N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Hypertrophic Cardiomyopathy.

PURPOSE OF REVIEW: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac condition with potential for severe complications including sudden cardiac death. Early diagnosis allows appropriate risk stratification and prompt intervention to minimise the potential for adverse outcomes. The implications of poorly coordinated screening are significant, either missing relatives at high-risk or burdening low-risk individuals with a diagnosis associated with reduced life expectancy. We aim to guide clinicians through the diagnostic pathway through to novel treatment options. Several conditions mimic the condition, and we discuss the phenocopies and how to differentiate from HCM. RECENT FINDINGS: We summarise the latest developments informing clinical decision making in the modern era of myosin inhibitors and future gene editing therapies. Early identification will enable prompt referral to specialist centres. A diagnostic flowchart is included, to guide the general cardiology and heart failure clinician in important decision making regarding the care of the HCM patient and importantly their relatives at risk. We have highlighted the importance of screening because genotype-positive/phenotype-negative patients are likely to have the most to gain from novel therapies.

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).

Sequencing of medical therapy in heart failure with a reduced ejection fraction.

The management of heart failure with a reduced ejection fraction is a true success story of modern medicine. Evidence from randomised clinical trials provides the basis for an extensive catalogue of disease-modifying drug treatments that improve both symptoms and survival. These treatments have undergone rigorous scrutiny by licensing and guideline development bodies to make them eligible for clinical use. With an increasing number of drug therapies however, it has become a complex management challenge to ensure patients receive these treatments in a timely fashion and at recommended doses. The tragedy is that, for a condition with many life-prolonging drug therapies, there remains a potentially avoidable mortality risk associated with delayed treatment. Heart failure therapeutic agents have conventionally been administered to patients in the chronological order they were tested in clinical trials, in line with the aggregate benefit observed when added to existing background treatment. We review the evidence for simultaneous expedited initiation of these disease-modifying drug therapies and how these strategies may focus the heart failure clinician on a time-defined smart goal of drug titration, while catering for patient individuality. We highlight the need for adequate staffing levels, especially heart failure nurse specialists and pharmacists, in a structure to provide the capacity to deliver this care. Finally, we propose a heart failure clinic titration schedule and novel practical treatment score which, if applied at each heart failure patient contact, could tackle treatment inertia by a constant assessment of attainment of optimal medical therapy.

Dilated cardiomyopathy: the role of genetics, highlighted in a family with Filamin C (FLNC) variant.

Dilated cardiomyopathy (DCM) is a heterogenous group of disorders characterised by left ventricular dilatation and dysfunction, in the absence of factors affecting loading conditions such as hypertension or valvular disease, or significant coronary artery disease. The prevalence of idiopathic DCM is estimated between 1:250 and 1:500 individuals. Determining the aetiology of DCM can be challenging, particularly when evaluating an individual and index case with no classical history or investigations pointing towards an obvious acquired cause, or no clinical clues in the family history to suggest a genetic cause. We present a family affected by DCM associated with Filamin C variant, causing sudden cardiac death at a young age and heart failure due to severe left ventricular impairment and myocardial scarring. We review the diagnosis and treatment of DCM, its genetic associations and potential acquired causes. Thorough assessment is mandatory to risk stratify and identify patients who may benefit from primary prevention implantable cardioverter defibrillator therapy according to international guidelines. Genetic testing has some limitations, and is positive in only 20%-35% of DCM, but should be considered in specific cases to identify families who may benefit from cascade screening after appropriate counselling. The management of often complex familial cardiomyopathy requires specialist input for every case, and the appropriate infrastructure to coordinate investigations.

Stress perfusion cardiovascular magnetic resonance and serial fractional flow reserve assessment of the left anterior descending artery in patients undergoing right coronary artery chronic total occlusion revascularization.

BACKGROUND: Fractional flow reserve (FFR) assessment of remote arteries, in the context of a bystander chronic total occlusion (CTO), can lead to false positive results. Adenosine stress cardiovascular magnetic resonance (CMR) evaluates perfusion defects across the entire myocardium and may therefore be a reliable tool in the work-up of remote lesions in CTO patients. The IMPACT-CTO study investigated donor artery invasive physiology before, immediately post, and at 4 months following right coronary artery (RCA) CTO percutaneous coronary intervention (PCI). The aim of this subanalysis was to assess the concordance between baseline perfusion CMR and serial FFR evaluation of left anterior descending artery (LAD) ischemia in patients from the IMPACT-CTO study. METHODS: Baseline adenosine stress CMR examinations from 26 patients were analyzed for qualitative evidence of LAD ischemia. The results were correlated with the serial LAD FFR measurements. RESULTS: The present findings demonstrated that before RCA CTO PCI, there was 62% agreement between perfusion CMR and FFR (ischemic threshold £ 0.8) in the assessment of LAD ischemia (k = 0.29; fair concordance). At 4 months after revascularization, there was 77% agreement (k = 0.52; moderate concordance) between the index CMR assessment of LAD ischemia and the follow-up LAD FFR. Concordance was improved at a LAD FFR ischemic threshold of £ 0.75. CONCLUSIONS: In this hypothesis generating study, baseline CMR assessment of LAD ischemia correlated better with the 4 months LAD FFR data (threshold £ 0.8) as compared to the FFR measurements taken prior to RCA CTO revascularization.

Predictors of left ventricular remodelling in patients with dilated cardiomyopathy - a cardiovascular magnetic resonance study.

AIMS: There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling. METHODS AND RESULTS: Prospective study of patients with recent-onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = -0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease-modifying heart failure medication (beta-blocker, P = 0.28; angiotensin-converting enzyme inhibitor, P = 0.92) did not predict follow-up LVEF. CONCLUSIONS: Substantial recovery of LV function occurs within 12 months in most patients with recent-onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

The impact of coronary chronic total occlusion percutaneous coronary intervention upon donor vessel fractional flow reserve and instantaneous wave-free ratio: Implications for physiology-guided PCI in patients with CTO.

OBJECTIVE: To investigate the immediate and short term impact of right coronary artery (RCA) chronic total coronary occlusion (CTO) percutaneous coronary intervention (PCI) upon collateral donor vessel fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR). BACKGROUND: CTO PCI influences collateral donor vessel physiology, making the indication and/or timing of donor vessel revascularization difficult to determine. METHODS: In patients with RCA CTO, FFR, iFR, and collateral function index (FFRcoll ) were measured in LAD and LCx pre-CTO PCI, immediately post and at 4 month follow-up. RESULTS: 34 patients underwent successful PCI. In the predominant donor vessel immediately post PCI, FFR, and FFRcoll did not change (0.76 ± 0.12 to 0.75 ± 0.13, P = 0.267 and 0.31 ± 0.10 vs. 0.34 ± 0.11, P = 0.078), but iFR increased significantly (0.86 ± 0.10 to 0.88 ± 0.10, P = 0.012). At follow-up, there was a significant increase in predominant donor FFR and iFR (0.76 ± 0.12 to 0.79 ± 0.11, P = 0.047 and 0.86 ± 0.10 to 0.90 ± 0.07, P = 0.003), accompanied by a significant reduction in FFRcoll (0.31 ± 0.10 to 0.18 ± 0.07 P < 0.0001). These changes resulted in a reclassification of the predominant donor vessel from ischemic to nonischemic in 18% (FFR) and 25% (iFR) of the cases, respectively. CONCLUSIONS: Successful recanalization of an RCA CTO resulted in a modest but statistically significant increase in the predominant donor vessel immediately post CTO PCI in the case of iFR and at 4-month follow-up for FFR and iFR compared to pre-PCI with a concomitant reduction in collateral function.

Assessing the Eligibility Criteria in Phase III Randomized Controlled Trials of Drug Therapy in Heart Failure With Preserved Ejection Fraction: The Critical Play-Off Between a "Pure" Patient Phenotype and the Generalizability of Trial Findings.

AIMS: To investigate the effect of the different eligibility criteria used by phase III clinical studies in heart failure with preserved ejection fraction (HFpEF) on patient selection, phenotype, and survival. METHODS AND RESULTS: We applied the key eligibility criteria of 7 phase III HFpEF studies (Digitalis Investigation Group Ancillary, Candesartan in Patients With Chronic Heart Failure and Preserved Left-Ventricular Ejection Fraction, Perindopril in Elderly People With Chronic Heart Failure, Irbesartan in Heart Failure With Preserved Systolic Function, Japanese Diastolic Heart Failure, Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist, and Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF; ongoing]) to a typical and well-characterized HFpEF population (n = 557) seen in modern European cardiological practice. Follow-up was available for a minimum of 24 months in each patient. Increasing the number of study eligibility criteria identifies a progressively smaller group of patients from real-life practice suitable for recruitment into clinical trials; using the J-DHF criteria, 81% of our clinic patients would have been eligible, whereas the PARAGON-HF criteria significantly reduced this proportion to 32%. The patients identified from our clinical population had similar mortality rates using the different criteria, which were consistently higher than those reported in the actual clinic trials. CONCLUSIONS: Trial eligibility criteria have become stricter with time, which reduces the number of eligible patients, affecting both generalizability of any findings and feasibility of completing an adequately powered trial. We could not find evidence that the additional criteria used in more recent randomized trials in HFpEF have identified patients at higher risk of all-cause mortality.

Afro-Caribbean Heart Failure in the United Kingdom: Cause, Outcomes, and ATTR V122I Cardiac Amyloidosis.

BACKGROUND: It has been reported that subjects of African descent present with heart failure at a younger age and because of different causes than whites. We present contemporary data from UK Afro-Caribbean patients in London. METHODS AND RESULTS: All patients with heart failure presenting to St George's Hospital Heart Failure clinic between 2005 and 2012 were included (n=1392). Patients were predominantly white (71%) and male (67%), and median age at presentation was 73 years (range, 18-100 years). In 211 Afro-Caribbean patients, the most common cause of heart failure was nonischemic dilated cardiomyopathy in 27.5% (whites, 19.9%; P<0.001). Lower rates of ischemic cardiomyopathy were observed (13% versus 41%; P<0.001). The fourth most common cause of heart failure in Afro-Caribbeans was cardiac amyloidosis (11.4%). The prevalence may have been even higher as not all patients were tested for amyloidosis. Patients with ATTR V122I had the worst prognosis compared with other causes of Afro-Caribbean heart failure and white patients. To better understand this condition, we analyzed data from the largest international cohort of ATTR V122I patients, followed up at the UK National Amyloidosis Center (n=72). Patients presented with cardiac failure (median age, 75 [range, 59-90] years). Median survival was 2.6 years from diagnosis. CONCLUSIONS: In London, the cause of heart failure varies depending on ethnicity and affects age of presentation and outcomes. In Afro-Caribbean patients, ATTR V122I is an underappreciated cause of heart failure, and cardiomyopathy is often misattributed to hypertension. As promising TTR therapies are in development, increased awareness and proactive detection are needed.

Cardiac Amyloid - An Update.

Cardiac amyloidosis is a condition characterised by rapidly progressive heart failure and poor prognosis. The two main subtypes, immunoglobulin light chains (AL) and transthyretin (ATTR), have been investigated extensively in recent years. Cardiac imaging has advanced with the widespread use of cardiac MRI with late gadolinium enhancement imaging and newer techniques including T1 mapping to quantify amyloid burden. Nuclear imaging has developed as a highly accurate method to confirm cardiac amyloid deposits non-invasively with very high sensitivity in ATTR amyloidosis. Despite advances in imaging, cardiac biopsy remains the gold standard diagnostic test to confirm and type amyloidosis. Hereditary ATTR amyloidosis of V122I type has been the focus of important studies in the past year, due to the high prevalence of the amyloidogenic allele in patients of African descent. Recent research concluded a significant number of Afro-Caribbean heart failure patients are likely to have undiagnosed cardiac amyloidosis. Misdiagnosis may lead to inappropriate treatment with potentially harmful 'standard' heart failure medications with no evidence base in amyloidosis. Treatment options have, until recently, been limited but cardiac amyloidosis is the focus of novel therapeutic regimes. New insights into the pathophysiological mechanisms resulting in disease have suggested exciting targets for drug therapy.

CMR-based differentiation of AL and ATTR cardiac amyloidosis.

OBJECTIVES: This study was devised to describe the different cardiac magnetic resonance (CMR) appearances in light chain amyloid (AL) and transthyretin-related amyloidosis (ATTR). BACKGROUND: CMR is increasingly used to investigate patients with suspected amyloidosis. Global subendocardial late gadolinium enhancement (LGE) has been reported as typical of AL amyloidosis, whereas different patterns have been noted in ATTR amyloidosis. METHODS: We performed de novo analyses on original DICOM magnetic resonance imaging in 46 patients with cardiac AL amyloidosis and 51 patients with ATTR type who had been referred to a specialist amyloidosis center between 2007 and 2012 after CMR. Histological examination was performed in all cases, with immunohistochemistry, to confirm systemic amyloidosis. RESULTS: Patients' median age was 68 ± 10 years, and 74% were male. Left ventricular mass was markedly increased in ATTR amyloidosis (228 g [202 to 267 g]) compared with AL type (167 g [137 to 191 g]) (p < 0.001). LGE was detected in all but 1 cardiac amyloidosis patient (AL type) and was substantially more extensive in ATTR compared with AL amyloidosis. Ninety percent of ATTR patients demonstrated transmural LGE compared with 37% of AL patients (p < 0.001). Right ventricular LGE was apparent in all ATTR patients but in only 33 AL patients (72%) (p < 0.001). Despite these findings, survival was significantly better in cardiac ATTR amyloidosis compared with AL type. We derived an LGE scoring system (Query Amyloid Late Enhancement) that independently differentiated ATTR from AL amyloidosis and, when incorporated into a logistic regression model with age and wall thickness, detected ATTR type with 87% sensitivity and 96% specificity. CONCLUSIONS: Transmural patterns of LGE distinguished ATTR from AL cardiac amyloidosis with high accuracy in this real-world analysis of CMR. Precise diagnosis of cardiac amyloidosis is crucial given the role of chemotherapy in AL type and with novel therapies for ATTR type currently in development.

Cardiac transthyretin amyloidosis.

Cardiac amyloidosis of transthyretin fibril protein (ATTR) type is an infiltrative cardiomyopathy characterised by ventricular wall thickening and diastolic heart failure. Increased access to cardiovascular magnetic resonance imaging has led to a marked increase in referrals to our centre of Caucasian patients with wild-type ATTR (senile systemic) amyloidosis and Afro-Caribbean patients with the hereditary ATTR V122I type. Both subtypes present predominantly as isolated cardiomyopathy. The differential diagnosis includes cardiac amyloid light-chain (AL) amyloidosis, which has a poorer prognosis and can be amenable to chemotherapy. We review here the clinical features of cardiac ATTR amyloidosis and describe the diagnostic tests to determine ATTR type. Correct diagnosis is ever more crucial given that several novel therapies for ATTR amyloidosis are on the near horizon.