Neurological involvement in Ile68Leu (p.Ile88Leu) ATTR amyloidosis: not only a cardiogenic mutation

Ile68Leu transthyretin-related amyloidosis (ATTR) is known as a mainly or exclusively cardiogenic variant. We hypothesized that an accurate specialized neurological evaluation could reveal a consistent frequency of mixed phenotypes.Forty-six consecutive subjects with transthyretin (TTR) Ile68Leu (p.Ile88Leu) mutation (29 patients and 17 unaffected carriers) underwent an in-depth cardiac and neurologic evaluation at a single center.All 29 patients showed cardiac involvement. In 20 (69%) cases, it was associated with neurological abnormalities (i.e. a mixed phenotype): 10 (35% of the total) had signs and symptoms of neuropathy, 5 (17%) had abnormalities at the neurologic specialist examination but without symptoms, and 5 (17%) had abnormal nerve conduction study only. None of the asymptomatic carriers showed neurological abnormalities or cardiac involvement. The Neuropathy Impairment Score was5 in seven patients at baseline, and became5 in six more patients during follow-up. The probability of experiencing a major adverse cardiac event (MACE) during follow-up was higher in the mixed than cardiologic phenotype (At least two-thirds of patients with Ile68Leu ATTR and amyloidotic cardiomyopathy show an associated - definite or probable - neurologic impairment of variable degree if accurately evaluated in a neurologic setting. This proportion can rise during follow-up. The mixed phenotype carries a worse prognosis compared to the exclusively cardiologic one. These observations show that more patients could be eligible for treatment with gene silencers than currently indicated and highlight the need for an in-depth and continuous multidisciplinary evaluation of Ile68Leu ATTR patients

The role of stress echocardiography in transcatheter aortic valve implantation and transcatheter edge-to-edge repair era: A systematic review

Objectives: In the last decade, percutaneous treatment of valve disease has changed the approach toward the treatment of aortic stenosis (AS) and mitral regurgitation (MR). The clinical usefulness of stress echocardiography (SE) in the candidates for transcatheter aortic valve implantation (TAVI) and transcatheter edge-to-edge repair (TEER) of MR remains to be established. Therefore, the key aim of this review is to assess the main applications of SE in patients undergoing TAVI or TEER. Methods: We searched for relevant studies to be included in the systematic review on PubMed (Medline), Cochrane library, Google Scholar, and Biomed Central databases. The literature search was conducted in February 2022. The inclusion criteria of the studies were: observational and clinical trials or meta-analysis involving patients with AS or MR evaluated with SE (excluding those in which SE was used only for screening of pseudo-severe stenosis) and treated with percutaneous procedures. Results: Thirteen studies published between 2013 and 2021 were included in the review: five regarding candidates for TEER and eight for TAVI. In TEER candidates, seeing an increase in MR grade, and stroke volume of > 40% during SE performed before treatment was, respectively, related to clinical benefits (p = 0.008) and an increased quality of life. Moreover, overall, 25% of patients with moderate secondary MR at rest before TEER had the worsening of MR during SE. At the same time, in SE performed after TEER, an increase in mean transvalvular diastolic gradient and in systolic pulmonary pressure is expected, but without sign and symptoms of heart failure. Regarding TAVI, several studies showed that contractile reserve (CR) is not predictive of post-TAVI ejection fraction recovery and mortality in low-flow low-gradient AS either at 30 days or at long-term. Conclusion: This systematic review shows in TEER candidates, SE has proved useful in the optimization of patient selection and treatment response, while its role in TAVI candidates is less defined. Therefore, larger trials are needed to test and confirm the utility of SE in candidates for percutaneous procedures of valve diseases

Stroke volume and myocardial contraction fraction in transthyretin amyloidosis cardiomyopathy: A systematic review

BackgroundCardiac amyloidosis (CA) is primarily a restrictive cardiomyopathy in which the impairment of diastolic function is dominant. Despite this, the left ventricular ejection fraction (LVEF) may be depressed in the late stage of the disease, but it poorly predicts prognosis in the earlier phases and does not represent well the pathophysiology of CA. Many echocardiographic parameters resulted important diagnostic and prognostic tools in patients with CA. Stroke volume (SV) and myocardial contraction fraction (MCF) may be obtained both with echocardiography and cardiac magnetic resonance (MRI). They reflect many factors intrinsically related to the pathophysiology of CA and are therefore potentially associated with symptoms and prognosis in CA.ObjectivesTo collect and summarize the current evidence on SV and MCF and their clinical and prognostic role in transthyretin (TTR-CA).Methods and resultsWe performed a systematic review following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We searched the literature database for studies focusing on SV and MCF in patients with TTR-CA. We analysed the following databases: PUBMED, Cochrane Library, EMBASE, and Web of Science database. Fourteen studies were included in the review. Both SV and MCF have important prognostic implications and are related to mortality. Furthermore, SV is more related to symptoms than LVEF and predicts tolerability of beta-blocker therapy in TTR-CA. Finally, SV showed to be an excellent measure to suggest the presence of TTR-CA in patients with severe aortic stenosis.ConclusionStroke volume and MCF are very informative parameters that should be routinely assessed during the standard echocardiographic examination of all patients with TTR-CA. They carry a prognostic role while being associated with patients’ symptoms.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/ME7DS

Framework for strategic wind farm site prioritisation based on modelled wolf reproduction habitat in Croatia

In order to meet carbon reduction targets, many nations are greatly expanding their wind power capacity. However, wind farm infrastructure potentially harms wildlife, and we must therefore find ways to balance clean energy demands with the need to protect wildlife. Wide-ranging carnivores live at low density and are particularly susceptible to disturbance from infrastructure development, so are a particular concern in this respect. We focused on Croatia, which holds an important population of wolves and is currently planning to construct many new wind farms. Specifically, we sought to identify an optimal subset of planned wind farms that would meet energy targets while minimising potential impact on wolves. A suitability model for wolf breeding habitat was carried out using Maxent, based on six environmental variables and 31 reproduction site locations collected between 1997 and 2015. Wind farms were prioritised using Marxan to find the optimal trade-off between energy capacity and overlap with critical wolf reproduction habitat. The habitat suitability model predictions were consistent with the current knowledge: probability of wolf breeding site presence increased with distance to settlements, distance to farmland and distance to roads and decreased with distance to forest. Spatial optimisation showed that it would be possible to meet current energy targets with only 31% of currently proposed wind farms, selected in a way that reduces the potential ecological cost (overall predicted wolf breeding site presence within wind farm sites) by 91%. This is a highly efficient outcome, demonstrating the value of this approach for prioritising infrastructure development based on its potential impact on wide-ranging wildlife species

Transthyretin amyloidosis in aortic stenosis: clinical and therapeutic implications

About one in seven elderly patients with severe calcific aortic stenosis (AS) also have ATTR amyloid cardiomyopathy (AC-TTR). The reasons for this close association are not fully known, but the two entities are not only related by common epidemiology. For example, it is possible to hypothesize that an amyloidotic infiltration of the aortic valve, even partial, can act as a trigger for the development of endothelial damage and subsequent calcification. Another hypothesis is the increased myocardial strain induced by AS may locally favour the process of amyloidogenesis and tissue infiltration. In a patient with AS, the coexistence of AC-TTR can be suspected by careful analysis of the echocardiogram and the ECG, especially if a clinical history of carpal tunnel syndrome coexists. Bone tracer scintigraphy allows a diagnosis of certainty. Recently, several studies have evaluated the prognostic implications of the coexistence of the two entities in candidates for percutaneous aortic valve replacement, showing how amyloidosis would not significantly impact the results of the procedure, but would only be associated with a greater risk of distant heart failure. In patients with AS associated with AC-TTR, valve replacement should not be ruled out in the presence of the usual clinical-haemodynamic indications

Peak atrial longitudinal strain is predictive of atrial fibrillation in patients with chronic obstructive pulmonary disease and coronary artery disease

BACKGROUND: The peak atrial longitudinal strain (PALS) has been validated in the prediction of atrial fibrillation (AF) in the general population. If this finding can be applied to patients with chronic obstructive pulmonary disease (COPD) and concomitant coronary artery disease (CAD) is unknown. METHODS AND RESULTS: We analyzed two different study populations of patients with COPD and acute CAD in SCAP trial (Clinical trial.org identifier NCT02324660) and COPD and stable CAD in the NATHAN‐NEVER trial (clinical trial.org identifier NCT02519608). All patients enrolled underwent spirometry and clinical specialistic evaluation to test COPD diagnosis. During the index evaluation, all patients underwent echocardiography. The primary endpoint of the study was the occurrence of AF. Overall, 175 patients have been enrolled. PALS was significantly lower in patients with COPD compared to patients without COPD (26% ± 8% vs. 30% ± 8% for PALS4CV, P = .003). After a mean follow‐up of 49 ± 15 months, 26 patients experienced at least one episode of AF. At multivariable analysis, only PALS (HR: 0.92, 95% CI: 0.86‐0.98, P = .014) resulted as an independent predictor of AF in COPD patients with CAD, with the best cutoff value of 25.5% (sensitivity 87% and specificity 70%). CONCLUSION: The present study confirmed a high incidence of AF events in COPD patients and that PALS is altered and able to independently predict AF in a specific cohort of patients with CAD and COPD. This study points out the need to integrate PALS measurement in the echocardiographic workup of all COPD patients, to early identify those at high risk of AF development

Peak atrial longitudinal strain is predictive of atrial fibrillation in patients with chronic obstructive pulmonary disease and coronary artery disease

Background: The peak atrial longitudinal strain (PALS) has been validated in the prediction of atrial fibrillation (AF) in the general population. If this finding can be applied to patients with chronic obstructive pulmonary disease (COPD) and concomitant coronary artery disease (CAD) is unknown. Methods and results: We analyzed two different study populations of patients with COPD and acute CAD in SCAP trial (Clinical trial.org identifier NCT02324660) and COPD and stable CAD in the NATHAN-NEVER trial (clinical trial.org identifier NCT02519608). All patients enrolled underwent spirometry and clinical specialistic evaluation to test COPD diagnosis. During the index evaluation, all patients underwent echocardiography. The primary endpoint of the study was the occurrence of AF. Overall, 175 patients have been enrolled. PALS was significantly lower in patients with COPD compared to patients without COPD (26% ± 8% vs. 30% ± 8% for PALS4CV, P = .003). After a mean follow-up of 49 ± 15 months, 26 patients experienced at least one episode of AF. At multivariable analysis, only PALS (HR: 0.92, 95% CI: 0.86-0.98, P = .014) resulted as an independent predictor of AF in COPD patients with CAD, with the best cutoff value of 25.5% (sensitivity 87% and specificity 70%). Conclusion: The present study confirmed a high incidence of AF events in COPD patients and that PALS is altered and able to independently predict AF in a specific cohort of patients with CAD and COPD. This study points out the need to integrate PALS measurement in the echocardiographic workup of all COPD patients, to early identify those at high risk of AF development

Drug-based cardiovascular prevention in patients with Marfan Syndrome: a systematic review

Introduction: Marfan Syndrome (MFS) is a rare and complex genetic disorder associated with increased aortic growth and aortic disease. The effectiveness of cardiovascular medical therapies aiming to slow down aortic growth has been tested in several trials, particularly beta-blockers and angiotensin receptor blockers, however showing conflicting results. Evidence acquisition: We conducted a systematic review on PubMed (Medline), Cochrane library, Google Scholar, and Biomed Central databases between January and February 2022. We selected relevant articles focusing on patients with MFS treated with beta-blockers, angiotensin receptors blockers, or both, and reporting data on the effect of the drugs on 1) slowing down aortic dilatation; 2) the reduction of aortic complication (aortic dissection, mortality, aortic surgery); and with a 3) follow-up length of at least two years. A total of 16 studies were selected. Evidence synthesis: Beta-blockers remain the mainstay of therapy as they have proven to slow aortic enlargement. Angiotensin receptor blockers are a useful alternative and with proven benefit as an add-on therapy to limit aortic growth. Neither beta-blockers, nor angiotensin receptor blockers have shown meaningful results on clinical aortic endpoints. Conclusions: The current evidence of pharmacological treatment for MFS patients is conflicting due to the lack of large, randomized clinical trials with adequate follow-up studies and homogeneous age grouping. Beta-blockers and angiotensin receptor blockers are the only available treatments to reduce aortic growth. A recently published patient-level meta-analysis confirmed that angiotensin receptor blockers and beta-blockers have a similar effect on reducing the rate of increase of the aortic root Z score, used singularly or as add-on therapy. Considering the current evidence on new features related with MFS (such as mitral annular disjunction - MAD) bearing a potential additional increased arrhythmic risk, it is of paramount importance to establish the role of beta-blockers and angiotensin receptor blockers in clinical endpoints of this population as well

Cardiopulmonary exercise testing predicts prognosis in amyloid cardiomyopathy: a systematic review and meta-analysis

BackgroundThe clinical value of cardiopulmonary exercise testing (CPET) in cardiac amyloidosis (CA) is uncertain. Due to the growing prevalence of the disease and the current availability of disease-modifying drugs, prognostic stratification is becoming fundamental to optimizing the cost-effectiveness of treatment, patient phenotyping, follow-up, and management. Peak VO2 and VE/VCO2 slope are currently the most studied CPET variables in clinical settings, and both demonstrate substantial, independent prognostic value in several cardiovascular diseases. We aim to study the association of peak VO2 and VE/VCO2 slope with prognosis in patients with CA. Methods and resultsWe performed a systematic review and searched for clinical studies performing CPET for prognostication in patients with transthyretin-CA and light-chain-CA. Studies reporting hazard ratio (HR) for mortality and peak VO2 or VE/VCO2 slope were further selected for quantitative analysis. HRs were pooled using a random-effect model. Five studies were selected for qualitative and three for quantitative analysis. A total of 233 patients were included in the meta-analysis. Mean peak VO2 resulted consistently depressed, and VE/VCO2 slope was increased. Our pooled analysis showed peak VO2 (pooled HR 0.89, 95% CI 0.84-0.94) and VE/VCO2 slope (pooled HR 1.04, 95% CI 1.01-1.07) were significantly associated with the risk of death in CA patients, with no significant statistical heterogeneity for both analyses. ConclusionsCPET is a valuable tool for prognostic stratification in CA, identifying patients at increased risk of death. Large prospective clinical trials are needed to confirm this exploratory finding

Left atrial pressure in patients with respiratory failure due to SARS-CoV-2 infection and supraventricular arrythmias

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