Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease.

BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established. METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points. RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21). CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).

Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction.

RATIONALE: Preclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. OBJECTIVE: We investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction. METHODS AND RESULTS: Patients undergoing primary percutaneous coronary intervention (n=80) were randomized to receive intracoronary (10 mL) sodium nitrite (1.8 µmol) or NaCl (placebo) before balloon inflation. The primary end point was infarct size assessed by measuring creatine kinase release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac MRI on day 2. Baseline characteristics were similar between the groups. No evidence of differences in creatine kinase release (P=0.92), troponin T (P=0.85), or cardiac MRI-assessed infarct size (P=0.254) were evident. In contrast, there was an improvement [corrected] in myocardial salvage index (P=0.05) and reduction in [corrected] major adverse cardiac event at 1 year (2.6% versus 15.8%; P=0.04) in the nitrite group. In a 66-patient subgroup with thrombolysis in myocardial infarction ≤1 flow, there was reduced serum creatine kinase (P=0.030) and a 19% reduction in cardiac MRI-determined infarct size (P=0.034) with nitrite. No adverse effects of nitrite were detected. CONCLUSIONS: In this phase II study, intracoronary nitrite infusion did not alter infarct size, although a trend to improved myocardial salvage index and a significant reduction in major adverse cardiac event was evident. In a subgroup of patients with thrombolysis in myocardial infarction flow ≤1, nitrite reduced infarct size and major adverse cardiac event and improved myocardial salvage index, indicating that a phase III clinical trial assessing intracoronary nitrite administration as an adjunct to percutaneous coronary intervention in ST-elevated myocardial infarction patients is warranted. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01584453.

Design and rationale of the MR-INFORM study: stress perfusion cardiovascular magnetic resonance imaging to guide the management of patients with stable coronary artery disease.

BACKGROUND: In patients with stable coronary artery disease (CAD), decisions regarding revascularisation are primarily driven by the severity and extent of coronary luminal stenoses as determined by invasive coronary angiography. More recently, revascularisation decisions based on invasive fractional flow reserve (FFR) have shown improved event free survival. Cardiovascular magnetic resonance (CMR) perfusion imaging has been shown to be non-inferior to nuclear perfusion imaging in a multi-centre setting and superior in a single centre trial. In addition, it is similar to invasively determined FFR and therefore has the potential to become the non-invasive test of choice to determine need for revascularisation. TRIAL DESIGN: The MR-INFORM study is a prospective, multi-centre, randomised controlled non-inferiority, outcome trial. The objective is to compare the efficacy of two investigative strategies for the management of patients with suspected CAD. Patients presenting with stable angina are randomised into two groups: 1) The FFR-INFORMED group has subsequent management decisions guided by coronary angiography and fractional flow reserve measurements. 2) The MR-INFORMED group has decisions guided by stress perfusion CMR. The primary end-point will be the occurrence of major adverse cardiac events (death, myocardial infarction and repeat revascularisation) at one year. Clinical trials.gov identifier NCT01236807. CONCLUSION: MR INFORM will assess whether an initial strategy of CMR perfusion is non-inferior to invasive angiography supplemented by FFR measurements to guide the management of patients with stable coronary artery disease. Non-inferiority of CMR perfusion imaging to the current invasive reference standard (FFR) would establish CMR perfusion imaging as an attractive non-invasive alternative to current diagnostic pathways.

Effect of deferiprone or deferoxamine on right ventricular function in thalassemia major patients with myocardial iron overload.

BACKGROUND: Thalassaemia major (TM) patients need regular blood transfusions that lead to accumulation of iron and death from heart failure. Deferiprone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular (LV) function but little is known of their relative effects on the right ventricle (RV), which is being increasingly recognised as an important prognostic factor in cardiomyopathy. Therefore data from a prospective randomised controlled trial (RCT) comparing these chelators was retrospectively analysed to assess the RV responses to these drugs. METHODS: In the RCT, 61 TM patients were randomised to receive either deferiprone or deferoxamine monotherapy, and CMR scans for T2* and cardiac function were obtained. Data were re-analysed for RV volumes and function at baseline, and after 6 and 12 months of treatment. RESULTS: From baseline to 12 months, deferiprone reduced RV end systolic volume (ESV) from 37.7 to 34.2 mL (p=0.008), whilst RV ejection fraction (EF) increased from 69.6 to 72.2% (p=0.001). This was associated with a 27% increase in T2* (p<0.001) and 3.1% increase in LVEF (p<0.001). By contrast, deferoxamine showed no change in RVESV (38.1 to 39.1 mL, p=0.38), or RVEF (70.0 to 69.9%, p=0.93) whereas the T2* increased by 13% (p<0.001), but with no change in LVEF (0.32%; p=0.66). Analysis of between drugs treatment effects, showed significant improvements favouring deferiprone with a mean effect on RVESV of -1.82 mL (p=0.014) and 1.16% for RVEF (p=0.009). Using regression analysis the improvement in RVEF at 12 months was shown to be greater in patients with lower baseline EF values (p<0.001), with a significant difference in RVEF of 3.5% favouring deferiprone over deferoxamine (p=0.012). CONCLUSION: In this retrospective analysis of a prospective RCT, deferiprone monotherapy was superior to deferoxamine for improvement in RVEF and end-systolic volume. This improvement in the RV volumes and function may contribute to the improved cardiac outcomes seen with deferiprone.

Single-stage repair of aneurysm of the ascending aorta associated with aortic coarctation.

A 38-year-old man with a history of uncontrolled hypertension was investigated for atypical chest pains and found to have an aneurysm of the ascending aorta and a coexisting coarctation of the aorta. The timing and sequence of surgical repair of these 2 pathologies are controversial. We report an elective single-stage operation in which the ascending aorta was replaced and an extracardiac bypass from the ascending to the descending aorta was performed with excellent results.

Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance.

BACKGROUND: The UK Thalassaemia Register records births, deaths and selected clinical data of patients with thalassaemia who are resident in the UK. A study of survival and causes of death was undertaken which aimed to include the possible impact of T2* cardiovascular magnetic resonance (CMR). METHODS: The Register was updated to the end of 2003, copies of death certificates were obtained, and causes of death in beta thalassaemia major were extracted. In addition, patients who had T2* CMR assessment of cardiac iron load and/or received the oral iron chelator deferiprone were identified from clinical records. RESULTS: The main causes of death were anaemia (before 1980), infections, complications of bone marrow transplantation and cardiac disease due to iron overload. From 1980 to 1999 there were 12.7 deaths from all causes per 1,000 patient years. Forty per cent of patients born before 1980 had T2* cardiovascular magnetic resonance between 2000 and 2003, and 36% of these patients were prescribed deferiprone before end of 2003. In 2000-2003, the death rate from all causes fell significantly to 4.3 per 1,000 patient years (-62%, p < 0.05). This was mainly driven by the reduction in the rate of deaths from iron overload which fell from 7.9 to 2.3 deaths per 1,000 patient years (-71%, p < 0.05). CONCLUSION: Since 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload. The most likely causes for this include the introduction of T2* CMR to identify myocardial siderosis and appropriate intensification of iron chelation treatment, alongside other improvements in clinical care.

Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction.

BACKGROUND: In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis. METHODS: T2* cardiovascular magnetic resonance (CMR) was performed in 167 TM patients receiving standard subcutaneous deferoxamine monotherapy, and 22 had severe myocardial siderosis (T2* < 8 ms) with impaired left ventricular (LV) function. Fifteen of these patients received combination therapy with subcutaneous deferoxamine and oral deferiprone with CMR follow-up. RESULTS: At baseline, deferoxamine was prescribed at 38 +/- 10.2 mg/kg for 5.3 days/week, and deferiprone at 73.9 +/- 4.0 mg/kg/day. All patients continued both deferiprone and deferoxamine for 12 months. There were no deaths or new cardiovascular complications. The myocardial T2* improved (5.7 +/- 0.98 ms to 7.9 +/- 2.47 ms; p = 0.010), with concomitant improvement in LV ejection fraction (51.2 +/- 10.9% to 65.6 +/- 6.7%; p < 0.001). Serum ferritin improved from 2057 (CV 7.6%) to 666 (CV 13.2%) microg/L (p < 0.001), and liver iron improved (liver T2*: 3.7 +/- 2.9 ms to 10.8 +/- 7.3 ms; p = 0.006). CONCLUSION: In patients with severe myocardial siderosis and impaired LV function, combined chelation therapy with subcutaneous deferoxamine and oral deferiprone reduces myocardial iron and improves cardiac function. This treatment is considerably less onerous for the patient than conventional high dose continuous subcutaneous or intravenous deferoxamine monotherapy, and may be considered as an alternative. Very prolonged tailored treatment with iron chelation is necessary to clear myocardial iron, and alterations in chelation must be guided by repeated myocardial T2* scans. TRIAL REGISTRATION: This trial is registered as NCT00103753.

Recent developments in acute coronary syndromes.

Coronary artery disease is the leading cause of death in the UK with a high clinical, social and economic burden. The management of acute coronary syndromes is rapidly evolving and clinicians are constantly challenged with incorporating new clinical pathways and guidelines into their practices. It is important for clinicians to have a sound working knowledge of acute coronary syndromes, and be updated on the emerging evidence to guide therapy and improve outcomes in these patients.

Applicants regard structured interviews as a fair method of selection: an audit of candidates.

OBJECTIVE: To discover whether applicants regard structures interviews as a fair method of selection for jobs. DESIGN: Audit study of short-listed candidates for postgraduate specialty training programmes in the London Deanery. SETTING: Postgraduate applications for the London Deanery. MAIN OUTCOME MEASURES: Satisfaction or otherwise with the application and selection process for postgraduate specialty training programmes amongst short-listed candidates in the London Deanery. Questions were asked under five categories: the applicant, the advertisement, the application form, the short-listing process, and the interview. RESULTS: 89 of 118 forms were completed and analysed. Candidates thought the advertisement was clear on who to contact (97%), when short-listed candidates would be notified of their interview (66%) and when interviews would occur (93%). The design of the application form and the short-listing process both scored a median of 1 or 2 (strongly agree or agree) on all points. The interview process itself also scored well, with most candidates scoring broadly positively. CONCLUSIONS: As in the previous study, the overall response was broadly a positive one from the candidates' perspective, with the majority of candidates finding the system fair and objective.

Applying user-generated quality criteria to develop an Internet intervention for patients with heart disease.

Internet interventions can help people to self-manage chronic disease. However, they are only likely to be used if they meet patients' perceived needs. We have developed an Internet intervention in two stages to meet the needs of patients with coronary heart disease (CHD). First, user-generated criteria were applied to an existing US-based intervention called 'CHESS Living with Heart Disease' which provides information, emotional and social support, self-assessment and monitoring tools, and behavioural change support. This identified the development work required. Then we conducted a user evaluation with a panel of five patients with CHD. Overall, users generally made positive comments about the information content. However they were critical of presentation, ease of navigation through the content, understanding what was offered in the different services and finding the information they were after. Applying user-generated quality criteria proved useful in developing an intervention to meet the needs of UK patients with CHD.

Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron.

The transferability of the T2* technique for measurement of tissue iron between magnetic resonance (MR) scanners is unknown. Heart and liver multi-breath-hold T2* sequences were installed on MR scanners at six different sites. T2* was assessed locally in five or more patients with thalassemia major (n=39), and subjects were re-scanned at the standardization center in London. Inter-center reproducibility of T2* in heart and liver was 5.0% and 7.1%, with mean absolute differences in T2* of 1.3 ms and 0.45 ms, respectively. The MR multi-breath-hold T2* technique for tissue iron quantification is transferable between scanners with good reproducibility.

Myocardial tissue characterization and the role of chronic anemia in sickle cell cardiomyopathy.

PURPOSE: To use cardiovascular magnetic resonance (CMR) techniques to examine possible causes for the left ventricular (LV) dilatation that occurs in sickle cell disease (SCD), including the effects of chronic anemia, iron-induced cardiomyopathy, and regional fibrosis due to sludge infarcts that occur during sickle crises. MATERIALS AND METHODS: A total of 47 patients with sickle cell anemia were assessed for LV function and myocardial iron levels using CMR measurements; 30 of these were also assessed for regional fibrosis using late gadolinium-enhancement CMR. The LV function was compared to both normal controls and transfusion dependent non-iron-loaded (NIL) thalassemia major (TM) patients. RESULTS: Only one SCD patient had significant myocardial iron loading, and only two patients had regional fibrosis. There were significant differences in ventricular volumes of the sickle patients compared with both the normal controls and the NIL-TM population (P < 0.01). CONCLUSION: The LV changes seen in SCD are partly the result of a chronic anemia but there appears to be another contributory factor. This extra factor is not myocardial iron loading or regional fibrosis, although a homogenous fibrotic disorder affecting the left ventricle cannot be excluded.

Normalized left ventricular volumes and function in thalassemia major patients with normal myocardial iron.

PURPOSE: To determine the reference range in thalassemia major (TM) for left ventricular (LV) function. MATERIALS AND METHODS: We used cardiovascular magnetic resonance (CMR) to measure heart volumes and function in 81 TM patients with normal myocardial T2* measurements (T2* > 20 msec) and by inference without excess myocardial iron. Forty age- and gender-matched healthy controls were also studied. RESULTS: Resting LV volumes and function normalized to body surface area differed significantly between TM patients and controls. The lower limit and the mean for ejection fraction (EF) were higher in TM patients (males 59 vs. 55%, mean 71% vs. 65%; females 63 vs. 59%, mean 71% vs. 67%; both P < 0.001). The upper limit and mean for end-diastolic volume index were higher in TM patients (males 152 vs. 105 mL/m(2), mean 97 vs. 84 mL/m(2); females 121 vs. 99 mL/m(2), mean 87 vs. 79 mL/m(2); both P < 0.05). In TM patients the cardiac index (P < 0.001) was increased. CONCLUSION: At rest, TM patients with a normal myocardial T2* have different "normal" values for LV volume and function parameters compared to controls, and this has the potential to lead to a misdiagnosis of cardiomyopathy. We present new reference "normal" ranges in TM to alleviate this problem.

Development of thalassaemic iron overload cardiomyopathy despite low liver iron levels and meticulous compliance to desferrioxamine.

It is believed that myocardial iron deposition and the resultant cardiomyopathy only occur in the presence of severe liver iron overload. Using cardiovascular magnetic resonance, it is now possible to assess myocardial and liver iron levels as well as cardiac function in the same scan, allowing this supposition to be examined. We describe a patient with progressive myocardial iron deposition and the development of early iron overload cardiomyopathy despite excellent compliance to standard subcutaneous desferrioxamine, minimal liver iron and well-controlled serum ferritin levels. These indirect markers remained far below the thresholds conventionally believed to be associated with increased cardiac risk.

Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis.

Most deaths in beta-thalassemia major result from cardiac complications due to iron overload. Differential effects on myocardial siderosis may exist between different chelators. A randomized controlled trial was performed in 61 patients previously maintained on subcutaneous deferoxamine. The primary end point was the change in myocardial siderosis (myocardial T2(*)) over 1 year in patients maintained on subcutaneous deferoxamine or those switched to oral deferiprone monotherapy. The dose of deferiprone was 92 mg/kg/d and deferoxamine was 43 mg/kg for 5.7 d/wk. Compliance was 94% +/- 5.3% and 93% +/- 9.7% (P = .81), respectively. The improvement in myocardial T2(*) was significantly greater for deferiprone than deferoxamine (27% vs 13%; P = .023). Left ventricular ejection fraction increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P = .003). The changes in liver iron level (-0.93 mg/g dry weight vs -1.54 mg/g dry weight; P = .40) and serum ferritin level (-181 microg/L vs -466 microg/L; P = .16), respectively, were not significantly different between groups. The most frequent adverse events were transient gastrointestinal symptoms for deferiprone-treated patients and local reactions at the infusion site for deferoxamine. There were no episodes of agranulocytosis. Deferiprone monotherapy was significantly more effective than deferoxamine over 1 year in improving asymptomatic myocardial siderosis in beta-thalassemia major.

Left ventricular diastolic function compared with T2* cardiovascular magnetic resonance for early detection of myocardial iron overload in thalassemia major.

PURPOSE: To compare left ventricular (LV) diastolic function with myocardial iron levels in beta thalassemia major (TM) patients, using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS: We studied 67 regularly transfused patients with TM and 22 controls matched for age, gender, and body surface area. The early peak filling rate (EPFR) and atrial peak filling rate (APFR) were determined from high-temporal-resolution ventricular volume-time curves. Myocardial iron estimation was achieved using myocardial T2* measurements. RESULTS: Myocardial iron loading was found in 46 TM patients (69%), in whom the EPFR correlated poorly with T2* (r = -0.20, P = 0.19). The APFR (r = 0.49, P < 0.001) and EPFR/APFR ratio (r = -0.62, P < 0.001) correlated better with T2*. The sensitivity of the diastolic parameters for detecting myocardial iron loading ranged from 4% (EPFR and APFR) to 17% (EPFR/APFR ratio). CONCLUSION: Myocardial iron overload results in diastolic myocardial dysfunction, but low sensitivity limits the use of a single estimation for early detection of iron overload, for which T2* has a superior categorical limit of normality.

Intercentre reproducibility of magnetic resonance T2* measurements of myocardial iron in thalassaemia.

In transfusion-dependent thalassemia major, iron-induced cardiomyopathy is the predominant cause of morbidity and mortality. Assessment of myocardial iron loading using MRI gradient echo T2* measurements have been described, but has only been performed at one centre in London. We assessed the transferability of this method by comparing the results from three different MR scanners in three different countries. Ten patients with thalassemia major underwent myocardial T2* assessment using a Siemens Sonata Scanner in London. Patients were also scanned with either a similar T2* sequence on a GE Systems CVI scanner in Athens, or a GE Systems signa echospeed scanner in Cagliari. Two scans were performed at the respective site in all patients to assess interstudy reproducibility at each site. The mean difference and coefficient of variability for the heart between scanners was 0.08 ms and 9.7% between London and Athens; and 0.30 ms and 1.6% between London and Cagliari. The interstudy mean difference and coefficient of variability for the heart in Athens was 0.6 ms and 3.5%, and 0.2 ms and 2.4% in Cagliari. In conclusion, the myocardial iron estimations were consistent between the three centres with scanners of differing manufacture, suggesting that this technique may have widespread application in the assessment of patients with iron overload conditions such as thalassaemia.

Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study.

RATIONALE: Phosphodiesterase type 5 (PDE5) inhibition has been proposed for the treatment for pulmonary arterial hypertension (PAH). OBJECTIVE: This study compared adding sildenafil, a PDE5 inhibitor, to conventional treatment with the current practice of adding bosentan, an endothelin receptor antagonist. METHODS: Twenty-six patients with PAH, idiopathic or associated with connective tissue disease, World Health Organization (WHO) functional class III, were randomized in a double-blind fashion to receive sildenafil (50 mg twice daily for 4 weeks, then 50 mg three times daily) or bosentan (62.5 mg twice daily for 4 weeks, then 125 mg twice daily) over 16 weeks. MEASUREMENTS: Changes in right ventricular (RV) mass (using cardiovascular magnetic resonance), 6-minute walk distance, cardiac function, brain natriuretic peptide, and Borg dyspnea index. MAIN RESULTS: When analyzed by intention to treat, there were no significant differences between the two treatment groups. One patient on sildenafil died suddenly. Patients on sildenafil who completed the protocol showed significant changes from baseline, namely, reductions in RV mass (-8.8 g; 95% confidence interval [CI], -2, -16; n = 13, p = 0.015) and plasma brain natriuretic peptide levels (-19.4 fmol x ml(-1); 95% CI, -5, -34; p = 0.014) and improvements in 6-minute walk distance (114 m; 95% CI, 67, 160; p = 0.0002), cardiac index (0.3 L x min(-1) x m(-2); 95% CI, 0.1, 0.4; p = 0.008), and systolic left ventricular eccentricity index (-0.2; 95% CI, -0.02, -0.37; p = 0.031). Bosentan improved 6-minute walk distance (59 m; 95% CI, 29, 89; n = 12, p = 0.001) and cardiac index (0.3; 95% CI, 0.1, 0.4; p = 0.008). CONCLUSIONS: Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH, WHO functional class III. Safety monitoring is important until more experience is obtained.