Cardiac transplant rejection assessment with 18F-FDG PET-CT: initial single-centre experience for diagnosis and management.

BACKGROUND: Rejection is a major cause of mortality and morbidity in heart transplant (HTx) recipients. Current methods for diagnosing rejection have limitations. Imaging methods to map the entire left ventricle and reliably identify potential sites of rejection is lacking. Animal studies suggest FDG PET-CT (FDG PET) could have potential application in human HTx recipients. METHODS: Between December 2020 and February 2022, all HTx recipients at Harefield Hospital, London, with definite or suspected rejection underwent FDG PET in addition to routine work-up. RESULTS: Thirty HTx recipients (12 with definite and 18 with suspected rejection) underwent FDG PET scans. Overall, 12 of the 30 patients had FDG PET with increased myocardial avidity, of whom 2 died (17%). Eighteen patients of the 30 patients had FDG PET with no myocardial avidity and all are alive (100%, p = 0.15). All patients with definite rejection, scanned within 2 weeks of starting anti-rejection treatment, showed increased myocardial avidity. In 5 cases, FDG PET showed myocardial avidity beyond 6 weeks despite pulsed steroid treatment, suggesting unresolved myocardial rejection. CONCLUSION: Preliminary findings suggest FDG PET may have a role in diagnosing cardiac transplant rejection. Future blinded studies are needed to help further validate this.

Association of Renin-Angiotensin-Aldosterone System Inhibitors With Clinical Outcomes, Hemodynamics, and Myocardial Remodeling Among Patients With Advanced Heart Failure on Left Ventricular Assist Device Support.

BACKGROUND: We evaluated the potential benefits of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with left ventricular assist device support. METHODS AND RESULTS: A total of 165 consecutive patients undergoing left ventricular assist device implant and alive at 6-month on support were studied. RAASi status after 6-month visit along with clinical reasons for nonprescription/uptitration were retrospectively assessed. The primary outcome was a composite of heart failure hospitalization or cardiovascular death between 6 and 24 months after left ventricular assist device implant. Remodeling and hemodynamic outcomes were explored by studying the association of RAASi new prescription/uptitration versus unmodified therapy at 6-month visit with the change in echocardiographic parameters and hemodynamics between 6 and 18 months. After the 6-month visit, 76% of patients were on RAASi. Patients' characteristics among those receiving and not receiving RAASi were mostly similar. Of 85 (52%) patients without RAASi new prescription/uptitration at 6-month visit, 62% had no apparent clinical reason. RAASi were independently associated with the primary outcome (adjusted hazard ratio, 0.31 [95% CI, 0.16-0.69]). The baseline rates of optimal echocardiographic profile (neutral interventricular septum, mitral regurgitation less than mild, and aortic valve opening) and hemodynamic profile (cardiac index ≥2.2 L/min per m2, wedge pressure <18 mm Hg, and right atrial pressure <12 mm Hg) were similar between groups. At 18 months, patients receiving RAASi new prescription/uptitration at 6 months had higher rates of optimal hemodynamic profile (57.5% versus 37.0%; P=0.032) and trends for higher rates of optimal echocardiographic profile (39.6% versus 22.9%; P=0.055) compared with patients with 6-month unmodified therapy. Optimal 18-month hemodynamic and echocardiographic profiles were associated with the primary outcome (log-rank=0.022 and log-rank=0.035, respectively). CONCLUSIONS: RAASi are associated with improved outcomes and improved hemodynamics among mechanically unloaded patients.

Predictors and clinical implications of residual mitral regurgitation following left ventricular assist device therapy.

BACKGROUND: Correction of mitral regurgitation (MR) at the time of left ventricular assist device (LVAD) implantation remains controversial. There is conflicting evidence regarding the clinical impact of residual MR, and studies have not examined whether MR aetiology or right heart function impacts the likelihood of residual MR. METHODS: This is a retrospective single-centre study of 155 consecutive patients with LVAD implantation from January 2011 to March 2020. Exclusion criteria were no MR pre-LVAD (n=8), inaccessible echocardiography (n=9), duplicate records (n=10) and concomitant mitral valve repair (n=1). Statistical analysis was performed using STATA V.16 and SPSS V.24. RESULTS: Carpentier IIIb MR aetiology was associated with more severe MR pre-LVAD (severe 18/27 (67%) vs non-severe 32/91 (35%), p=0.004) and a higher likelihood of residual MR (8/11 (72%) vs 30/74 (41%), p=0.045). Of 95 patients with significant MR pre-LVAD, 15 (16%) had persistent significant MR, which was associated with higher mortality (p=0.006), post-LVAD right ventricle (RV) dilatation (10/15 (67%) vs 28/80 (35%), p=0.022) and RV dysfunction (14/15 (93%) vs 35/80 (44%), p<0.001). Aside from ischaemic aetiology, other pre-LVAD parameters that were associated with significant residual MR included left ventricular end-systolic diameter (LVESD) (6.9 cm (5.7-7.2) vs 5.9 cm (5.5-6.5), p=0.043), left atrial volume index (LAVi) (78 mL/m2 (56-88) vs 57 mL/m2 (47-77), p=0.021), posterior leaflet displacement (2.5 cm (2.3-2.9) vs 2.3 cm (1.9-2.7), p=0.042) and basal right ventricular end-diastolic diameter (RVEDD) (5.1±0.8 cm vs 4.5±0.8 cm, p=0.010). CONCLUSION: LVAD therapy improves MR and tricuspid regurgitation severity in the majority, but 14% have persistent significant residual MR, associated with right ventricular dysfunction and higher long-term mortality. This may be predicted pre-LVAD by greater LVESD, RVEDD and LAVi and by ischaemic aetiology.

Oral milrinone for management of refractory right ventricular failure in patients with left ventricular assist devices.

AIMS: We present a single-centre retrospective experience using oral milrinone in patients with a left ventricular assist device (LVAD) and concurrent refractory right ventricular failure. METHODS AND RESULTS: All patients implanted with LVAD between January 2013 and July 2021 from a high-volume advanced heart failure service were reviewed. Eight patients were initiated on oral milrinone during this period. Oral milrinone was started 1.5 [inter-quartile range (IQR) 1-2.3] years after LVAD implantation and continued for 1.2 (IQR 0.5-2.8) years. Therapeutic milrinone levels were achieved (232.2 ± 153.4 ng/mL) with 62.4 ± 18% of time within the therapeutic range. Two patients had adverse events (non-sustained ventricular tachycardia and ventricular fibrillation effectively treated by internal cardioverter defibrillator) but did not require milrinone discontinuation. Four deaths occurred, one after transplant and three from disease progression determined to be unrelated to oral milrinone use. Three patients continue oral milrinone therapy in the community. There was no significant difference found after the initiation of oral milrinone on any of the physiological measures; however, there were trends in reduction of New York Heart Association class from 3.4 ± 0.5 to 3.0 ± 0.8 (P = 0.08), reduction of right atrial/wedge pressure from 0.9 ± 0.3 to 0.5 ± 0.2 (P = 0.08), and improvement of right ventricular stroke work index from 3.8 ± 2 to 5.8 ± 2.7 (P = 0.16). CONCLUSIONS: Oral milrinone appears safe for long-term use in the outpatient setting when combined with therapeutic monitoring in this complex medical cohort with limited management options. Further study is needed to ascertain whether this treatment is effective in reducing heart failure symptoms and admissions.

Challenges of Chronic Cardiac Problems in Survivors of Takotsubo Syndrome.

A hallmark feature of the Takotsubo syndrome (TTS) is the reversible nature of the observed cardiac dysfunction. This is underlined in diagnostic criteria. However, it would appear this reversibility is a subtle process, and that myocardial catecholamine toxicity can cause lasting permanent abnormalities of myocardial physiology. A growing body of evidence suggests persisting abnormalities may predispose post-TTS patients to cardiac and noncardiac morbidity and mortality. The cardiology community needs to understand more clearly how TTS evolves, how to identify high-risk patients with incomplete resolution, and perform studies to assess which treatment(s) are effective to improve cardiac recovery and clinical outcomes.

Editor's Choice-Biomarkers of acute cardiovascular and pulmonary diseases.

Acute cardiothoracic and respiratory diseases frequently remain a challenge to diagnose and differentiate in the emergency setting. The main diseases that manifest with chest pain include ischaemic heart disease, myocarditis, acute pericarditis, aortic dissection/rupture and pulmonary embolism (PE). Diseases that primarily present with dyspnoea include heart failure (HF), acute respiratory distress syndrome (ARDS), pneumonia, asthma exacerbations and chronic obstructive pulmonary disease. Pre-test probabilities of clinical findings play a vital part in diagnostic decisions, and the use of a Bayesian approach to these greatly improves the ability to stratify patients more accurately. However, blood tests (biomarkers) are increasingly used to assist in rapid decision-making in the emergency setting in combination with imaging methods such as chest radiograph, ultrasound and increasingly computed tomography, as well as physiological tests such as the electrocardiogram in addition to physical examination. Specific tests for ischaemic heart disease and myocarditis (cardiac troponins), HF (B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP)), aortic dissection (smooth muscle markers) and PE (D-dimer) have been developed. Surfactant protein-D and interleukin-8 have been developed for ARDS. Additionally, circulating microRNAs have emerged as promising biomarker candidates in cardiovascular disease. With this increasing array of biochemical markers to aid in the diagnosis of chest diseases presenting with chest pain and dyspnoea, we herein review the clinical usefulness of these markers, in particular in differentiating cardiac from pulmonary diseases. A symptom-oriented assessment as necessary for use in the critical setting is described in addition to discussion of individual biomarkers.

The Current and Future Landscape of SERCA Gene Therapy for Heart Failure: A Clinical Perspective.

Gene therapy has been applied to cardiovascular disease for over 20 years but it is the application to heart failure that has generated recent interest in clinical trials. There is laboratory and early clinical evidence that delivery of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy is beneficial for heart failure and this therapy could become the first positive inotrope with anti-arrhythmic properties. In this review we will discuss the rationale for SERCA2a gene therapy as a viable strategy in heart failure, review the published data, and discuss the ongoing clinical trials, before concluding with comments on the future challenges and potential for this therapy.

Circulating microRNAs for predicting and monitoring response to mechanical circulatory support from a left ventricular assist device.

AIMS: There are few non-invasive techniques to predict and monitor patients' responses to left ventricular assist device (LVAD) therapy. MicroRNAs (miRs) are small non-coding RNAs with intricate roles in cardiovascular disease. They are stable in the circulation, readily quantified, and may be useful as new biomarkers. This study sought to identify candidate miR biomarkers for further investigation. METHODS AND RESULTS: We studied 53 plasma and 20 myocardial samples from 19 patients who underwent HeartMate II LVAD implantation, and used a screening microarray to analyse the change in expression of 1113 miRs after 6 months LVAD support. Twelve miRs showed significant variation and underwent validation, yielding miR-1202 and miR-483-3p as candidate biomarkers. In the test cohort, circulating miR-483-3p showed early and sustained up-regulation with LVAD support, with median (interquartile range) fold changes from baseline of 2.17 (1.43-2.62; P = 0.011), 2.27 (1.12-2.42; P = 0.036), 1.87 (1.64-4.36; P = 0.028), and 2.82 (0.70-10.62; P = 0.249) at 3, 6, 9, and 12 months, respectively, whilst baseline plasma miR-1202 identified good vs. poor LVAD responders [absolute expression 1.296 (1.293-1.306) vs. 1.311 (1.310-1.318) arbitrary units; P = 0.004]. Both miRs are enriched in ventricular myocardium, suggesting the heart as the possible source of the plasma fraction. CONCLUSIONS: This is the first report of circulating miR biomarkers in LVAD patients. We demonstrate the feasibility of this approach, report the potential for miR-483-3p and miR-1202, respectively, to monitor and predict response to LVAD therapy, and propose further work to study these hypotheses and elucidate roles for miR-483-3p and miR-1202 in clinical practice and in underlying biological processes.

Pathophysiology of takotsubo syndrome: temporal phases of cardiovascular responses to extreme stress.

Takotsubo syndrome (TTS), also known as takotsubo cardiomyopathy, is an acute heart failure syndrome that typically occurs after a period of great emotional stress. The archetypal patient is a postmenopausal woman who presents with chest pain, ST-segment elevation and acute hypokinesia of the apical and middle segment of the left ventricle that extends beyond the territory of a single coronary artery, coupled with hyperkinesia of the basal myocardium. Recent preclinical and clinical studies have shown the importance of high catecholamine levels in precipitating TTS. We propose that this is caused by activation of ß-adrenoceptors and the subsequent activation of a negatively-inotropic pathway, perhaps to protect the heart from catecholamine overload. We explore the pathophysiology of TTS according to its "phases", both preclinically and clinically. This will show that the condition is not one of static apical hypokinesia that simply improves, but rather a dynamic condition that changes as the disease progresses. We hope that further exploration of TTS using its "phases" will aid in its characterization, diagnosis and treatment.

Takotsubo cardiomyopathy.

How can an earthquake cause cardiogenic shock? Can a bereft lover really die from a broken heart? Takotsubo cardiomyopathy is an intriguing reversible condition which still mystifies and excites the layman and physician alike. This article explores the clinical essentials for recognizing and managing this group of complex patients.