Cardiovascular magnetic resonance predictors of heart failure in hypertrophic cardiomyopathy: the role of myocardial replacement fibrosis and the microcirculation.

INTRODUCTION: Heart failure (HF) in hypertrophic cardiomyopathy (HCM) is associated with high morbidity and mortality. Predictors of HF, in particular the role of myocardial fibrosis and microvascular ischemia remain unclear. We assessed the predictive value of cardiovascular magnetic resonance (CMR) for development of HF in HCM in an observational cohort study. METHODS: Serial patients with HCM underwent CMR, including adenosine first-pass perfusion, left atrial (LA) and left ventricular (LV) volumes indexed to body surface area (i) and late gadolinium enhancement (%LGE- as a % of total myocardial mass). We used a composite endpoint of HF death, cardiac transplantation, and progression to NYHA class III/IV. RESULTS: A total of 543 patients with HCM underwent CMR, of whom 94 met the composite endpoint at baseline. The remaining 449 patients were followed for a median of 5.6 years. Thirty nine patients (8.7%) reached the composite endpoint of HF death (n = 7), cardiac transplantation (n = 2) and progression to NYHA class III/IV (n = 20). The annual incidence of HF was 2.0 per 100 person-years, 95% CI (1.6-2.6). Age, previous non-sustained ventricular tachycardia, LV end-systolic volume indexed to body surface area (LVESVI), LA volume index ; LV ejection fraction, %LGE and presence of mitral regurgitation were significant univariable predictors of HF, with LVESVI (Hazard ratio (HR) 1.44, 95% confidence interval (95% CI) 1.16-1.78, p = 0.001), %LGE per 10% (HR 1.44, 95%CI 1.14-1.82, p = 0.002) age (HR 1.37, 95% CI 1.06-1.77, p = 0.02) and mitral regurgitation (HR 2.6, p = 0.02) remaining independently predictive on multivariable analysis. The presence or extent of inducible perfusion defect assessed using a visual score did not predict outcome (p = 0.16, p = 0.27 respectively). DISCUSSION: The annual incidence of HF in a contemporary ambulatory HCM population undergoing CMR is low. Myocardial fibrosis and LVESVI are strongly predictive of future HF, however CMR visual assessment of myocardial perfusion was not.

The prehospital patient pathway and experience of care with acute heart failure: a comparison of two health care systems.

AIMS: This study aimed to analyse community management of patients during the symptomatic period prior to admission with acute decompensated heart failure (ADHF). METHODS AND RESULTS: We conducted a prospective, two-centre, two-country observational study evaluating care pathways and patient experience in patients admitted to hospital with ADHF. Quantitative and qualitative data were gathered from patients, carers, and general practitioners (GPs). From the Irish centre, 114 patients enrolled, and from the English centre, 50 patients. Symptom duration longer than 72 h prior to hospitalization was noted among 70.4% (76) Irish and 80% (40) English patients, with no significant difference between those with a new diagnosis of HF [de novo HF (dnHF)] and those with known HF [established HF (eHF)] in either cohort. For the majority, dyspnoea was the dominant symptom; however, 63.3% (31) of these Irish patients and 47.2% (17) of these English patients did not recognize this as an HF symptom, with no significant difference between dnHF and eHF patients. Of the 46.5% (53) of Irish and 38% (19) of English patients reviewed exclusively by GPs before hospitalization, numbers prescribed diuretics were low (11.3%, six; and 15.8%, three, respectively); eHF patients were no more likely to receive diuretics than dnHF patients. Barriers to care highlighted by GPs included inadequate access to basic diagnostics, specialist support and up-to-date patient information, and lack of GP comfort in managing HF. CONCLUSION: The aforementioned findings, consistent across both health care jurisdictions, show a clear potential to intervene earlier and more effectively in ADHF or to prevent the need for hospitalization.

Predictors and Mechanisms of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

Global and regional cardiac function in lifelong endurance athletes with and without myocardial fibrosis.

The aim of the present study was to compare cardiac structure as well as global and regional cardiac function in athletes with and without myocardial fibrosis (MF). Cardiac magnetic resonance imaging with late gadolinium enhancement was used to detect MF and global cardiac structure in nine lifelong veteran endurance athletes (58 ± 5 years, 43 ± 5 years of training). Transthoracic echocardiography using tissue-Doppler and myocardial strain imaging assessed global and regional (18 segments) longitudinal left ventricular function. MF was present in four athletes (range 1-8 g) and not present in five athletes. MF was located near the insertion points of the right ventricular free wall on the left ventricle in three athletes and in the epicardial lateral wall in one athlete. Athletes with MF demonstrated a larger end diastolic volume (205 ± 24 vs 173 ± 18 ml) and posterior wall thickness (11 ± 1 vs 9 ± 1 mm) compared to those without MF. The presence of MF did not mediate global tissue velocities or global longitudinal strain and strain rate; however, regional analysis of longitudinal strain demonstrated reduced function in some fibrotic regions. Furthermore, base to apex gradient was affected in three out of four athletes with MF. Lifelong veteran endurance athletes with MF demonstrate larger cardiac dimensions and normal global cardiac function. Fibrotic areas may demonstrate some co-localised regional cardiac dysfunction, evidenced by an affected cardiac strain and base to apex gradient. These data emphasize the heterogeneous phenotype of MF in athletes.

CMR Guidance for Recanalization of Coronary Chronic Total Occlusion.

OBJECTIVES: This study explored whether cardiac magnetic resonance (CMR) could help select patients who could benefit from revascularization by identifying inducible myocardial ischemia and viability in the perfusion territory of the artery with chronic total occlusion (CTO). BACKGROUND: The benefit of revascularization using percutaneous coronary intervention (PCI) in CTO is controversial. CMR offers incomparable left ventricular (LV) systolic function assessment in addition to potent ischemic burden quantification and reliable myocardial viability analysis. Whether CMR guided CTO revascularization would be helpful to such patients has not yet been explored fully. METHODS: A prospective study of 50 consecutive CTO patients was conducted. Of 50 patients undergoing baseline stress CMR, 32 (64%) were selected for recanalization based on the presence of significant inducible perfusion deficit and myocardial viability within the CTO arterial territory. Patients were rescanned 3 months after successful CTO recanalization. RESULTS: At baseline, myocardial perfusion reserve (MPR) in the CTO territory was significantly reduced compared with the remote region (1.8 ± 0.72 vs. 2.2 ± 0.7; p = 0.01). MPR in the CTO region improved significantly after PCI (to 2.3 ± 0.9; p = 0.02 vs. baseline) with complete or near-complete resolution of CTO related perfusion defect in 90% of patients. Remote territory MPR was unchanged after PCI (2.5 ± 1.2; p = NS vs. baseline). The LV ejection fraction increased from 63 ± 13% to 67 ± 12% (p < 0.0001) and end-systolic volume decreased from 65 ± 38 to 56 ± 38 ml (p < 0.001) 3 months after CTO PCI. Importantly, despite minimal post-procedural infarction due to distal embolization and side branch occlusion in 8 of 32 patients (25%), the total Seattle Angina Questionnaire score improved from a median of 54 (range 45 to 74) at baseline to 89 (range 77 to 98) after CTO recanalization (p < 0.0001). CONCLUSIONS: In this small group of patients showing CMR evidence of significant myocardial inducible perfusion defect and viability, CTO recanalization reduces ischemic burden, favors reverse remodeling, and ameliorates quality of life.

Cost-effectiveness of natriuretic peptide-based screening and collaborative care: a report from the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) study.

AIMS: Prevention of cardiovascular disease and heart failure (HF) in a cost-effective manner is a public health goal. This work aims to assess the cost-effectiveness of the St Vincent's Screening TO Prevent Heart Failure (STOP-HF) intervention. METHODS AND RESULTS: This is a substudy of 1054 participants with cardiovascular risk factors [median age 65.8 years, interquartile range (IQR) 57.8:72.4, with 4.3 years, IQR 3.4:5.2, follow-up]. Annual natriuretic peptide-based screening was performed, with collaborative cardiovascular care between specialist physicians and general practitioners provided to patients with BNP levels >50 pg/mL. Analysis of cost per case prevented and cost-effectiveness per quality-adjusted life year (QALY) gained was performed. The primary clinical endpoint of LV dysfunction (LVD) with or without HF was reduced in intervention patients [odds ratio (OR) 0.60; 95% confidence interval (CI) 0.38-0.94; P = 0.026]. There were 157 deaths and/or emergency hospitalizations for major adverse cardiac events (MACE) in the control group vs. 102 in the intervention group (OR 0.68; 95% CI 0.49-0.93; P = 0.01). The cost per case of LVD/HF prevented was €9683 (sensitivity range -€843 to €20 210), whereas the cost per MACE prevented was €3471 (sensitivity range -€302 to €7245). Cardiovascular hospitalization savings offset increased outpatient and primary care costs. The cost per QALY gain was €1104 and the intervention has an 88% probability of being cost-effective at a willingness to pay threshold of €30 000. CONCLUSION: Among patients with cardiovascular risk factors, natriuretic peptide-based screening and collaborative care reduced LVD, HF, and MACE, and has a high probability of being cost-effective. TRIAL REGISTRATION: NCT00921960.

LV Apical Rupture Complicating Acute Myocardial Infarction: The Role of CMR.

PURPOSE: This case illustrates an acute myocardial infarction with occlusion of the left anterior descending coronary artery complicated by apical ventricular rupture and apical thrombus. PROCEDURES: An electrocardiogram, transthoracic echocardiogram (TTE), coronary angiography and cardiac magnetic resonance imaging (CMR) guided optimal management of the patient. FINDINGS: Coronary angiography revealed multivessel disease with an ostial occlusion of the LAD. Echocardiography showed apical dilatation of the left ventricle with a large, echogenic mass at the apex. Contrast echocardiography confirmed the presence of a large apical thrombus, separated from the LV cavity by myocardium. A CMR showed a completed LAD infarct and a filling thrombus was noted in the aneurysmal apical region inferring a contained rupture of the LV apex. PRINCIPLE CONCLUSIONS: Accurate and definitive delineation of unusual cardiac anatomy is best provided by complementary multimodality cardiac imaging, echocardiography and CMR. TTE can miss LV thrombi, particularly when they are large, aneurysmal and apical in nature. CMR provides the cardiac surgeon the ability to visualise in 3D the functional and morphological abnormalities, helping guide necessary intervention. Optimal management of patients with ventricular rupture remains controversial both in terms of timing and choice of intervention.

Recognition and significance of pathological T-wave inversions in athletes.

BACKGROUND: Pathological T-wave inversion (PTWI) is rarely observed on the ECG of healthy athletes, whereas it is common in patients with certain cardiac diseases. All ECG interpretation guidelines for use within athletes state that PTWI (except in leads aVR, III and V1 and in V1-V4 when preceded by domed ST segment in asymptomatic Afro-Caribbean athletes only) cannot be considered a physiological adaptation. The aims of the present study were to prospectively determine the prevalence of cardiac pathology in athletes presenting with PTWI, and to examine the efficacy of cardiac magnetic resonance in the work-up battery of further examinations. METHODS AND RESULTS: Athletes presenting with PTWI (n=155) were investigated with clinical examination, ECG, echocardiography, exercise testing, 24h Holter ECG, and cardiac magnetic resonance. Cardiac disease was established in 44.5% of athletes, with hypertrophic cardiomyopathy (81%) the most common pathology. Echocardiography was abnormal in 53.6% of positive cases, and cardiac magnetic resonance identified a further 24 athletes with disease. Five athletes (7.2%) considered normal on initial presentation subsequently expressed pathology during follow-up. Familial history of sudden cardiac death and ST-segment depression associated with PTWI were predictive of cardiac disease. CONCLUSIONS: PTWI should be considered pathological in all cases until proven otherwise, because it was associated with cardiac pathology in 45% of athletes. Despite echocardiography identifying pathology in half of these cases, cardiac magnetic resonance must be considered routine in athletes presenting with PTWI with normal echocardiography. Although exclusion from competitive sport is not warranted in the presence of normal secondary examinations, annual follow-up is essential to ascertain possible disease expression.

Life expectancy for community-based patients with heart failure from time of diagnosis.

AIMS: Heart failure has been demonstrated in previous studies to have a dismal prognosis. However, the modern-day prognosis of patients with new onset heart failure diagnosed in the community managed within a disease management programme is not known. The purpose of this study is to report on prognosis of patients presenting with new onset heart failure in the community who are subsequently followed in a disease management program. METHODS AND RESULTS: A review of patients referred to a rapid access heart failure diagnostic clinic between 2002 and 2012 was undertaken. Details of diagnosis, demographics, medical history, medications, investigations and mortality data were analysed. A total of 733 patients were seen in Rapid Access Clinic for potential new diagnosis of incident of heart failure. 38.9% (n=285) were diagnosed with heart failure, 40.7% (n=116) with HF-REF and 59.3% (n=169) with HF-PEF. There were 84 (29.5%) deaths in the group of patients diagnosed with heart failure; 41 deaths (35.3%) occurred in patients with HF-REF and 43 deaths (25.4%) occurred in patients with HF-PEF. In patients with heart failure, 52.4% (n=44) died from cardiovascular causes. 63.8% of HF patients were alive after 5 years resulting on average in a month per year loss of life expectancy over that period compared with aged matched simulated population. CONCLUSIONS: In this community-based cohort, the prognosis of heart failure was better than reported in previous studies. This is likely due to the impact of prompt diagnosis, the improvement in therapies and care within a disease management structure.

The St Vincent's potentially inappropriate medicines study: development of a disease-specific consensus list and its evaluation in ambulatory heart failure care.

AIMS: Heart failure (HF) patients may be at risk of prescription of potentially inappropriate medicines (PIMs) yet no disease-specific list is available to assess PIM use in this population. A Consensus Potentially Inappropriate Medicines in Heart Failure (PIMHF) list was developed, assessed, and compared with an established, general tool in an ambulatory HF population. METHODS AND RESULTS: The Consensus PIMHF list was compiled using modified Delphi methodology with a multidisciplinary team. The list consisted of 11 items. The medication profile of 350 patients was assessed. The association of a Consensus PIMHF item use over a median follow-up period of 1.8 (interquartile range 1.3-2.1) years with the primary endpoint of death, acute hospitalization, or unscheduled outpatient visit was examined. Fifty-one patients (14.6%) were prescribed ≥1 Consensus PIMHF item. In univariable analysis, patients prescribed ≥1 Consensus PIMHF item were 58% more likely to experience the primary endpoint than those with none [95% confidence interval (CI) 1.02-2.45]. When adjusted for age, sex, and HF severity, this difference remained [hazard ratio (HR) 1.88, 95% CI 1.16-3.06] and these associations were in contrast to the use of a more general tool (HR 1.24, 95% CI 0.83-1.84). However, when further adjusted to include co-morbidity score and polypharmacy, there was no association with outcome using either tool (HR 1.40, 95% CI 0.83-2.38; HR 1.05, 95% CI 0.69-1.60, respectively). CONCLUSION: The Consensus PIMHF list provides the first HF-specific medicines review tool. These results provide some support for more disease-specific tools with limited lists of PIMs to rationalize medicines management in HF. However, more prospective work on the application of these tools in practice is needed.

Coronary microvascular ischemia in hypertrophic cardiomyopathy - a pixel-wise quantitative cardiovascular magnetic resonance perfusion study.

BACKGROUND: Microvascular dysfunction in HCM has been associated with adverse clinical outcomes. Advances in quantitative cardiovascular magnetic resonance (CMR) perfusion imaging now allow myocardial blood flow to be quantified at the pixel level. We applied these techniques to investigate the spectrum of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and to explore its relationship with fibrosis and wall thickness. METHODS: CMR perfusion imaging was undertaken during adenosine-induced hyperemia and again at rest in 35 patients together with late gadolinium enhancement (LGE) imaging. Myocardial blood flow (MBF) was quantified on a pixel-by-pixel basis from CMR perfusion images using a Fermi-constrained deconvolution algorithm. Regions-of-interest (ROI) in hypoperfused and hyperemic myocardium were identified from the MBF pixel maps. The myocardium was also divided into 16 AHA segments. RESULTS: Resting MBF was significantly higher in the endocardium than in the epicardium (mean ± SD: 1.25 ± 0.35 ml/g/min versus 1.20 ± 0.35 ml/g/min, P<0.001), a pattern that reversed with stress (2.00 ± 0.76 ml/g/min versus 2.36 ± 0.83 ml/g/min, P<0.001). ROI analysis revealed 11 (31%) patients with stress MBF lower than resting values (1.05 ± 0.39 ml/g/min versus 1.22 ± 0.36 ml/g/min, P=0.021). There was a significant negative association between hyperemic MBF and wall thickness (ß=-0.047 ml/g/min per mm, 95% CI: -0.057 to -0.038, P<0.001) and a significantly lower probability of fibrosis in a segment with increasing hyperemic MBF (odds ratio per ml/g/min: 0.086, 95% CI: 0.078 to 0.095, P=0.003). CONCLUSIONS: Pixel-wise quantitative CMR perfusion imaging identifies a subgroup of patients with HCM that have localised severe microvascular dysfunction which may give rise to myocardial ischemia.

Role of late gadolinium enhancement cardiovascular magnetic resonance in the risk stratification of hypertrophic cardiomyopathy.

OBJECTIVE: Myocardial fibrosis identified by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM) is associated with adverse cardiovascular events, but its value as an independent risk factor for sudden cardiac death (SCD) is unknown. We investigated the role of LGE-CMR in the risk stratification of HCM. METHODS: We conducted a prospective cohort study in a tertiary referral centre. Consecutive patients with HCM (n=711, median age 56.3 years, IQR 46.7-66.6; 70.0% male) underwent LGE-CMR and were followed for a median 3.5 years. The primary end point was SCD or aborted SCD. RESULTS: Overall, 471 patients (66.2%) had myocardial fibrosis (median 5.9% of left ventricular mass, IQR: 2.2-13.3). Twenty-two (3.1%) reached the primary end point. The extent but not the presence of fibrosis was a significant univariable predictor of the primary end point (HR per 5% LGE: 1.24, 95% CI 1.06 to 1.45; p=0.007 and HR for LGE: 2.69, 95% CI 0.91 to 7.97; p=0.073, respectively). However, on multivariable analysis, only LV-EF remained statistically significant (HR: 0.92, 95% CI 0.89 to 0.95; p<0.001). For the secondary outcome of cardiovascular mortality/aborted SCD, the presence and the amount of fibrosis were significant predictors on univariable but not multivariable analysis after adjusting for LV-EF and non-sustained ventricular tachycardia. CONCLUSIONS: The amount of myocardial fibrosis was a strong univariable predictor of SCD risk. However, this effect was not maintained after adjusting for LV-EF. Further work is required to elucidate the interrelationship between fibrosis and traditional predictors of outcome in HCM.

Dilated cardiomyopathy and progressive familial intrahepatic cholestasis.

This case is of a 29-year-old man with progressive familial intrahepatic cholestasis type 1 also known as Byler's disease. At the age of 21, our patient developed non-ischaemic dilated cardiomyopathy. Cardiac MRI demonstrated global wall thinning, with significant areas of myocardial fibrosis in the mid and epicardial walls from base to apex on postgadolinium late contrast enhanced images. No shared genetic loci between dilated cardiomyopathy and Byler's or cholestatic liver disease have yet been found. This presents the first documented case of non-ischaemic dilated cardiomyopathy, with evidence of mid wall fibrosis, in association with an established diagnosis of progressive familial intrahepatic cholestasis type 1 since childhood.

Aspirin use in heart failure: is low-dose therapy associated with mortality and morbidity benefits in a large community population?

Background- Aspirin use in heart failure (HF) is controversial. The drug has proven benefit in comorbidities associated with HF; however, retrospective analysis of angiotensin-converting enzyme inhibitor trials and prospective comparisons with warfarin have shown increased risk of morbidity with aspirin use. This study aims to evaluate the association of low-dose aspirin with mortality and morbidity risk in a large community-based cohort. Methods and Results- This was a retrospective cohort study of patients attending an HF disease management program. Aspirin use at baseline and its association with mortality and HF hospitalization in the population was examined. Of 1476 patients (mean age, 70.4±12.4 years; 63% men), 892 (60.4%) were prescribed aspirin. Low-dose aspirin (75 mg/d) was prescribed to 828 (92.8%) patients. Median follow-up time was 2.6 (0.8-4.5) years. During the follow-up period, 464 (31.4%) patients died. In adjusted analysis, low-dose aspirin use was associated with reduced mortality risk compared with nonaspirin use (hazard ratio=0.58; 95% confidence interval, 0.46-0.74), and this was confirmed by a propensity-matched subgroup analysis. Low-dose aspirin use was associated with reduced risk of HF hospitalization compared with nonaspirin use in the total population (adjusted hazard ratio=0.70; 95% confidence interval, 0.54-0.90). In adjusted analysis, there was no difference in mortality or HF hospitalization between high-dose aspirin users (>75 mg/d) and nonaspirin users. Conclusions- In this study, low-dose aspirin therapy was associated with a significant reduction in mortality and morbidity risk during long-term follow-up. These results suggest that low-dose aspirin may have a continuing role in secondary prevention in HF and underline the need for more trials of low-dose aspirin use in HF.