Strategic discussion on funding and access to therapies targeting rare diseases in Spain: an expert consensus paper.

BACKGROUND: In recent years, significant advances have been made in the field of rare diseases (RDs). However, there is a large number of RDs without specific treatment and half of these treatments have public funding in Spain. The aim of the FINEERR project was to carry out a multidisciplinary strategic discussion on the challenge of funding and access to RD-targeted drugs in Spain, in order to agree on specific proposals for medium-term improvement and hence support decision-making in the Spanish National Healthcare System (SNHS). RESULTS: The FINEERR Project was organized around a CORE Advisory Committee, which provided an overview, agreed on the design and scope of the project, and selected the members within each of four working groups (WG). Overall, 40 experts discussed and reached a consensus on different relevant aspects, such as conditioning factors for initial funding and access, evaluation and access to RD-targeted therapies, funding of these therapies, and implementation of a new funding and access model. From these meetings, 50 proposals were defined and classified by their level of relevance according to the experts. A descriptive analysis of responses was performed for each proposal. Thereafter, experts completed another questionnaire where they ranked the 25 most relevant proposals according to their level of feasibility of being implemented in the SNHS. The most relevant and feasible proposals were to improve: process of referral of patients with RDs, control over monitoring mechanisms, and communication between healthcare professionals and patients. CONCLUSIONS: The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies in Spain to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs.

Transient entrainment of bundle-branch reentry by atrial and ventricular stimulation: elucidation of the tachycardia mechanism through analysis of the surface ECG.

BACKGROUND: Different responses to entrainment have been reported in relation to the pacing site of a variety of tachycardias. However, transient entrainment of bundle-branch reentrant tachycardia (BBRT) has not been investigated systematically. METHODS AND RESULTS: We attempted entrainment of 13 BBRTs in 9 patients by pacing first the right ventricle and then the right atrium. The initial pacing cycle length (CL) was 10 ms faster than the tachycardia CL. Subsequent pacing sequences were performed with 5- to 10-ms CL decrements until tachycardia termination or loss of postatropine 1:1 AV conduction. Both full ventricular-paced and AV-conducted QRS complex references were obtained during sinus rhythm pacing from the same sites and with similar CL as during entrainment. Transient entrainment was achieved by ventricular and atrial stimulation in 11 and 8 tachycardias, respectively. Constant fusion was always present during entrainment by ventricular stimulation. There was no change in the QRS complex (orthodromically concealed fusion) during entrainment by atrial stimulation in 6 of 6 tachycardias with left bundle-branch block morphology and in 1 of 2 tachycardias with right bundle-branch block morphology. CONCLUSIONS: BBRT, especially if it has a left bundle-branch block morphology, can be differentiated from other wide-QRS-complex tachycardia mechanisms through analysis of the ECGs recorded during tachycardia entrainment by atrial and ventricular stimulation. This diagnostic approach may be especially useful when it is difficult to record a stable or sufficiently sized His bundle electrogram or when spontaneous changes in the ventricular CL precede similar changes in the His bundle CL.

Vectorcardiograms in severe aortic insufficiency. Clockwise rotation of QRS loop in the horizontal plane.

In La Paz Hospital, Madrid, recently, vectorcardiograms (VCGs) were performed on 74 patients with aortic insufficiency. These cases presenting electrocardiographic and radiologic signs of left ventricular hypertrophy, were divided into three groups. In 25 patients (Group 1) the QRS loop in the horizontal plane (HP) showed counterclockwise rotation; 43 patients (Group 2) showed clockwise rotation; and 6 patients (Group 3) showed a pattern of left bundle branch block (LBBB). In Group 2, 31 of the 43 patients (group 2-A) had a Qloop of normal orientation and generally increased voltage, and in the remaining 12 patients (group 2-B) the Q loop was absent. All of the patients in Group 2 had severe aortic insufficiency. Thus, that group's valuation of the left ventricular hypertrophy using maximum QRS vector voltage in the HP, was higher than in Group 1 mean 3.75mV in Group 2 versus mean 2.71mV in Group 1 (p less than 0.01). Postoperative VCGs were performed in 12 patients of group 2-A, showing in all of them a clockwise to counterclockwise rotation change of the QRS loop in the HP. On the other hand, this fact was observed in only two of the eight patients in group 2-B. The clockwise rotation of the QRS loop in the HP is an important datum in our report, particularly in the diagnosis of severe aortic insufficiency. Conversely, a clockwise to counterclockwise rotation change would be a positive sign of good post operative evolution. Finally, two reasons are given to explain this anomalous rotation in the horizontal plane: dilatation and fibrosis.

Anterograde and retrograde bradycardiac block in the His-Purkinje system. Finding in a patient with acute myocardial infarction.

A patient with an acute inferior myocardial infarction developed a complete atrioventricular block and intermitent periods of atrioventricular conduction with QRS complexes showing right bundle branch block associated with left anterior hemiblock. Recordings of the His bundle electrogram showed that the atrioventricular block was infrahisian and that in periods of resumed atrioventricular conduction, the His-ventricle (H-V) interval was long. Ventricular escape beats showed concealed conduction to the atrioventricular node. Anterograde atrioventricular conduction was always resumed through the left posterior division when the preceding division when the preceding intervals between ventricular escape beats and the atrium (V-A intervals) were shorter than 580 msec. The same phenomenon occurred with right ventricular pacing. A retrograde His potential could be observed. Retrograde conduction of ventricular escape beats and ventricular paced beats was blocked if the H-V interval and the interval between the His bundle and the ventricular paced beat (H-V interval) were long (more than 600 msec and 550 msec, respectively). The existence of an intermittent anterograde and retrograde bradycardiac infrahisian block was inferred from the previously mentioned data; a fixed retrograde atrial nodal block was also present.

Fascicular block within the His bundle.

The findings in a patient with complete atrioventricular block and normal morphology and duration of the QRS complex are presented. A His bundle electrogram was obtained, which led to the location of the atrioventricular block within the His bundle. A careful review of the electrocardiograms obtained during the seven years preceding the onset of complete atrioventricular block showed a QRS complex with the features of left anterior hemiblock and a progressive impairment of atrioventricular conduction. From these data, we inferred that the different degrees of atrioventricular block and the left anterior hemiblock were caused by lesions within the His bundle involving the fibers destined for the left anterior division of the left branch. After the onset of complete atrioventricular block, with the subsidiary pacemaker located in the His bundle distal to the lesions, the QRS complex became normal, indicating the integrity of the bundle branches and fasciculi. The atrial and proximal His potential intervals and those between distal His and ventricular potentials were normal.

Atrioventricular nodal dysfunction in patients with atrial septal defect. Abnormalities of conduction and reciprocal rhythms.

Electrophysiologic studies were performed in 17 unselected patients (mean age, 20 years) with atrial septal defect (ASD) of the ostium secundum type. In nine (52.9 percent) signs were found of atrioventricular (A-V) nodal dysfunction, in seven (41.1 percent) prolonged A-H interval, and in three (17.6 percent) prolonged effective refractory period of A-V node and in five (29.4 percent) A-V nodal tachycardia and reentry. Three of the four cases showed anterograde conduction (Ae-H interval) faster than retrograde conduction (H-A3 interval) during the tachycardia. In one patient with reentry a similar phenomenon was observed. In the remaining patient the conduction time was reversed (Ae-H longer than H-Ae). In two patients infrahisian and intrahisian block (first and second degree) with persistence of the tachycardia was observed. Patent or latent abnormalities in A-V node function are a frequent finding in patients with ASD. In the sinus node, any kind of significant abnormality can be found.

[Palliative interatrial septostomy in severe pulmonary hypertension]. / Septostomía interatrial paliativa en la hipertensión pulmonar severa.

Three patients with severe pulmonary hypertension underwent palliative atrial septostomy by dilating the interatrial septum with valvuloplasty catheter-balloons. In two cases successful dilation improved cardiac index and symptoms of cardiac failure (13 and 11 months follow-up). One patient died immediately post-septotomy due to severe hypoxemia. Severe pulmonary hypertension with low cardiac output and high right ventricular filling pressures has a very poor short-term prognosis. Atrial septostomy is a useful palliative procedure and can serve as a bridge to heart and/or lung transplantation. It is not free of risk and the resultant systemic hypoxemia can lead to dead; that is why we recommend progressive balloon diameters, stopping the procedure when improvement of cardiac index is achieved with the minimal systemic oxygen desaturation.

[Atrioventricular block at the nodal level and block of an accessory pathway during percutaneous mitral valvuloplasty]. / Bloqueo auriculoventricular a nivel del nodo y de una vía accesoria durante una valvuloplastia mitral percutánea.

We describe the simultaneous occurrence of a temporal complete atrioventricular block and a persistent disappearance of preexcitation, in a patient with rheumatic mitral stenosis and a ventricular preexcitation, after an effective percutaneous mitral valvuloplasty. These conduction disturbances were attributed to atrioventricular node and paraseptal atrioventricular pathway trauma, due to transseptal manipulation during the mitral valvuloplasty.

[Distal hemoperfusion during coronary angioplasty with prolonged balloon inflation]. / Hemoperfusión distal durante la angioplastia coronaria con inflado prolongado de balón.

We present the results of 6 coronary angioplasties associated with coronary distal hemoperfusion by an injection pump. The inflation mean time was 5 min 10 sec and the quantity of perfused blood was 43 +/- 14 ml. The procedure was successful in all cases. No biochemical alterations were detected in the perfused blood. A significant clinical and electrocardiographic improvement was observed in all but 2 cases. The cause was the occlusion of a collateral branch and a high flow pattern, respectively. Technical aspects and usefulness of this and other perfusion systems are analysed.

[Percutaneous transluminal angioplasty in aortic coarctation in young adults]. / Angioplastia transluminal percutánea en la coartación aórtica del adulto joven.

The results of percutaneous balloon angioplasty in 9 cases of adult aortic coarctation are described. One case was associated with bicuspid aortic valve and another with organic aortic stenosis. Two of them were female, and the rest were male. The mean age range between 15-26 years (19 +/- 4.2). Pressure gradients fell from 59 +/- 13 mmHg to 15 +/- 11 mmHg postdilatation (p less than 0.0001), and the internal lumen diameters increase from 5 +/- 3 mm up to 13 +/- 2 mm (p less than 0.0001). In one case an intimal dissection appears as complication. At consequence of these results, the percutaneous balloon angioplasty seems to be a good therapeutic procedure in the adult aortic coarctation.

[Left atrial thrombus. Its evolution with oral anticoagulation]. / Trombo auricular izquierdo. Evolución con anticoagulación oral.

UNLABELLED: Left ventricular thrombi were found in 25 patients by two-dimensional echocardiography. All patients were in atrial fibrillation, 16 had mitral or mitroaortic valve diseases and nine mitral or mitroaortic bioprosthetic valves. Nine patients (36%) had history of arterial embolism. At diagnostic time, oral anticoagulation with coumadin was instaured in all the patients. Periodic clinic and echocardiography follow-up was performed. Left atrial thrombi either disappeared (18 patients [72%]) or reduced their size (one patient). Six patients with mitral stenosis were considered as candidates to percutaneous mitral valvuloplasty, which was performed in 4 patients whose thrombi disappeared with anticoagulation therapy in 6 months. During the follow-up one patient had cerebral embolism without sequelae. CONCLUSIONS: 1st. Patients with left atrial thrombi have high risk for arterial embolism. 2nd. Left atrial thrombi disappear in a high proportion after prescribing oral anticoagulation, which has some important therapeutic implications.

[The return to work after coronary revascularization]. / Retorno al trabajo después de la revascularización coronaria.

INTRODUCTION: Work resumption after a therapeutical intervention has been considered as a sensitive indicator of its success. There are some reports analyzing working status after coronary artery revascularization in western countries. However, to our knowledge, similar studies have not been published in Spain. PATIENTS AND METHODS: We studied 210 patients after coronary artery revascularization surgery or percutaneous transluminal coronary angioplasty. Exclusion criteria were age of 65 or more years and female sex gender (n = 64). RESULTS: Working patient rate before and after coronary revascularization was respectively 63.2% and 28.9% for surgery, and 57.1% and 41.4% for percutaneous angioplasty (p = 0.11). None of the former inactive patients, with the exception of one in the surgery group, went back to work after the revascularization procedure. Asymptomatic patients after percutaneous angioplasty had a higher postprocedure working rate than symptomatic ones (58.1% vs 11.1%, p < 0.0001). Patients in the surgery group did not show this relation (30% vs 25%, p = 0.69). CONCLUSIONS: Surprisingly, coronary artery revascularization interventions, mainly coronary surgery, seems to behave in our environment as important determinants of working cessation.

[The independent origins of the anterior descending, circumflex and right coronary arteries from the right coronary sinus]. / Orígenes independientes de las arterias coronarias descendente anterior, circunfleja y derecha del seno coronario derecho.

We present a patient with chronic ischaemic cardiac disease and anomalous left anterior descending and circumflex coronary arteries with independent origin from the right Valsalva sinus. Each one had his own ostium and the left anterior descending artery followed an intramyocardial pathway through the interventricular septum whereas the circumflex artery had a retrocardiac pathway. The clinical picture of the patient was related to the presence of atherosclerotic obstructive lesions in right, whose origin and curse were normal, and circumflex coronary arteries. He was treated medically at first but without obtaining complete control therefore he needed surgical treatment which was undertaken without technical difficulties. We reviewed the anomalies of the main coronary arteries, in the origin and course, with its clinical signification, diagnosis and therapeutics topics.

[Papillary muscle rupture during subaortic membrane balloon dilatation]. / Rotura de músculo papilar durante la dilatación con balón de una membrana subaórtica.

A 37 year-old female patient underwent catheter-balloon dilation for discrete subaortic stenosis. During the procedure severe mitral regurgitation was produced requiring emergency surgery. Transesophageal and intraoperative findings were posteriormedial papillary muscle rupture. Retrospective viewing of the cineangiogram during balloon inflation revealed distal balloon indentation, corresponding to the injured papillary muscle. This severe complication of the left ventricular outflow tract angioplasty should be avoided by careful positioning of the guidewire and balloon before inflation.

[Variable response to the biological inhibition of platelets by abciximab in patients subjected to percutaneous coronary angioplasty]. / Respuesta variable a la inhibición biológica de las plaquetas por abciximab en pacientes sometidos a revascularización coronaria percutánea.

INTRODUCTION AND OBJECTIVES: Abciximab has been shown to reduce the risk of thrombotic complications during coronary angioplasty, however there are still many aspects to be resolved. The aim of this study was to investigate the various biological effects of abciximab on platelets during coronary angioplasty. METHODS: The degree of platelet inhibition (with 5 and 20 mol/l concentrations of ADP), occlusion time (measurement of platelet haemostatic capacity, PFA-100), and the platelet activation markers were determined in 15 patients who underwent basal coronary angioplasty and abciximab treatment. Determinations were obtained before, 15 minutes after procedure initiation, at procedure termination, and 24 hours after procedure termination. RESULTS: More than 80% platelet aggregation inhibition was observed in 13 patients during the procedure, but after 24 hours (p < 0.05) was only detected in two. The occlusion time during the procedure was > 300 sec. in 13 patients, 6 of whom evolved to normal values after 24 hours (p < 0.05). A high correlation (p = 0.02) was found between these two parameters during the intervention, but not after 24 hours. No platelet inhibition or occlusion time changes were observed in 2 patients during the study. The expression of p-selectin increased significantly during the procedure (p < 0.05). CONCLUSIONS: The variability of platelet function inhibition and existence of circulating activation during coronary angioplasty following the administration of abciximab support the use of early analytical controls with the objective of modifying guidelines for use in order to optimize its effect or to combine it with other antithrombotic agents.

[Acute posttraumatic myocardial infarct: the necessity of an early interventionist posture]. / Infarto agudo de miocardio postraumático: necesidad de una actitud intervencionista precoz.

We describe five cases of posttraumatic anterior acute myocardial infarction in young patients, without previous heart disease. One case was treated with intracoronary thrombolysis and angioplasty, 3 cases received systemic thrombolysis, and the last one did not have any re-permeabilization therapy, having arrived to the hospital 72 hours after the episode. The coronary angiograms showed at the left anterior descending artery: thrombosis in 3 cases, coronary dissection in one case, and slow flow with no morphological lesions in the other. The case which not received thrombolytic therapy developed a severe left ventricular dysfunction. In conclusion we emphasize an early angiographic study, in order to decide the re-permeabilization therapy.