To the Editor, we read with great interest the article by Ntiloudi et al[1], describing hospitalization for heart failure (HF) as a powerful predictor of mortality among adults with pulmonary hypertension related to congenital heart disease (PH-ACHD). Although pulmonary arterial hypertension (PAH) targeted therapy has improved their survival, long-term complications such as HF hospitalization commonly occurred, and dismal prognosis with a mortality rate of 18.5% deeply broke our heart, thus requiring earlier diagnosis, risk stratification and therapeutic intervention.
Hospitalization for HF, a sign of clinical worsening, is associated with poor outcomes and generally used as one of composite endpoints in PAH[2], Ntiloudi et al stated nearly one-quarter of patients were hospitalized for HF, and they encountered a ninefold increased mortality risk compared to those not-hospitalized, since NYHA functional class III/IV raised a tenfold risk of death, its combination with HF hospitalization may better predict outcomes. A previous study[3] reported 29% patients with idiopathic and associated PAH were hospitalized for acute right heart failure at least once during a 39.1-month follow up, and those with hospitalizations had worse NYHA functional class, inferior right ventricle function, lower six minute walk test (6MWT) distance and worse outcomes defined by death/transplant (67% vs 33%). These two findings indicated a potential role of HF hospitalization for identifying higher risk population in PAH.
Although multiple factors were reported to predict mortality in PAH-CHD, clinical risk stratification remains a challenge. Current multivariable risk stratification model encompassing age, shunt location, pericardial effusion, 6MWT distance and oxygen saturation facilitates outcome evaluation for adult patients with Eisenmenger syndrome[4]. Older age unanimously correlated with worse prognosis[1, 4], yet shunt location did not have a finger in the pie[1], which might be explained by small sample size and heterogeneous cohort. Hospitalization for heart failure is a promising risk stratification tool for PH-ACHD and could be considered in the above multivariable model.
As mentioned by Ntiloudi et al, essential factors such as BNP level, functional capacity, echocardiographic and hemodynamic data were unavailable, thus further larger multicenter studies regarding all aforementioned factors are encouraged to validate the role of hospitalization for HF in risk stratification and the suggested prognostic model.

Qi Jin, Qin Luo, Zhihui Zhao, Zhihong Liu
Center for Pulmonary Vascular Diseases, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
QJ and QL contributed equally.
Correspondence to Professor Zhihong Liu, Center for Pulmonary Vascular Diseases, Fuwai Hospital, 167 Beilishi Road, Xicheng District, Beijing 100037, China; zhihongliufuwai@163.com
Contributors QJ and QL read the article and wrote the letter. ZZ read the article and revised the letter. ZL provided the concept and revised the manuscript. All authors approved the final version.
Competing interests None declared.

REFERENCES
1. Ntiloudi D, Apostolopoulou S, Vasiliadis K, Frogoudaki A, Tzifa A, Ntellos C, Brili S, Manginas A, Pitsis A, Kolios M et al: Hospitalisations for heart failure predict mortality in pulmonary hypertension related to congenital heart disease. Heart 2018; pii: heartjnl-2018-313613. Doi: 10.1136/heartjnl-2018-313613.
2. Takatsuki S, Nakayama T, Ikehara S, Matsuura H, Ivy DD, Saji T: Pulmonary Arterial Capacitance Index Is a Strong Predictor for Adverse Outcome in Children with Idiopathic and Heritable Pulmonary Arterial Hypertension. J Pediatr 2017; 180:75-79 e72.
3. Talavera MLL, Favaloro LE, Caneva JO, Klein F, Boughen RP, Osses JM, Bertolotti AM, Favaloro RR: Prognostic value of right heart failure hospitalizations in pulmonary arterial hypertension. Eur J Heart Fail 2014; 16:294-294.
4. Kempny A: Prognostication in PAH–CHD. In: Pulmonary Hypertension in Adult Congenital Heart Disease. Edited by Dimopoulos K, Diller G-P. Cham: Springer International Publishing; 2017: 315-328.

We read with great interest the article by Elias et al (1) regarding the longer term clinical outcomes from the EXPLORE trial. The authors are to be congratulated for conducting this important study to address the optimal management of patients presenting with a concurrent CTO in a non-infarct related artery (non-IRA) during a STEMI. The results at 1 year are similar to those in the initial 4 month outcome (2), with no difference in the primary endpoints of cardiac MRI determined LVEF or LVEDV in either CTO-PCI and CTO-No PCI groups. At a median of 3.9 years, there was no difference in long term MACE, although an apparent increase in cardiovascular mortality (6% vs 1%, p=0.02).

Whilst this important study adds to the much needed literature on randomised studies related to PCI of CTOs, the results should be interpreted with caution. Firstly, large scale contemporaneous studies in CTO PCI have had procedural success rates in the region of 90% (3), whilst in EXPLORE (2) this rate was considerably lower, at 73% by core laboratory. This suggests either a more anatomically complex subset of patients, or else attempts by non-dedicated CTO PCI operators, both of which affect the interpretation of the intention to treat population.

Furthermore, the mortality data should be reviewed with care. At 12 months, there were 4 cardiovascular deaths (2.7%) in the CTO PCI group, with no deaths in the CTO-No PCI groups. These rates are significantly lower compared with other trials in the modern era of primary-PCI for STEMI, such as TOTAL (4) (3.7% 12 month cardiovascular mortality in 10,064 patients and 10.8% in patients with concurrent CTO in non-IRA) and HORIZONS-AMI (5) (2.9% 12 month mortality in 3,602 patients). This lower than expected event rate may affect the ability to detect differences between treatment arms. Furthermore, the mechanism of the deaths in the CTO-PCI group at 12 months was stent thrombosis (ST) in all 4 cases. Whilst drug eluting stents were used for all CTO-PCI and the majority of culprit STEMI lesions, along with mandated dual antiplatelet therapy for all patients, the overall rate of probable or definite ST was relatively high at 5.6%, in contrast to TOTAL4 and HORIZONS-AMI5, which had a 1.9% and 3% ST rate at 12 months. Given the CTO PCI procedure was conducted at operator discretion it would be interesting to note whether intravascular imaging was used, as IVUS guided CTO PCI has been shown to reduce rates of ST. Clarification on this would be important, and may help to explain the high rate of ST.

24.0% of patients in the CTO-No PCI group underwent either CTO PCI or CABG within 1 year. Clearly this high cross over rate has implications for data analysis, and further underlines the inherent issues with attempting to conduct a meaningful CTO PCI trial. Finally, this study was addressing the issue of early complete revascularisation in patients with a STEMI and concurrent CTO. We have previously shown (6) with landmark analysis, that even beyond 1 month, the presence of a CTO in patients with a STEMI is associated with significantly poorer prognosis above and beyond that of multi-vessel disease. Clearly, the “double jeopardy” with a CTO of a non-infarct related artery and STEMI results in a greater territory of ischaemic myocardium with an early rate of cardiogenic shock and mortality. However, whether a staged PCI procedure after allowing recovery of the myocardium would result in improved outcomes should be an area of ongoing research.

References

1. Elias J, van Dongen IM, Ramunddal T, Laanmets P, Eriksen E, Meuwissen M, Michels HR, Bax M, Ioanes D, Suttorp MJ, Strauss BH, Barbato E, Marques KM, Claessen B, Hirsch A, van der Schaaf RJ, Tijssen JGP, Henriques JPS, Hoebers LP and investigators E. Long-term impact of chronic total occlusion recanalisation in patients with ST-elevation myocardial infarction. Heart. 2018;104:1432-1438.
2. Henriques JP, Hoebers LP, Ramunddal T, Laanmets P, Eriksen E, Bax M, Ioanes D, Suttorp MJ, Strauss BH, Barbato E, Nijveldt R, van Rossum AC, Marques KM, Elias J, van Dongen IM, Claessen BE, Tijssen JG, van der Schaaf RJ and Investigators ET. Percutaneous Intervention for Concurrent Chronic Total Occlusions in Patients With STEMI: The EXPLORE Trial. J Am Coll Cardiol. 2016;68:1622-1632.
3. Park S-J. DECISION-CTO: Optimal Medical Therapy With or Without Stenting For Coronary Chronic Total Occlusion. American College of Cardiology Annual Scientific Session (ACC 2017). 2017.
4. Jolly SS, Cairns JA, Yusuf S, Rokoss MJ, Gao P, Meeks B, Kedev S, Stankovic G, Moreno R, Gershlick A, Chowdhary S, Lavi S, Niemela K, Bernat I, Cantor WJ, Cheema AN, Steg PG, Welsh RC, Sheth T, Bertrand OF, Avezum A, Bhindi R, Natarajan MK, Horak D, Leung RC, Kassam S, Rao SV, El-Omar M, Mehta SR, Velianou JL, Pancholy S, Dzavik V and Investigators T. Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial. Lancet. 2016;387:127-35.
5. Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW and Investigators H-AT. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet. 2009;374:1149-59.
6. Allahwala UK, Jolly SS, Dzavik V, Cairns JA, Kedev S, Balasubramanian K, Stankovic G, Moreno R, Valettas N, Bertrand O, Lavi S, Velianou JL, Sheth T, Meeks B, Brilakis ES and Bhindi R. The Presence of a CTO in a Non-Infarct-Related Artery During a STEMI Treated With Contemporary Primary PCI Is Associated With Increased Rates of Early and Late Cardiovascular Morbidity and Mortality: The CTO-TOTAL Substudy. JACC Cardiovasc Interv. 2018;11:709-711.

I read with great interest the paper by Elias et al regarding the mid-term and long-term clinical outcome of the Evaluating Xience and left ventricular function in Percutaneous Coronary Interventions on occlusiOns afteR ST elevation myocardial infarction (EXPLORE) trial. [1] The authors are to be congratulated for this detailed analysis evaluating the effect of chronic total occlusions – percutaneous coronary intervention (CTO-PCI) compared with CTO-No PCI on clinical outcome, left ventricular function and angina status in patients with ST elevation myocardial infarction (STEMI) with a concurrent CTO. The message of their study is that early CTO-PCI in patients with STEMI presenting with a concurrent CTO during primary PCI should not be performed routinely.
The authors also analysed the study population combined and found higher long-term mortality in patients who were older (>60 years) (11% vs 3%; HR 3.74; 95% CI 1.37 to 10.21; P=0.01), who had diabetes (15% vs 6%; HR 2.94; 95% CI 1.19 to 7.30; P=0.02), had a higher left ventricular enddiastolic volume at baseline (12% vs 1%; HR 13.04; 95% CI 1.70 to 100.30; P=0.01) and who had a high SYNTAX score (10% vs 4%; HR 2.50; 95% CI 1.01 to 6.20; P=0.048). They also stated that cardiac death was more frequent in the CTO-PCI arm (6.0% vs 1.0%, P=0.02) with no difference in all-cause mortality. However, it is known that a major prognostic factor in STEMI patients with a concurrent CTO is the presence of collateral feeding donor arteries from an infarct-related artery (IRA). Of patients with CTO, those with collateral flow from the IRA have significantly higher mortality than the non-IRA group (at 30 days: 52.2% vs. 10.9%, P<0.0001).[2] Obviously, in acute phase of these unstable conditions, the myocardium in the “remote” zone of infarction (CTO-zone) also ceases to contract. It is uncertain whether primary angioplasty in the IRA led to recover in the contractile function in the CTO zone. It would be very helpful if Elias et al could provide additional angiographic data regarding the IRA and the donor artery of CTO in their population (and the impact of PCI-CTO in this group). Surprisingly, in most post-myocardial infarction PCI-CTO studies relevant data are lacking.

1. Elias J, van Dongen IM, Råmunddal T, Laanmets P, et al. Long-term impact of chronic total occlusion recanalisation in patients with ST-elevation myocardial infarction. Heart. 2018 Feb 20. pii: heartjnl-2017-312698. doi: 10.1136/heartjnl-2017-312698. [Epub ahead of print]
2. Fujii T, Sakai K, Nakano M, et al. Impact of the origin of the collateral feeding donor artery on short-term mortality in ST-elevation myocardial infarction with comorbid chronic total occlusion. Int J Cardiol. 2016;218:158-163.

Dear Editor,
With great interest, I read the article by Sainsbury and associates[1] and congratulate them for extensively reviewing the unsolved issue of refractory angina. How many suffer from this condition worldwide remains unclear. However, it is believed that hundreds of thousands of Americans are affected, and that this number increases annually. Likely, millions are affected worldwide. Diffuse coronary artery disease is the main reason for refractory angina, because such arteries are non-amenable to percutaneous interventions or bypass grafting. Comorbidities are a second reason, especially in our aging population. Yet history is a cycle; medicine’s history no exception. Old concept, experiments, and theories that have fallen by the wayside can sometimes be resurrected and re-explored, released from the technological constraints of their time. The coronary sinus reducer system is one good example, since the concept stems from studies on the effects of cardiac vein ligation performed in the 1930s by Canadian surgeon Mercier Fauteux[2]. Two additional concepts might be resurrected and adapted to modern technologies. One is the concept of internal mammary artery (IMA) occlusion which, at that time, was performed through a small bilateral incision between the second and third ribs. The belief was that localized hypertension superior to the obstruction increased perfusion pressure in channels leading to the heart, specifically through the peri-cardio-phrenic branch[3]. Recently, I have resurrected this concept and suggested performing endovascular occlusion of the IMAs[4]. More recently, others have demonstrated that occluding the IMAs arteries could increase the collateral flow index and fractional flow reserve ipsilaterally, while decreasing angina[5]. These data are encouraging and spur further investigations. However, I also feel that Vineberg’s operation, consisting of tunnelization of IMAs into the left ventricle wall, is worthy of resurrection. This procedure, performed for about two decades, once was successful at relieving angina[2]. A huge collateral network developed between the IMAs and coronary arteries, and the IMAs often remained patent even at long-term follow-up. There is no reason to a-priori exclude IMA intra-myocardial tunnelization in patients for whom bypass is contraindicated, and vast opportunities exist for novel experimental and clinical studies on this technique.
Words = 345

References

1. Sainsbury PA, Fisher M, de Silva R. Alternative interventions for refractory angina. Heart. 2017 ;103(23):1911-1922.

2. Picichè M. The history of myocardial revascularization before the advent of cardiopulmonary bypass, in: M. Picichè (Ed.), Dawn and Evolution of Cardiac Procedures:Research Avenues in Cardiac Surgery and Interventional Cardiology, Springer- Verlag, Heidelberg 2012, pp. 65–77.

3. Picichè M. Noncoronary Collateral Myocardial Blood Flow: The Human Heart’s Forgotten Blood Supply. The Open Cardiovasc Med J 2015; 9:105-113.

4. Picichè M. Embolization of the internal thoracic arteries in refractory angina. Int J Cardiol. 2016;212:310.

5. Stoller M, Seiler C. Effect of permanent right internal mammary artery closure on coronary collateral function and myocardial ischemia. Circ Cardiovasc Interv 2017;10:e004990.