 μg/L, 12 h after admission, by which time her pain had been superseded by dull pressure over the precordium. Coronary angiography (preceded by automated red-cell exchange to a haemoglobin S level of 19%) showed smooth coronary arteries with no occlusion. No ventilation-perfusion mismatches were shown on lung scintigraphy, and the patient proceeded to a cardiac MRI. An inversion recovery gradient echo sequence acquired 15 min after injection of intravenous gadolinium contrast demonstrated a region of subendocardial hyperenhance ment in the lateral wall of the left ventricle consistent with an infarct (fi gure). Brightblood cine sequences showed that this anomaly was associated with a wall motion abnormality. Her chest pain resolved fully and electrocardiogram became normal within 4 days. When seen for follow-up in August, 2006, she remained asymptomatic. Sickle-cell disease was fi rst described in 1910 by the Chicago physician J B Herrick who contemporaneously postulated that thrombosis in the coronary artery leads to myocardial infarction. Such thrombus generally forms where the coronary arteries are narrowed as a result of atherosclerotic plaque. Case reports of myocardial infarction in sickle-cell disease are uncommon, and in most cases coronary angiography showed no signifi cant coronary-artery occlusion. An autopsy study demonstrated myocardial infarction in the absence of signifi cant obstructive or atherosclerotic lesions in 9·7% of patients. In contrast to the normal fi ndings in major coronary vessels, the small arteries are narrow in many patients with sickle-cell disease. On this background, aggregation of blood cells and their interaction with coagulation factors can cause acute occlusion. Release of infl ammatory mediators from leucocytes and platelets induces coronary vasospasm, to which scavenging of nitric oxide by haemoglobin liberated through intravascular haemolysis may contribute further. Fat embolism, secondary to bonemarrow infarction, has been implicated in occurrence of myocardial infarction during painful sickle-cell crisis. A strength of cardiac MRI is its ability to provide non-invasive myocardial-tissue characterisation at a high spatial resolution. Hyperenhancement of infarcted tissue occurs owing to an increased volume of distribution and delayed wash-out of contrast. Late enhancement can be seen in other causes of cardiomyopathy and in myocarditis, but ischaemic infarction is always characterised by subendocardial enhancement. Myocardial infarction should be included in the diff erential diagnosis of chest pain in sickle-cell disease despite normal coronary angiography.

Angiographic characteristics of infarct-related and non-infarct-related stenoses in patients in whom stable angina progressed to acute myocardial infarction

BACKGROUND In patients with coronary artery disease, angiographic and postmortem studies have shown that coronary stenoses in infarct-related arteries often have complex morphology. It is not known whether in patients with multivessel disease stenosis morphology in non-infarct-related arteries is different from those of the infarct-related arteries. METHODS AND RESULTS In 24 consecutive patients we examined the angiographic characteristics of both the infarct-related stenoses and non-infarct-related stenoses before and after spontaneous acute myocardial infarction, by visual inspection and computerized edge detection of coronary angiograms. Before myocardial infarction, the severity of the infarct-related stenoses was <50% in 14 patients and > or =50% in 10 patients (p=not significant) and of non-infarct-related stenoses was <50% in 16 and > or=50% in 13. A significantly greater proportion of infarct-related stenoses with severity > or =50% progressed to non-Q-wave than to Q-wave myocardial infarction (71% vs 50%, p < 0.05). Before myocardial infarction, the percentage of concentric, eccentric, and irregular infarct-related stenoses was 8%, 13%, and 50%, respectively, whereas in the non-infarct-related stenoses it was 62%, 17%, and 21%, respectively (p < 0.01). A similar proportion of irregular morphology progressed to Q-wave or non-Q-wave myocardial infarction. CONCLUSIONS In patients with stable angina who had acute myocardial infarction develop, the infarct-related and non-infarct-related stenoses on average are similar in severity but different in morphology. Nonsevere stenoses more frequently progress to Q-wave than to non-Q-wave myocardial infarction.