Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis.

ABSTRACT: Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry-based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

Monitoring cardiac amyloidosis with multimodality imaging.

Cardiac amyloidosis (CA) refers to an infiltrative process involving amyloid fibril deposition in the myocardium causing restrictive cardiomyopathy. While various types can affect the heart, the predominant forms are immunoglobulin light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. This review article explores the expanding field of imaging techniques used to diagnose AL-CA and ATTR-CA, highlighting their usefulness in prognostication and disease surveillance. Echocardiography is often the initial imaging modality to suspect CA and, since the incorporation of nonbiopsy criteria using bone scintigraphy, diagnosing ATTR-CA has become more attainable following exclusion of plasma cell dyscrasia. Cardiac magnetic resonance is progressively emerging as a vital tool for imaging CA, and is used in diagnosis, prognostication, and disease surveillance. The use of cardiac magnetic resonance in AL-CA is discussed, as it has been shown to accurately evaluate organ response to chemotherapy. As novel drug treatments emerge in the realm of ATTR-CA, the use of cardiovascular imaging surveillance to monitor disease progression is discussed, as it is gaining prominence as a critical consideration. The ongoing phase III trials investigating treatments for patients with ATTR-CA, will undoubtedly enhance our understanding of cardiac imaging surveillance.

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). METHODS AND RESULTS: A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. CONCLUSION: p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis.

AIMS: To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. METHODS AND RESULTS: A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. CONCLUSION: The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Humoral response to heterologous prime-booster vaccination in heart transplant recipients aged 18-70 years primed with a viral vector SARS-CoV-2 vaccine.

Solid organ transplant recipients have demonstrated a blunted immune response to standard 2-dose vaccination against SARS-CoV-2. This study sought to determine the humoral response to heterologous booster vaccination (viral vector vaccine dose 1 and 2 + mRNA booster). Heart transplant recipients, aged 18 to 70 years of age who initially received two doses of the viral vector ChAdOx1 nCoV-19 vaccine followed by a BNT162b2 mRNA booster were recruited. A detectable antibody response in the absence of prior SARS-CoV-2 was the primary outcome measured. This was defined as an anti-spike titre of ≥0.8 U/mL on the Elecsys anti-SARS-CoV-2 S immunoassay. A total of 80 heart transplant patients (mean age 49 ± 13 years, 28% female) were included. Blood samples were drawn at a median of 30 (IQR 28-33) days after the BNT162b2 mRNA booster. The frequency of a detectable antibody response increased from 37.5% (n = 30) after dose 2 to 56% (n = 45) post dose 3 (p < 0.001). A non-detectable antibody response was significantly more common in recipients with a shorter time interval from transplantation (p < 0.001), lower likelihood of cardiac allograft vasculopathy (p = 0.003) and in those prescribed a triple versus dual immunosuppressant regime (p = 0.009) and a tacrolimus versus cyclosporine basedregimen (p = 0.007). Despite heterologous prime-booster vaccination 44% of this vulnerable population ultimately continue to have no detectable antibodies.

A survey-based triage tool to identify patients potentially eligible for referral to an advanced heart failure centre.

AIMS: Accurate prevalence data for ambulatory advanced heart failure (HF) in European countries remains limited. This study was designed to identify the population of patients potentially eligible for referral for assessment for advanced surgical HF therapies to a National advanced HF and cardiac transplant centre. METHODS AND RESULTS: A survey comprising 13 potential clinical markers of advanced HF was developed, modified from the 'I NEED HELP' tool from the 2018 position statement of the Heart Failure Association of the European Society of Cardiology, and distributed to all HF clinic services (secondary and tertiary units) nationwide. Each HF clinic unit was asked to complete the survey on consecutive patients over a 3 month period fulfilling the following three criteria: (i) age <65 years; (ii) ejection fraction <40% and (iii) HF of >3 months duration. As a comparison, the number of actual referrals to the advanced HF clinic were also audited over a 9 month period. In all, 21 of 26 HF clinic units participated in the survey. Across the period of inclusion, 4950 all-comer HF patients were seen across all sites. Of these, 375 (7.5%) fulfilled the inclusion criteria and were surveyed (74.4% male, median age 57 years [IQR: 11 years]). In total, 246 (66%) of the surveyed patients had ≥1 potential markers for advanced HF, representing just under 5% of the total all-comer HF population seen across the same time period. Of these, 67 patients (27%) had ≥2, 48 (20%) had 3 and 40 (16%) had ≥4 potential markers. The most frequently noted markers were ≥1 HF hospitalization or unscheduled clinic review (56%), intolerance to renin-angiotensin-aldosterone system inhibitors due to hypotension or renal dysfunction (29%) and intolerance to beta-blockers due to hypotension (27%). Almost one-quarter of patients reported NYHA Class III or IV symptoms. During the advanced HF clinic audit, the number of patients actually referred to the advanced HF clinic during the same time period was <5% of this potentially eligible cohort. CONCLUSIONS: In this index prospective National survey, approximately 5% of an all-comer routine HF clinic population and two-thirds of a pre-selected HF with reduced EF under 65 years cohort were found to have at least one clinical or biochemical marker suggesting advanced or impending advanced HF. Almost one-quarter of patients in this chronic outpatient 'snapshot' population have NYHA III-IV symptoms. This simple one-page triage survey-modified from the 'I NEED HELP' tool-is useful to identify a population potentially eligible for referral to an advanced HF centre for assessment for advanced surgical therapies, thereby aiding resource and service planning.

Humoral response to SARS-CoV-2 adenovirus vector vaccination (ChAdOx1 nCoV-19 [AZD1222]) in heart transplant recipients aged 18 to 70 years of age.

BACKGROUND: Recent studies have suggested a blunted immune response to messenger RNA vaccines in solid organ transplant (SOT) recipients. Given the paucity of data on adenovirus vector vaccines use in immunosuppressed SOT recipients, we sought to describe the safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine in a heart transplant population. METHODS: Heart transplant recipients aged 18 to 70 years scheduled to receive 2 doses of the ChAdOx1 nCoV-19 vaccine were enrolled into a prospective study involving serum analysis to define their antibody response. An antibody concentration against the spike protein receptor-binding domain of ≥0.8 U/mL was deemed a detectable antibody response. RESULTS: A total of 99 heart transplant recipients (mean age 51 ± 12.5 years, 28% female) were enrolled. No major adverse events were recorded after vaccination; minor symptoms included injection site pain (24%), fatigue (21%) and headache (14%). Of 7 patients with prior SARS-CoV-2 confirmed by PCR testing, all (100%) had detectable antibody responses following first and second vaccine doses. In those with no prior SARS-CoV-2 infection (n = 92), 24% (n = 22) showed an antibody response after dose 1, increasing to 34.8% (n = 32) after dose 2, p < 0.001. Chronic kidney disease (CKD) stage ≥3 (OR 4.7, 95% CI 1.5-15, p = 0.009) and mycophenolate use (OR 4.1, 95% CI 1.2-14, p = 0.02) were independently associated with a nondetectable antibody response. CONCLUSIONS: Almost two-thirds of heart transplant recipients aged 18 to 70 years without a history of prior SARS-CoV-2 infection failed to develop a detectable antibody response following administration of the ChAdOx1 nCoV-19 vaccine. Patient phenotyping may help predict which patients are less likely to develop detectable antibody responses.

Electrical parameters with His-bundle pacing: Considerations for automated programming.

BACKGROUND: Programming of His-bundle pacing may be challenging because current implantable pulse generators are not specifically designed for this pacing modality. OBJECTIVE: The purpose of this study was to evaluate electrical parameters in order to propose preset programming options with different configurations. METHODS: Data were collected from 50 patients with His pacing leads connected to various ports (atrial, right ventricular, or left ventricular) of pacemakers and defibrillators during a detailed device interrogation, which included capture thresholds with various pacing vectors, measurement of timing intervals, and performance of automatic threshold algorithms. RESULTS: His-bundle pacing thresholds were significantly lower during unipolar pacing compared to bipolar and extended bipolar polarities. However, current drain was offset due to lower impedance. The His pace-right ventricular sensed intervals were measured at 40-150 ms (mean 85 ± 25 ms), with the longest delays in patients with uncorrected right bundle branch block and selective His capture. This has implications for ventricular safety pacing windows (which were inactivated without evidence of crosstalk) and delays to minimize unnecessary ventricular backup pacing (which was also affected by refractory periods). The measured intervals also impacted the performance of automatic threshold algorithms, which performed differently depending on which port the His lead was connected to and did not distinguish between His and myocardial capture. CONCLUSION: Our report provides data that could serve to configure automated programming settings to simplify management of His-bundle pacing.

Latest Updates on Lipid Management.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Despite the clinical long-term and near-term benefits of lowering cholesterol in, respectively, primary and secondary prevention of ASCVD, cholesterol levels remain under-treated, with many patients not achieving their recommended targets. The present article will review the latest updates on lipid management with emphases on the different classes of cholesterol-lowering agents and their clinical uses.

Coronary Sinus Electrograms May Predict New-onset Atrial Fibrillation After Typical Atrial Flutter Radiofrequency Ablation (CSE-AF).

BACKGROUND: Complex fractionated electrograms (EGMs) of the coronary sinus electrograms (CSEs) are employed as a target during radiofrequency ablations (RFA) of atrial fibrillation (AF). Anatomically, CSEs includes both of left atrium (LA), coronary sinus musculature and right atrium (RA) electrograms. AIM: To determine the significance of fractionated CSE and delayed potentials as a predictor of new-onset AF after radiofrequency ablation (RFA) of isolated atrial flutter (AFL). METHODS: Consecutive patients underwent AFL ablation. Fractionated and/or continuous discrete activities were recorded from coronary sinus electrograms during sinus rhythm and during pacing. Earliest CSE to the S nadir or peak R in milliseconds was recorded and considered as propagation delay for EGMs. RESULTS: Forty patients were included during a mean follow-up period of 55.1± 15.8 months. Twenty patients (50 %) developed AF while the remaining 20 patients maintained sinus rhythm(SR) during the follow-up period. Proximal and mid CSEs were significantly fractionated in AF group compared to group with no AF development (65 % and 60% Vs. 35 % and 30 %, p = 0.03, respectively). However, during pacing from distal duo-decapolar catheter (pole 1-2), distal CSEs alone were significantly fractionated (p < 0.05) compared to SR group. Significant delayed propagation of proximal CSE during pacing and in sinus rhythm were observed in AF group (12.3 ± 9.2 ms vs 7.1 ± 3.6 ms, p = 0.03) and (7.2 ± 2.9 ms Vs 8.1 ± 4.6 ms, p= 0.02) in the same order. CONCLUSION: Incidence of AF is associated with fractionated proximal and mid CSE in sinus rhythm and distal CSE during paced rhythm after isolated AFL ablation. Delayed proximal CSE propagation is correlated with AF incidence.

Intra-aortic balloon pump entrapment and surgical removal: a case report.

Intra-aortic balloon pump (IABP) use following myocardial infarction is now infrequent and reserved for cases of cardiogenic shock. As their use declines, so does our ability to promptly recognize and manage potential problems that may arise. A serious but rare complication of IABP insertion is balloon entrapment within the arterial tree. In this report, we share our experience of a case of balloon entrapment within the right common iliac artery and successful removal of the device via groin cut down under general anaesthesia.

Knockdown of m-calpain increases survival of primary hippocampal neurons following NMDA excitotoxicity.

The calpain family of cysteine proteases has a well-established causal role in neuronal cell death following acute brain injury. However, the relative contribution of calpain isoforms to the various forms of injury has not been determined as available calpain inhibitors are not isoform-specific. In this study, we evaluated the relative role of m-calpain and mu-calpain in a primary hippocampal neuron model of NMDA-mediated excitotoxicity. Baseline mRNA expression for the catalytic subunit of m-calpain (capn2 ) was found to be 50-fold higher than for the mu-calpain catalytic subunit (capn1) based on quantitative real-time PCR. Adeno-associated viral vectors designed to deliver short hairpin RNAs targeting capn1 or capn2 resulted in 60% and 90% knockdown of message respectively. Knockdown of capn2 but not capn1 increased neuronal survival after NMDA exposure at 21 days in vitro. Nuclear translocation of calpain substrates apoptosis inducing factor, p35/p25 and collapsin response mediator protein (CRMP) 2-4 was not detected after NMDA exposure in this model. However, nuclear translocation of CRMP-1 was observed and was prevented by capn2 knockdown. These findings provide insight into potential mechanisms of calpain-mediated neurodegeneration and have important implications for the development of isoform-specific calpain inhibitor therapy.

Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-gamma?

Inflammation-mediated dysregulation of the kynurenine pathway has been implicated as a contributor to a number of major brain disorders. Consequently, we examined the impact of a systemic inflammatory challenge on kynurenine pathway enzyme expression in rat brain. Indoleamine 2,3-dioxygenase (IDO) expression was induced in cortex and hippocampus following systemic lipopolysaccharide (LPS) administration. Whilst IDO expression was paralleled by increased circulating interferon (IFN)-gamma concentrations, IFN-gamma expression in the brain was only modestly altered following LPS administration. In contrast, induction of IDO was associated with increased central tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 expression. Similarly, in cultured glial cells LPS-induced IDO expression was accompanied by increased TNF-alpha and IL-6 expression, whereas IFN-gamma was not detectable. These findings indicate that IFN-gamma is not required for LPS-induced IDO expression in brain. A robust increase in kynurenine-3-monooxygenase (KMO) expression was observed in rat brain 24h post LPS, without any change in kynurenine aminotransferase II (KAT II) expression. In addition, we report that constitutive expression of KAT II is approximately 8-fold higher than KMO in cortex and 20-fold higher in hippocampus. Similarly, in glial cells constitutive expression of KAT II was approximately 16-fold higher than KMO, and expression of KMO but not KAT II was induced by LPS. These data are the first to demonstrate that a systemic inflammatory challenge stimulates KMO expression in brain; a situation that is likely to favour kynurenine metabolism in a neurotoxic direction. However, our observation that expression of KAT II is much higher than KMO in rat brain is likely to counteract potential neurotoxicity that could arise from KMO induction following an acute inflammation.