To the Editor We read with interest the review article “Physical activity and exercise recommendations for patients with valvular heart disease” by Doctors Nikhil Chatrath and Michael Papadakis, which was published in a recent edition of Heart.1 The focused clinical review is particularly useful for physicians and other health care workers dealing with patients with valvular heart disease (VHD). However, we would like to share some additional thoughts based upon our own experiences from Heart Valve Clinics and our previous publications derived from the EXTAS (exercise testing in aortic stenosis) cohort study.2 Indeed, some notions in their work, were previously explored by us in the EXTAS study and deserve mention. We showed that exercise testing (modified Bruce protocol) was safe, tolerable and revealed symptoms not confirmed on the history in approximately 40% of patients with asymptomatic severe and 24% moderate AS.2 Serial exercise testing added incremental prognostic information to baseline testing. Furthermore, in another follow-up study we showed that an early rapid rise in heart rate (defined as achieving at least 85% of target heart rate or ≥50% increase from baseline within the first 6 min) was associated with revealed symptoms later in the test and an increased risk of death in moderate AS in the following 2 years.3 We speculated that rapid risk in heart rate was probably a compensation for a fall in stroke volume to maintain cardiac output in early exercise which occurs in patients with spontaneous or revealed symptoms. By comparison, in asymptomatic patients the stroke volume rises in early exercise. Hence, a normal HR response to exercise test is clinically useful and reassuring when the presenting symptoms are doubtful. A positive exercise test (revealed symptoms, abnormal blood pressure response, arrhythmias or significant decline in functional capacity) or left ventricular (LV) dysfunction by echocardiography at baseline are guideline indications for valve intervention,4 and in these patients valve intervention rather than exercise prescription is necessary. However, exercise-based rehabilitation or training differs from formal exercise testing, and is useful both before and after valve intervention. Pre-intervention exercise training or exercise-based rehabilitation is associated with better post-intervention outcome, shorter hospital stay,5 and an early return to work or other activities. Pre-intervention obesity is often a concern for surgeons with regard to the potential for post-intervention rehabilitation. However, in daily clinical practice we encounter patients who are turned down for valve intervention (transcatheter valve implantation [TAVI] or conventional surgery) by the Heart team due to complex comorbidity, frailty and higher age, and are therefore assigned for conservative treatment. The question arises whether these patients may benefit from a low-intensity training or regular physical activity or not, and what will be the prescribed exercise intensity and frequency. Exercise-based rehabilitation or training is probably necessary for these patients to maintain and improve their physical function. However, there is a paucity of evidence in the literature to assess the benefit of exercise-based rehabilitation in patients with significant AS who are not found eligible for valve intervention, and hence no dedicated exercise recommendations exist. This should be investigated in prospective research studies in future.
Furthermore, we agree with the authors that most cardiologists dealing with patients with VHD may have limited knowledge of exercise prescription. However, this should ideally be incorporated into the remit of cardiac rehabilitation teams, which is often comprised of physicians and other health and fitness professionals in most European Hospitals, particularly in Scandinavia. Next, a comparison between aortic regurgitation related pressure and volume overload and the athletic heart was presented. However, a resting echo in athletic heart will exclude aortic regurgitation. Furthermore, in addition to borderline (low-normal) LV ejection fraction in the context of bradycardia, and significant improvement during exercise (contractile reserve), an athletic heart may typically show normal/higher systolic tissue Doppler velocities (S’), global longitudinal strain by speckle tracking echocardiography and other more sensitive marker of systolic LV function, such as the novel first-phase ejection fraction,6 compared with patients with VHD. Finally, a reduced LV ejection fraction in severe AS may be reversible reflecting “contractility-afterload mismatch”; i.e. reduced transaortic flow or LV ejection fraction but preserved contractile function. A relief of valve resistance (AS) in these patients either by TAVI or surgical valve replacement often leads to immediate increase in LV ejection fraction and/or normalization of transaortic flow.
Contributors SS wrote the first draft, RR revised it. Both authors approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this work.
Patient consent for publication Not applicable.
Ethics approval This work does not involve human participants.

References
1. Chatrath N, Papadakis M. Physical activity and exercise recommendations for patients with valvular heart disease. Heart 2022 Mar 2:heartjnl-2021-319824.
2. Saeed S, Rajani R, Seifert R, et al. Exercise testing in patients with asymptomatic moderate or severe aortic stenosis. Heart 2018 Nov;104(22):1836-1842.
3. Chambers JB, Rajani R, Parkin D, et al. Rapid early rise in heart rate on treadmill exercise in patients with asymptomatic moderate or severe aortic stenosis: a new prognostic marker? Open Heart 2019;6(1):e000950. doi: 10.1136/openhrt-2018-000950. eCollection 2019.
4. Baumgartner H, Falk V, Bax JJ, et al. ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; 38: 2739-2791.
5. Marmelo F, Rocha V, Moreira-Gonçalves D. The impact of prehabilitation on post-surgical complications in patients undergoing non-urgent cardiovascular surgical intervention: systematic review and meta-analysis. Eur J Prev Cardiol 2018;25:404–17.
6. Saeed S, Gu H, Rajani R, et al. First phase ejection fraction in aortic stenosis: A useful new measure of early left ventricular systolic dysfunction. J Clin Ultrasound 2021 Nov;49(9):932-935.

I read with great interest the report of Law et al [1]. The authors examined one-year mortality risk in 432 patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) to detect useful biomarkers. The adjusted hazard ratio (HR) (95% confidence interval [CI]) of the change in N-terminal pro-B-type natriuretic peptide concentration (∆ NT-proBNP) per 500 ng/L increase for mortality was 1.04 (1.01 to 1.07). In addition, the adjusted HRs (95% CIs) of the increases in ∆ NT-proBNP of >500 ng/L, >1000 ng/L and >2000 ng/L for mortality were 1.65 (1.18-2.31), 1.92 (1.37-2.70), and 2.87 (1.93-4.27), respectively. They concluded that the change in NT-proBNP concentration during the first year was an independent predictor of mortality in patients with wtATTR-CM. I have a comment about this study.

Ochi et al. examined two-year mortality risk in 47 patients with wtATTR-CM [2], and low serum albumin (≤3.75 g/dL), elevated high-sensitivity cardiac troponin T (hs-cTnT; >0.086 ng/mL), and low left ventricular ejection fraction (LVEF; <50%) are significantly associated with mortality in patients with wtATTR-CM. According to the total number of these 3 risk factors, patients were stratified into 4 subgroups: low risk (no risk factors), intermediate-low risk (1 risk factor), intermediate-high risk (2 risk factors), and high risk (3 risk factors). The estimated two-year survival rate of patients classified as low risk, intermediate-low risk, intermediate-high risk, and high risk was 93%, 80%, 83%, and 11%, respectively. Although they conducted a longer follow-up period, the number of samples was limited. In addition, they used baseline data as predictors of prognosis. Regarding to the results by Law et al [1], changes in serum albumin, hs-cTnT, and LVEF did not became significant predictors for one-year mortality.

Ochi et al. used B-type natriuretic peptide concentration, which was different in clinical meaning of NT-proBNP [2]. Taken together, further studies with longer follow-up is recommended to evaluate prognosis in patients with wtATTR-CM.

REFERENCES
1 Law S, Petrie A, Chacko L, et al. Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy.. Heart 2021 May 14. doi: 10.1136/heartjnl-2021-319063
2 Ochi Y, Kubo T, Baba Y, et al. Prediction of Medium-Term Mortality in Japanese Patients With Wild-Type Transthyretin Amyloidosis. Circ Rep 2020;2:314-21.

To the Editor
We read with interest the recent review by Griborio-Guzman AG et al [1] of the clinical presentation, diagnosis and management of cardiac myxomas. The authors highlighted that cardiac myxomas should be managed with prompt resection. Yet, the question of whether excision of an atrial myxoma qualifies as an emergency procedure remains unanswered.
In an attempt to address this question, we constructed a “best evidence topic” according to a structured protocol, as described previously [2]. A comprehensive MEDLINE literature search was conducted utilizing the PubMed interface (1966-August 2021) using the keywords: [(atrial myxoma) OR (cardiac myxoma) OR (heart myxoma)] AND [(resection) OR (removal) OR (excision)] AND [(emergency) OR (urgent) OR (immediate) OR (prompt)]. References of selected articles were then reviewed to detect relevant publications that did not come up with the original search. Two hundred and fifty-six papers were found using the reported search. From these, 11 papers were identified that provided best evidence to answer the question, all of them were single-group case-series.
In one of the earliest clinical series, Semb et al [3] emphasized that surgery should be performed as soon as the diagnosis is made, and observed that tumour fragmentation and embolization was more likely to occur when a lobulated, gelatinous and fragile myxoma was located in the central bloodstream.
Livi et al [4] reported that sudden death could occur due to complete obstruction of valvular orifice, and this convinced the authors of the necessity of a prompt operation once the diagnosis is made, regardless of the size and location of the tumour.
Sugimoto et al [5] believed that a cardiac myxoma should be excised as soon as possible because it may produce serious complications. While optimal timing of surgery after the onset of embolic complications (especially cerebral or myocardial infarction) remained controversial, the authors believed that early surgery may have to be performed when there is a threat of new embolic events.
Lijoi et al [6] advocated that surgical excision is undertaken as soon as possible after diagnosis in order to avoid such complications as systemic embolization and valvular incompetence with rapid deterioration.
Meyns et al [7] noted that embolization was not related to the size of the myxoma, but was dictated by the friability of the tissues. The authors recommended immediate excision of atrial myxoma once the diagnosis is established.
Keeling et al [8] highlighted that embolization risk was increased in patients presenting with a cardiac rhythm other than sinus rhythm, and in large, left-sided, polypoid and mitral valve myxomas. Their study concluded that immediate resection of cardiac myxomas should be performed to prevent sudden death and embolic events and that, by immediate resection, these risks may be very low.
Selkane et al [9] advocated that surgery for cardiac myxoma should comply with the usual recommendations for preoperative coronary angiography, and that emergency surgery should be available to acute symptomatic patients and those at a high risk of embolization.
Khan et al [10] performed immediate surgical treatment in all their patients, and this was associated with low rates of morbidity and mortality. The authors recommended that surgical excision should be carried out without delay, while coronary angiography was advised if coronary artery disease is suspected or if patient’s age was over 40 years.
Kuroczyński et al [11] recommended urgent resection of cardiac myxomas after establishing the diagnosis to prevent complications such as embolization or obstruction of the mitral orifice. They also recommended performing pre-operative coronary angiography in patients aged over 40 with risk factors for coronary heart disease.
Garatti et al [12] recommended that surgical excision of cardiac myxomas must be done as soon as possible after the diagnosis is established because of the high risk of valvular obstruction or systemic embolization.
Lastly, Rushel et al [13] believed that immediate surgical excision was indicated in all patients to prevent sudden death and embolic complications.
In summary, our “best evidence topic” review indicates that, even though comparative data is lacking, there is sufficient data to indicate that excision of an atrial myxoma qualifies as an emergency procedure in acute symptomatic patients, where acute valvular obstruction was conceivable (such as in large mobile left atrial myxomas) and where tumour embolization was more likely to occur (e.g. lobulated and gelatinous myxomas). Excision of other atrial myxomas can be performed on an urgent basis, which allows for a thorough preoperative optimization and assessment (including coronary angiography).

References
1. Griborio-Guzman AG, Aseyev OI, Shah H, Sadreddini M. Cardiac myxomas: clinical presentation, diagnosis and management. Heart. 2021 Sep 7:heartjnl-2021-319479. doi: 10.1136/heartjnl-2021-319479
2. Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact CardioVasc Thorac Surg 2003, 2:405-9
3. Semb BKH. Surgical considerations in the treatment of cardiac myxoma. J Thorac Cardiovasc Surg 10984; 87:251-259
4. Livi U, Bortolotti U, Milano A, Valente M, Prandi A, Frugoni C, de Mozzi P, Valfre C, Mazzucco A, Gallucci V. Cardiac myxomas: results of 14 years' experience. Thorac Cardiovasc Surg. 1984; 32:143-7
5. Sugimoto T, Ogawa K, Asada T, Mukohara N, Nishiwaki M, Higami T, Kawamura T. Surgical treatment of cardiac myxoma and its complications. Cardiovasc Surg. 1993; 1:395-8
6. Lijoi A, Scoti P, Faveto C, Canale C, Parodi E, Passerone GC, Dottori V, Venere G. Surgical management of intracardiac myxomas. A 16-year experience. Tex Heart Inst J. 1993; 20:231-4
7. Meyns B, Vancleemput J, Flameng W, Daenen W. Surgery for cardiac myxoma. A 20-year experience with long-term follow-up. Eur J Cardiothorac Surg. 1993; 7:437-40
8. Keeling IM, Oberwalder P, Anelli-Monti M, Schuchlenz H, Demel U, Tilz GP, Rehak P, Rigler B. Cardiac myxomas: 24 years of experience in 49 patients. Eur J Cardiothorac Surg. 2002; 22:971-7
9. Selkane C, Amahzoune B, Chavanis N, Raisky O, Robin J, Ninet J, Obadia JF. Changing management of cardiac myxoma based on a series of 40 cases with long-term follow-up. Ann Thorac Surg. 2003; 76:1935-8
10. Khan MA, Khan AA, Waseem M. Surgical experience with cardiac myxomas. J Ayub Med Coll Abbottabad. 2008; 20:76-9
11. Kuroczyński W, Peivandi AA, Ewald P, Pruefer D, Heinemann M, Vahl CF. Cardiac myxomas: short- and long-term follow-up. Cardiol J. 2009; 16:447-54
12. Garatti A, Nano G, Canziani A, Gagliardotto P, Mossuto E, Frigiola A, Menicanti L. Surgical excision of cardiac myxomas: twenty years’ experience at a single institution. Ann Thorac Surg. 2012; 93:825-31
13. Rushel SS, Mandal SC, Moinuddin S, Alamgir MK. Surgical Treatment of Cardiac Tumours: a 17-year Experience at Department of Cardiac Surgery, NICVD, Dhaka. Mymensingh Med J. 2019; 28:562-566

Dear Editor,
we thank you for your recent Editorial (1) that gives a balanced and useful view of the use of anti-interleukin1 agents for the treatment of recurrent pericarditis (2). As it is common, the authors conclude that “however, larger RCT data are required for further validation of the efficacy and safety of these novel medications in the treatment of recurrent pericarditis.” Here there is a technical issue, that sometimes may be not well appreciated. One of the first step in planning a RCT is to calculate the sample size. The point is that RCT that will randomize subjects to anti-IL 1 agents vs placebo will never be large, and will always include a small number of subjects, as compared to sample sizes common in other fields of cardiology, simply given the large treatment effect; for this reason is not ethical to randomize higher number of subjects. The calculated sample sizes are relatively small only due to the expected extremely high efficacy: e.g. the per protocol calculated sample sizes were 20 subjects in the AIRTRIP trial (3) and 56 in the RHAPSOSY trial (4). In practice we will never have “large” RCT on this topic, because these agents are expected to be so effective that the calculated sample sizes will be always small.

1. Anthony C, Collier P. Anti-interleukin-1 for recurrent pericarditis; maybe a fix (but prior studies do not really mix). Heart. 2021 May 10:heartjnl-2021-319282. doi: 10.1136/heartjnl-2021-319282. Online ahead of print.

2. Imazio M, Andreis A, Piroli F, et al. Anti-interleukin1 agents for the treatment of recurrent pericarditis: a systematic review and meta-analysis.Heart 2021. doi:10.1136/heartjnl-2020-318869. [Epub ahead of print: 18 Mar 2021].

3. Brucato A, Imazio M, Gattorno M, et al. Effect of Anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. JAMA 2016;316:1906–12.

4. Klein AL, Imazio M, Cremer P, et al. Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis. N Engl J Med 2021;384:31–41.