Balloon Aortic Valvuloplasty as Bridge-to-Decision in High Risk Patients with Severe Aortic Valve Stenosis

Background. A sizable group of patients with symptomatic aortic stenosis (AS) can undergo neither surgical aortic valve replacement (AVR) nor transcatheter aortic valve implantation (TAVI) because of clinical contraindications. The aim of this study was to assess the potential role of balloon aortic valvuloplasty (BAV) as a “bridge-to-decision” in selected patients with severe AS and potentially reversible contraindications to definitive treatment. Methods. We retrospectively enrolled 645 patients who underwent first BAV at our Institution between July 2007 and December 2012. Of these, the 202 patients (31.2%) who underwent BAV as bridge-to-decision (BTD) requiring clinical re-evaluation represented our study population. BTD patients were further subdivided in 5 groups: low left ventricular ejection fraction; mitral regurgitation grade ≥3; frailty; hemodynamic instability; comorbidity. The main objective of the study was to evaluate how BAV influenced the final treatment strategy in the whole BTD group and in its single specific subgroups. Results. Mean logistic EuroSCORE was 23.5±15.3%, mean age was 81±7 years. Mean transaortic gradient decreased from 47±17 mmHg to 33±14 mmHg. Of the 193 patients with BTD-BAV who received a second heart team evaluation, 72.5% were finally deemed eligible for definitive treatment (25.4%for AVR; 47.2% for TAVI): respectively, 96.7% of patients with left ventricular ejection fraction recovery; 70.5% of patients with mitral regurgitation reduction; 75.7% of patients who underwent BAV in clinical hemodynamic instability; 69.2% of frail patients and 68% of patients who presented relevant comorbidities. 27.5% of the study population was deemed ineligible for definitive treatment and treated with standard therapy/repeated BAV. In-hospital mortality was 4.5%, cerebrovascular accident occurred in 1% and overall vascular complications were 4% (0.5% major; 3.5% minor). Conclusions. Balloon aortic valvuloplasty should be considered as bridge-to-decision in high-risk patients with severe aortic stenosis who cannot be immediate candidates for definitive percutaneous or surgical treatment.

What are the components that contribute to variability in echocardiographic measurements in aortic stenosis?

INTRODUCTION Echocardiography is the standard clinical approach for quantification of the severity of aortic stenosis (AS). A comprehensive examination of its overall reproducibility and the simultaneous estimation of its variance components by multiple operators, readers, probe applications, and beats have not been undertaken. METHOD AND RESULTS Twenty-seven subjects with AS were scanned over 7 months in the echo-department by a median of 3 different operators. From each patient and each operator multiple runs of beats from multiple probe positions were stored for later analysis by multiple readers. The coefficient of variation was 13.3%, 15.9%, 17.6%, and 20.2% for the aortic peak velocity (Vmax), and velocity time integral (VTI), and left ventricular outflow tract (LVOT) Vmax and VTI respectively. The largest individual contributors to the overall variability were the beat-to-beat variability (9.0%, 9.3%, 9.5%, 9.4% respectively) and that of inability of an individual operator to precisely apply the probe to the same position twice (8.3%, 9.4%, 12.9%, 10.7% respectively). The tracing (inter-reader) and reader (inter-reader), and operator (inter-operator) contribution were less important. CONCLUSIONS Reproducibility of measurements in AS is poorer than often reported in the literature. The source of this variability does not appear, as traditionally believed, to result from a lack of training or operator and reader specific factors. Rather the unavoidable beat-to-beat biological variability, and the inherent impossibility of applying the ultrasound probe in exactly the same position each time are the largest contributors. Consequently, guidelines suggesting greater standardisation of procedures and further training for sonographers are unlikely to result in an improvement in precision. Clinicians themselves should be wary of relying on even three-beat averages as their expected coefficient of variance is 10.3% for the peak velocity at the aortic valve.

Studio sul ruolo dei fattori genetici coinvolti nella Valvola Aortica Bicuspide e/o nell'Aneurisma dell'Aorta Toracica

La Valvola Aortica Bicuspide (BAV) rappresenta la più comune anomalia cardiaca congenita, con un’incidenza dello 0,5%-2% nella popolazione generale. Si caratterizza per la presenza di due cuspidi valvolari anziché tre e comprende diverse forme. La BAV è frequentemente associata agli aneurismi dell’aorta toracica (TAA). La dilatazione dell’aorta espone al rischio di sviluppare le complicanze aortiche acute. Materiali e metodi Sono stati reclutati 20 probandi consecutivi sottoposti a chirurgia della valvola aortica e dell'aorta ascendente presso l'Unità di Chirurgia Cardiaca di Policlinico S.Orsola-Malpighi di TAA associata a BAV. Sono stati esclusi individui con una condizione sindromica predisponente l’aneurisma aortico. Ciascun familiare maggiorenne di primo grado è stato arruolato nello studio. L’analisi di mutazioni dell’intero gene ACTA2 è stata eseguita con la tecnica del “bidirectional direct sequencing”. Nelle forme familiari, l’intera porzione codificante del genoma è stata eseguita usando l’exome sequencing. Risultati Dopo il sequenziamento di tutti i 20 esoni e giunzioni di splicing di ACTA2 nei 20 probandi, non è stata individuata alcuna mutazione. Settantasette familiari di primo grado sono stati arruolati. Sono state identificate cinque forme familiari. In una famiglia è stata trovata una mutazione del gene MYH11 non ritenuta patogenetica. Conclusioni La mancanza di mutazioni, sia nelle forme sporadiche sia in quelle familiari, ci suggerisce che questo gene non è coinvolto nello sviluppo della BAV e TAA e, l’associazione che è stata riportata deve essere considerata occasionale. L’architettura genetica della BAV verosimilmente dovrebbe consistere in svariate differenti varianti genetiche che interagiscono in maniera additiva nel determinare un aumento del rischio.

The medical management after surgery for advanced heart failure

The aim of the Research of this Ph D Project is to improve the medical management after surgery for advanced heart failure, both after left ventricular assist devices (LVAD) implantation, and after heart transplantation in the long-term. Regarding heart transplantation (HTx), the Research Project is focused on diagnostics, classification, prevention and treatment of cardiac allograft vasculopathy (CAV), and on treatment of post-HTx cancers; the results are presented in the first part of this Thesis. In particular, the main aspect investigated are the prognostic role of information derived from coronary angiography, coronary tomography and intravascular ultrasound, and the different sensitivity of these techniques in predicting outcomes and in diagnosing CAV. Moreover, the role of mTOR inhibitors on CAV prevention or treatment is investigated, both alone and in combination with different anti-CMV prevention strategies, as well as the impact of mTOR inhibitors on clinical outcomes in the long term. Regarding LVAD, the main focus is on the role of transthoracic echocardiography in the management of patients with a continuous-flow, centrifugal, intrapericardial pump (HVAD, Heartware); this section is reported in the second part of this Thesis. The main aspects investigated are the use of echocardiography in patients with HVAD device and its interaction with the information derived from pump curves' analysis in predicting aortic valve opening status, a surrogate of the condition of support provided by the LVAD.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Congenital Nystagmus eye movements analysis and oculomotor system models evaluation

The term Congenital Nystagmus (Early Onset Nystagmus or Infantile Nystagmus Syndrome) refers to a pathology characterised by an involuntary movement of the eyes, which often seriously reduces a subject’s vision. Congenital Nystagmus (CN) is a specific kind of nystagmus within the wider classification of infantile nystagmus, which can be best recognized and classified by means of a combination of clinical investigations and motility analysis; in some cases, eye movement recording and analysis are indispensable for diagnosis. However, interpretation of eye movement recordings still lacks of complete reliability; hence new analysis techniques and precise identification of concise parameters directly related to visual acuity are necessary to further support physicians’ decisions. To this aim, an index computed from eye movement recordings and related to the visual acuity of a subject is proposed in this thesis. This estimator is based on two parameters: the time spent by a subject effectively viewing a target (foveation time - Tf) and the standard deviation of eye position (SDp). Moreover, since previous studies have shown that visual acuity largely depends on SDp, a data collection pilot study was also conducted with the purpose of specifically identifying eventual slow rhythmic component in the eye position and to characterise in more detail the SDp. The results are presented in this thesis. In addition, some oculomotor system models are reviewed and a new approach to those models, i.e. the recovery of periodic orbits of the oculomotor system in patients with CN, is tested on real patients data. In conclusion, the results obtained within this research consent to completely and reliably characterise the slow rhythmic component sometimes present in eye position recordings of CN subjects and to better classify the different kinds of CN waveforms. Those findings can successfully support the clinicians in therapy planning and treatment outcome evaluation.

Key issues in diagnosing and treating acute aortic syndromes: results from the metropolitan area of Bologna network

Background: Survival of patients with Acute Aortic Syndrome (AAS) may relate to the speed of diagnosis. Diagnostic delay is exacerbated by non classical presentations such as myocardial ischemia or acute heart failure (AHF). However little is known about clinical implications and pathophysiological mechanisms of Troponin T elevation and AHF in AAS. Methods and Results: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Troponin T values (either standard or high sensitivity assay, HS) were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or HS assay respectively, p = 0.001). Troponin positivity was associated with a twofold increased risk of long in-hospital diagnostic time (OR 1.92, 95% CI 1.05-3.52, p = 0.03), but not with in-hospital mortality. The combination of positive troponin and ACS-like ECG abnormalities resulted in a significantly increased risk of inappropriate therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). Patients with AHF were identified by the presence of dyspnea as presentation symptom or radiological signs of pulmonary congestion or cardiogenic shock. The overall frequency of AHF was 28 % (32% type A vs. 20% type B AAS, p = 0.01). AHF was due to a variety of pathophysiological mechanisms including cardiac tamponade (26%), aortic regurgitation (25%), myocardial ischemia (17%), hypertensive crisis (10%). AHF was associated with increased surgical delay and with increased risk of in-hospital death (adjusted OR 1.97 95% CI1.13-3.37,p=0.01). Conclusions: Troponin positivity (particularly HS) was a frequent finding in AAS. Abnormal troponin values were strongly associated with ACS-like ECG findings, in-hospital diagnostic delay, and inappropriate therapy. AHF was associated with increased surgical delay and was an independent predictor of in-hospital mortality.

Contribution of vascular resident mesenchymal stromal cells to abdominal aortic aneurysm pathogenesis: increased MMP-9 expression and ineffective immunomodulation

Background. Ageing and inflammation are critical for the occurrence of aortic diseases. Extensive inflammatory infiltrate and excessive ECM proteloysis, mediated by MMPs, are typical features of abdominal aortic aneurysm (AAA). Mesenchymal Stromal Cells (MSCs) have been detected within the vascular wall and represent attractive candidates for regenerative medicine, in virtue of mesodermal lineage differentiation and immunomodulatory activity. Meanwhile, many works have underlined an impaired MSC behaviour under pathological conditions. This study was aimed to define a potential role of vascular MSCs to AAA development. Methods. Aortic tissues were collected from AAA patients and healthy donors. Our analysis was organized on three levels: 1) histology of AAA wall; 2) detection of MSCs and evaluation of MMP-9 expression on AAA tissue; 3) MSC isolation from AAA wall and characterization for mesenchymal/stemness markers, MMP-2, MMP-9, TIMP-1, TIMP-2 and EMMPRIN. AAA-MSCs were tested for immunomodulation, when cultured together with activated peripheral blood mononuclear cells (PBMCs). In addition, a co-colture of both healthy and AAA MSCs was assessed and afterwards MMP-2/9 mRNA levels were analyzed. Results. AAA-MSCs showed basic mesenchymal properties: fibroblastic shape, MSC antigens, stemness genes. MMP-9 mRNA, protein and enzymatic activity were significantly increased in AAA-MSCs. Moreover, AAA-MSCs displayed a weak immunosuppressive activity, as shown by PBMC ongoing along cell cycle. MMP-9 was shown to be modulated at the transcriptional level through the direct contact as well as the paracrine action of healthy MSCs. Discussion. Vascular injury did not affect the MSC basic phenotype, but altered their function, a increased MMP-9 expression and ineffective immunmodulation. These data suggest that vascular MSCs can contribute to aortic disease. In this view, the study of key processes to restore MSC immunomodulation could be relevant to find a pharmacological approach for monitoring the aneurysm progression.