Ian Paterson

T1 Mapping With Cardiovascular MRI Is Highly Sensitive for Fabry Disease Independent of Hypertrophy and Sex

Background— Fabry disease (FD) is an X-linked disorder of lysosomal metabolism affecting multiple organs with cardiac disease being the leading cause of death. Current imaging evaluations of the heart are suboptimal. The goals of the current study are to evaluate the potential of quantitative T1 mapping with cardiovascular MRI as a disease-specific imaging biomarker. Methods and Results— A total of 31 patients with FD, 23 healthy controls, and 21 subjects with concentric remodeling or hypertrophy underwent cardiovascular MRI to measure left ventricular (LV) morphology, function, delayed enhancement, as well as myocardial T1 values, and derived parameters (extracellular volume). All subjects had LV ejection fraction >50% and similar volumes. FD and concentric remodeling or hypertrophy had similarly increased mass, wall thickness, and mass/volume as compared with controls. A total of 16 of 31 FD subjects and 10 of 21 concentric remodeling or hypertrophy subjects had LV hypertrophy. Noncontrast myocardial T1 values were substantially lower in FD as compared with controls and concentric remodeling or hypertrophy (1070±50, 1177±27, and 1207±33 ms, respectively; P<0.001), but extracellular volume was similar in all groups (21.7±2.4%, 22.2±3.1%, and 21.8±3.9%, respectively). Single-voxel NMR spectroscopy in 4 FD and 4 healthy control subjects showed a significant negative linear relationship between lipid content and noncontrast T1 values (r=−0.9; P=0.002). Female subjects had lower LV mass and wall thickness, longer myocardial T1 values and larger extracellular volume suggesting a key sex difference in cardiac remodeling. Conclusions— Reduced noncontrast myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function.

T1 Mapping with CMR Is Highly Sensitive for Fabry Disease Independent of Hypertrophy and Gender

Background— Fabry disease (FD) is an X-linked disorder of lysosomal metabolism affecting multiple organs with cardiac disease being the leading cause of death. Current imaging evaluations of the heart are suboptimal. The goals of the current study are to evaluate the potential of quantitative T1 mapping with cardiovascular MRI as a disease-specific imaging biomarker. Methods and Results— A total of 31 patients with FD, 23 healthy controls, and 21 subjects with concentric remodeling or hypertrophy underwent cardiovascular MRI to measure left ventricular (LV) morphology, function, delayed enhancement, as well as myocardial T1 values, and derived parameters (extracellular volume). All subjects had LV ejection fraction >50% and similar volumes. FD and concentric remodeling or hypertrophy had similarly increased mass, wall thickness, and mass/volume as compared with controls. A total of 16 of 31 FD subjects and 10 of 21 concentric remodeling or hypertrophy subjects had LV hypertrophy. Noncontrast myocardial T1 values were substantially lower in FD as compared with controls and concentric remodeling or hypertrophy (1070±50, 1177±27, and 1207±33 ms, respectively; P<0.001), but extracellular volume was similar in all groups (21.7±2.4%, 22.2±3.1%, and 21.8±3.9%, respectively). Single-voxel NMR spectroscopy in 4 FD and 4 healthy control subjects showed a significant negative linear relationship between lipid content and noncontrast T1 values (r=−0.9; P=0.002). Female subjects had lower LV mass and wall thickness, longer myocardial T1 values and larger extracellular volume suggesting a key sex difference in cardiac remodeling. Conclusions— Reduced noncontrast myocardial T1 values are the most sensitive and specific cardiovascular MRI parameter in patients with FD irrespective of sex and LV morphology and function.

Cardiovascular magnetic resonance in the diagnosis of acute heart transplant rejection: a review

BackgroundScreening for organ rejection is a critical component of care for patients who have undergone heart transplantation. Endomyocardial biopsy is the gold standard screening tool, but non-invasive alternatives are needed. Cardiovascular magnetic resonance (CMR) is well suited to provide an alternative to biopsy because of its ability to quantify ventricular function, morphology, and characterize myocardial tissue. CMR is not widely used to screen for heart transplant rejection, despite many trials supporting its use for this indication. This review summarizes the different CMR sequences that can detect heart transplant rejection as well as the strengths and weaknesses of their application.ResultsT2 quantification by spin echo techniques has been criticized for poor reproducibility, but multiple studies show its utility in screening for rejection. Human and animal data estimate that T2 quantification can diagnose rejection with sensitivities and specificities near 90%. There is also a suggestion that T2 quantification can predict rejection episodes in patients with normal endomyocardial biopsies.T1 quantification has also shown association with biopsy proven rejection in a small number of trials. T1 weighted gadolinium early enhancement appeared promising in animal data, but has had conflicting results in human trials. Late gadolinium enhancement in the diagnosis of rejection has not been evaluated.CMR derived measures of ventricular morphology and systolic function have insufficient sensitivity to diagnose mild to moderate rejection. CMR derived diastolic function can demonstrate abnormalities in allografts compared to native human hearts, but its ability to diagnose rejection has not yet been tested.There is promising animal data on the ability of iron oxide contrast agents to illustrate the changes in vascular permeability and macrophage accumulation seen in rejection. Despite good safety data, these contrast agents have not been tested in the human heart transplant population.ConclusionT2 quantification has demonstrated the best correlation to biopsy proven heart transplant rejection. Further studies evaluating diastolic function, late gadolinium enhancement, and iron oxide contrast agents to diagnose rejection are needed. Future studies should focus on combining multiple CMR measures into a transplant rejection scoring system which would improve sensitivity and possibly reduce, if not eliminate, the need for endomyocardial biopsy.

Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Rationale: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries. Objective: We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium. Methods and Results: RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r2=0.838 and r2=0.818, respectively; P<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10−7,−6,−5 mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01). Conclusions: Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.

Left ventricular torsion and untwisting during exercise in heart transplant recipients

Left ventricular (LV) rotation is the dominant deformation during relaxation and links systole with early diastolic recoil. LV torsion and untwisting rates during submaximal exercise were compared between heart transplant recipients (HTRs), young adults and healthy older individuals to better understand impaired diastolic function in HTRs. Two dimensional and colour M‐mode echocardiography with speckle‐tracking analysis were completed in eight HTRs (age: 61 ± 9 years), six recipient age‐matched (RM, age: 60 ± 11 years), and five donor age‐matched (DM, age: 35 ± 8 years) individuals (all males) at rest and during submaximal cycle exercise. LV peak torsion, peak rate of untwisting and peak intraventricular pressure gradients (IVPGs) were examined. LV torsion increased with exercise in DMs (6.5 ± 5.6 deg, P < 0.05), but not in RMs (−2.6 ± 7.0 deg) or HTRs (−0.9 ± 4.4 deg). The change from rest to exercise in the peak rate of untwisting was significantly greater for DMs (−2.1 ± 0.5 rads s−1, P < 0.05) compared to RMs (−0.7 ± 1.3 rads s−1) and HTRs (−0.2 ± 0.9 rads s−1). The amount of untwisting occurring prior to mitral valve opening substantially declined with exercise in RMs and HTRs only. The change in IVPGs was 1.3‐fold greater in DMs versus HTRs or RMs (P > 0.05). Peak LV torsion and untwisting are blunted during exercise in HTRs and RMs compared to DMs. These factors may contribute to the impaired diastolic filling found in HTRs during exercise. Similarities between HTRs and RMs during exercise suggest functional accelerated ageing of the cardiac allograft.

Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy

Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) IMAGE HF Project I-A: study protocol for a randomized controlled trial

BackgroundIschemic heart disease (IHD) is the most common cause of heart failure (HF); however, the role of revascularization in these patients is still unclear. Consensus on proper use of cardiac imaging to help determine which candidates should be considered for revascularization has been hindered by the absence of clinical studies that objectively and prospectively compare the prognostic information of each test obtained using both standard and advanced imaging.Methods/DesignThis paper describes the design and methods to be used in the Alternative Imaging Modalities in Ischemic Heart Failure (AIMI-HF) multi-center trial. The primary objective is to compare the effect of HF imaging strategies on the composite clinical endpoint of cardiac death, myocardial infarction (MI), cardiac arrest and re-hospitalization for cardiac causes.In AIMI-HF, patients with HF of ischemic etiology (n = 1,261) will follow HF imaging strategy algorithms according to the question(s) asked by the physicians (for example, Is there ischemia and/or viability?), in agreement with local practices. Patients will be randomized to either standard (SPECT, Single photon emission computed tomography) imaging modalities for ischemia and/or viability or advanced imaging modalities: cardiac magnetic resonance imaging (CMR) or positron emission tomography (PET). In addition, eligible and consenting patients who could not be randomized, but were allocated to standard or advanced imaging based on clinical decisions, will be included in a registry.DiscussionAIMI-HF will be the largest randomized trial evaluating the role of standard and advanced imaging modalities in the management of ischemic cardiomyopathy and heart failure. This trial will complement the results of the Surgical Treatment for Ischemic Heart Failure (STICH) viability substudy and the PET and Recovery Following Revascularization (PARR-2) trial. The results will provide policy makers with data to support (or not) further investment in and wider dissemination of alternative ‘advanced’ imaging technologies.Trial registrationNCT01288560

Correlation of cardiovascular magnetic resonance imaging findings and endomyocardial biopsy results in patients undergoing screening for heart transplant rejection.

BACKGROUND Endomyocardial biopsy (EMB) is the current gold standard to screen for heart transplant rejection but has important risks and limitations. Cardiovascular magnetic resonance imaging (CMRI) is increasingly used to characterize cardiac function and myocardial tissue. We evaluated the diagnostic accuracy of CMRI compared with EMB and clinically diagnosed heart transplant rejection. METHODS Comprehensive CMRI scans were performed on adult heart transplant recipients within 24 hours of EMB (routine or clinically indicated), before initiation of any anti-rejection therapy, and blinded to EMB results. Multivariable analysis was used to create CMRI diagnostic criteria for comparison with a positive EMB (Grade ≥ 2R or antibody-mediated rejection) and clinical rejection (change in medical therapy to treat rejection). RESULTS Sixty participants (75% male; mean age, 51 ± 14 years) were recruited, providing 73 comparisons between CMRI and EMB for the diagnosis of rejection. Multivariable logistic regression identified myocardial edema (T2 relaxation time) and right ventricular end-diastolic volume index as independent predictors of a positive EMB. Combining threshold right ventricular end-diastolic volume index and edema values predicted a positive EMB with very good accuracy: sensitivity, 93%; specificity, 78%; positive predictive value, 52%; and negative predictive valve, 98%. CMRI was more sensitive than EMB at predicting clinical rejection (sensitivity of 67% vs 58%). CONCLUSIONS CMRI has high sensitivity and high negative predictive value in predicting biopsy-positive heart transplant rejection and may be useful as a screening test before routine EMB. CMRI also has better sensitivity for clinically diagnosed heart transplant rejection and could be helpful in cases of negative rejection on the biopsy specimen.

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients

Metabolic modulation with dichloroacetate improves hemodynamics in genetically susceptible patients with idiopathic pulmonary arterial hypertension. Progress for PAH In addition to thickening and occlusion of the pulmonary arteries, mitochondrial respiration is suppressed in pulmonary arterial hypertension (PAH). Michelakis et al. treated lungs from patients with PAH with dichloroacetate (DCA), a drug used to treat cancer and congenital mitochondrial disease that inhibits the mitochondrial enzyme pyruvate dehydrogenase kinase. DCA increased mitochondrial function; however, the response was variable, and this variable response was mirrored in a phase 1 trial, with some patients showing improved hemodynamics and functional capacity. The authors determined that patients with inactivating mutations in two genes encoding mitochondrial proteins were less responsive to DCA. This work highlights the importance of considering patient genotype in clinical trial design and identifies a drug target for PAH. Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Effect of acute high-intensity interval exercise on postexercise biventricular function in mild heart failure

We studied the acute effect of high-intensity interval exercise on biventricular function using cardiac magnetic resonance imaging in nine patients [age: 49 ± 16 yr; left ventricular (LV) ejection fraction (EF): 35.8 ± 7.2%] with nonischemic mild heart failure (HF). We hypothesized that a significant impairment in the immediate postexercise end-systolic volume (ESV) and end-diastolic volume (EDV) would contribute to a reduction in EF. We found that immediately following acute high-intensity interval exercise, LV ESV decreased by 6% and LV systolic annular velocity increased by 21% (both P < 0.05). Thirty minutes following exercise (+30 min), there was an absolute increase in LV EF of 2.4% (P < 0.05). Measures of preload, left atrial volume and LV EDV, were reduced immediately following exercise. Similar responses were observed for right ventricular volumes. Early filling velocity, filling rate, and diastolic annular velocity remained unchanged, while LV untwisting rate increased 24% immediately following exercise (P < 0.05) and remained 18% above baseline at +30 min (P < 0.05). The major novel findings of this investigation are 1) that acute high-intensity interval exercise decreases the immediate postexercise LV ESV and increases LV EF at +30 min in patients with mild HF, and this is associated with a reduction in LV afterload and maintenance of contractility, and 2) that despite a reduction in left atrial volume and LV EDV immediately postexercise, diastolic function is preserved and may be modulated by enhanced LV peak untwisting rate. Acute high-intensity interval exercise does not impair postexercise biventricular function in patients with nonischemic mild HF.