Because of the paucity of large, randomized trials concerning the cardiac care of patients with cancer, treatment and prevention of chemotherapy-induced cardiotoxicity must rely on insights gained from small trials and case reports as well as the application of guidelines developed for the general population. In these clinical vignettes, we present patients referred by their oncologists to a cardiologist for specialized evaluation and management of cardiotoxicity with the goal of emphasizing the importance of identifying risk factors for cardiotoxicity, initiating evidence-based therapy, and establishing a close collaboration between oncologists and cardiologists. Patients undergoing chemotherapy treatment for cancer face a variety of potential therapy-related risks and side effects. In recent years, cardiovascular complications due to chemotherapy have been increasingly recognized. Such complications can range in severity from asymptomatic transient arrhythmias to irreversible myocardial necrosis, vasospasm-related myocardial ischemia, or pericarditis. Though the anthracycline class of compounds and trastuzumab are agents most frequently associated with cardiotoxicity, virtually any chemotherapeutic drug has the potential to cause cardiovascular side effects; patients with underlying heart disease are particularly vulnerable . Given the complexity of balancing competing oncologic and cardiac risks, many cancer patients may benefit from a multidisciplinary approach to their care. Here we present three clinical vignettes which demonstrate how the integration of oncology and cardiology can enhance overall care for patients undergoing treatment for cancer.EW is a 50-year-old female with a history of asthma and hypothyroidism who initially presented two years previously with a two-month history of increasing chest and back pain. Chest x-ray revealed a right lateral chest wall/pleural-based soft tissue mass with underlying fifth rib destruction and compression fractures of T9 and T11. Computed tomography of the chest revealed a 3.9 x 3.5 cm irregular left breast mass, bilateral axillary and subcarinal lymphadenopathy and widespread bony metastases predominately in the thoracic spine and sternum. Biopsy revealed invasive ductal breast cancer, which was estrogen receptor (ER)-positive, progesterone receptor (PR)-negative, and HER-2/neu-positive. Prior to the initiation of chemotherapy for metastatic breast cancer, the patient’s echocardiogram revealed a left ventricular ejection fraction (LVEF) of 60%. She then received a standard loading dose of trastuzumab followed by combined treatment with trastuzumab and paclitaxel. After three months of therapy, repeat echocardiography revealed a decrease in her LVEF to 39-45%. Of note, the patient had smoked a half a pack of cigarettes a day for 30 years. She also had a history of cocaine and alcohol abuse. Her family history was unremarkable.Cardiology consultation was sought to assist in management of the patient’s decline in LVEF, in light of the treating oncologist’s preference to continue HER-2/neu-targeted therapy for as long as possible during the course of treatment for metastatic breast cancer. .1. Because of the potential for cardiac toxicity, frequent assessment of LVEF is recommended. Though no formal guidelines or consensus statements currently exist regarding cardiac monitoring during trastuzumab, most experts recommend that left ventricular function be evaluated prior to the initiation of trastuzumab therapy to establish the baseline LVEF, and that LVEF should be reassessed every three months during trastuzumab therapy . In addiIn regard to LVEF screening modality, there is no evidence to suggest definitive superiority of either echocardiography or equilibrium radionuclide angiography (ERNA/ MUGA) for the purposes of monitoring cardiac function in the setting of chemotherapy. Both echocardiography and ERNA are acceptable modalities provided that a quantitative assessment of LVEF is performed so that small changes can be detected over time. Echocardiography may be more appropriate in patients who require additional assessment of valve function, diastolic function, cardiac chamber sizes, pericardial effusions, or regional wall motion. Echocardiography may also be more appropriate in those patients who will require frequent or ongoing monitoring in an effort to minimize exposure to radiation, given that the amount of total body irradiation delivered with each ERNA has been estimated by some to be as high as the equivalent of 100-200 chest x-rays . Convers2. The cardiotoxicity associated with trastuzumab is generally a type 2 cardiotoxicity; that is, a reversible decline in left ventricular function that is not caused by cardiomyocyte necrosis or the development of fibrosis [Once left ventricular function normalizes, trastuzumab therapy can be reinitiated, in part because the cardiotoxic effects of the agent do not appear to be a function of the cumulative dose. However, closer monitoring every 2-4 weeks) of LVEF is warranted  weeks of.3. Age greater than 50 years, along with preexisting left ventricular dysfunction and treatment with anthracylines, are risk factors for the development of trastuzumab-associated cardiotoxicity . However2) and cyclophosphamide, given once every two weeks. However, after completion of four planned cycles of chemotherapy, the patient reported progressive dyspnea on exertion and tachycardia to her oncologist. Cardiology consultation was requested to assess her symptomatic dyspnea, both in the context of her recent course of anthracycline chemotherapy, and given that she was otherwise due to start taxane-based adjuvant chemotherapy.DD is a 61-year-old female with hypertension, hypercholesterolemia and borderline diabetes who was diagnosed with an invasive carcinoma after routine mammography revealed an abnormality in the left breast. She ultimately underwent left mastectomy with axillary dissection, revealing a 1.6 cm, poorly differentiated, infiltrating ductal carcinoma with four of eight lymph nodes positive for metastatic carcinoma. The lesion was ER/PR-positive and HER-2/neu-negative. Prior to initiation of chemotherapy, she had undergone exercise stress testing with perfusion imaging, which revealed normal perfusion and left ventricular function. She also had a baseline ERNA study with an LVEF of 51%.She subsequently started standard adjuvant chemotherapy treatment with doxorubicin , may be treated with the agent with serial assessments of left ventricular function performed prior to each cycle of chemotherapy . GF is a 62-year-old female with refractory/relapsed diffuse large B-cell lymphoma (DLBCL). Her past medical history was otherwise remarkable for type 2 diabetes and hypertension. The patient was first diagnosed with DLBCL eighteen months prior when she presented with enlarged sub-mandibular lymph nodes. She initially received standard first-line chemotherapy  for a total of six cycles, along with radiation to the neck. She achieved a complete remission, but about a year later she developed hip and flank pain and was ultimately found to have recurrence of disease. Additional chemotherapy  was initiated, however the lymphoma proved resistant to therapy. Salvage chemotherapy  was initiated, from which the patient achieved significant response. She was then deemed a candidate for bone marrow transplant, and ultimately underwent high-dose BEAM chemotherapy  followed by autologous stem cell transplantation. The transplant was complicated by volume overload. Echocardiography at that time revealed an LVEF of 50%, concentric left ventricular hypertrophy, mild aortic insufficiency, and severe mitral regurgitation, which had not been present previously.Following transplant, the patient did well for approximately three months until she was found to have recurrent disease on routine restaging PET scan.Chemotherapy was again initiated, with the CEPP-R regimen .Several days after receiving chemotherapy, she was admitted to the hospital with lethargy and acute change in mental status. Her exam was remarkable for hypotension, confusion and sinus tachycardia. Head CT was unrevealing. Lab work-up revealed neutropenia, thrombocytopenia and an elevated troponin of 0.66 with an N-terminal pro-BNP of 34,400 pg/ml. Her EKG showed sinus tachycardia but no ischemic changes. Given concern for possible aspiration pneumonia, she was started on broad-spectrum antibiotics. Cardiology was subsequently consulted regarding the concern for myocardial infarction, both in terms of acute management and in terms of how this event might impact consideration of further chemotherapy for her DLBCL. Repeat echocardiography demonstrated a moderately dilated left atrium with a LVEF of 40%. There was normal right ventricular size and systolic function, as well as moderate aortic regurgitation and moderate to severe mitral regurgitation. There was no significant pericardial effusion. She was subsequently started on a beta-blocker, furosemide and an ACE inhibitor. 1. Cardiac complications from stem cell transplantation for hematologic malignancies are rare; however, agents used for the marrow preparation can have cardiac toxicities. For example, cyclophosphamide can cause a hemorrhagic pericarditis and myocarditis, which, although usually limited, can be life threatening .2. Although vasospasm caused by etoposide must be considered as a cause of the elevated serum troponin level, there were no electrocardiographic changes suggestive of vasospasm. Given the presentation suggestive of pneumonia, it is more likely that the patient had demand ischemia.3. The patient had previously received CHOP-R  prior to the bone marrow transplantation, which raises the possibility that the decrease in left ventricular function is related to treatment with anthracyclines.4. The presence of myocardial damage in the setting of demand ischemia raises the possibility that the patient has significant coronary artery disease. In addition, she has mildly reduced left ventricular function, the etiology of which (ischemic vs. chemotherapy-associated) has not been determined. As a result, she is certainly at increased risk for further decreases in left ventricular function with cardiotoxic chemotherapeutic regimens. Further risk stratification is somewhat problematic given her thrombocytopenia, which increases the risk of cardiac catheterization. After discussions between the oncologist and cardiologist, the prognosis of the patient from an oncologic standpoint was felt to be poor and further chemotherapy was not considered. The patient’s cardiac issues were treated medically with beta-blocker and ACE inhibitor.Cardiovascular complications of chemotherapy are fortunately uncommon. However, the development of cardiotoxicity during the course of chemotherapy can profoundly impact cancer treatment options, which may in turn affect overall cancer prognosis. Given the complexity of balancing oncologic risks with cardiac risks, many patients undergoing chemotherapeutic treatment for cancer may benefit from an integrated model of care between oncology and cardiology. The clinical vignettes presented here represent common scenarios in which multidisciplinary care is essential, including management of chemotherapy-related heart failure, prevention of cardiotoxicity, cardiac monitoring during chemotherapy and assessment of cardiac risk and prognosis in relation to selection of specific chemotherapy regimens. In short, the integration of oncology and cardiology can enhance overall care for many patients undergoing treatment for cancer, and should be considered as a standard approach for chemotherapy-related cardiotoxicity.


Sirs:Peripartum cardiomyopathy (PPCM) affects one in 300 to one in 100,000 pregnant patients, depending on cardiovascular risk factors  and gestational risk factors  . Accordil-thyroxin for thyroid hypofunction. She has obesity (BMI of 40 kg/m2) and previously smoked. During pregnancy, she has developed a gestational hypertension and diabetes that was treated with subcutaneous insulin therapy. The respiratory situation deteriorated rapidly, so that an intubation and mechanical ventilation had been necessary. In the following bronchoscopy spumous secretion could be aspirated. Due to highly cardiopulmonary instability she was transferred to our cardiological intensive care unit. In the thoracic X-ray and CT scan, a bilateral pneumonia and bilateral pleural effusions were detected (Fig. A Caucasian women aged 39 years was diagnosed with PPCM. Initially, the primipara presented in the Emergency Department of a local hospital with general fatigue, shortness of breath and oedematous ankles 4 days after normal delivery of a healthy baby. The symptoms started 2 days ago at home shortly after gynaecological discharge. She had no history of cardiopulmonary diseases and has taken no medication before pregnancy except ted Fig. A. Pulmonted Fig. B, but wited Fig. C. The leted Fig. D + E. Thted Fig. F. MoreovIn our case, the Impella device was used because of left ventricular dilation with severe functional mitral regurgitation which facilitated cardiac recompensation by continuous ventricular unloading. Moreover, specific therapy with bromocriptin that suppresses the production of prolactin by dopamine D2 receptor agonism may be beneficial in PPCM . Due to This single case underlines the necessity of adequate anticoagulation therapy in PPCM with moderately reduced LV function and bromocriptine treatment, especially if ventricular assist devices are used, although a moderate bleeding risk is existent. Moreover, it demonstrates the beneficial effects of mechanical ventricular unloading as a supportive therapy in severe heart failure in PPCM.


Wall stress is a useful concept to understand the progression of ventricular remodeling. We measured cumulative LV wall stress throughout the cardiac cycle over unit time and tested whether this “integrated wall stress (IWS)” would provide a reliable marker of total ventricular workload.-MI mice represents limited myocardial contractile reserve.We applied IWS to mice after experimental myocardial infarction (MI) and sham-operated mice, both at rest and under dobutamine stimulation. Small infarcts were created so as not to cause subsequent overt hemodynamic decompensation. IWS was calculated over one minute through simultaneous measurement of LV internal diameter and wall thickness by echocardiography and LV pressure by LV catheterization. At rest, the MI group showed concentric LV hypertrophy pattern with preserved LV cavity size, LV systolic function, and IWS comparable with the sham group. Dobutamine stimulation induced a dose-dependent increase in IWS in MI mice, but not in sham mice; MI mice mainly increased heart rate, whereas sham mice increased LV systolic and diastolic function. IWS showed good correlation with a product of peak-systolic wall stress and heart rate. We postulate that this increase in IWS in postWe hereby propose that IWS provides a useful estimate of total ventricular workload in the mouse model and that increased IWS indicates limited LV myocardial contractile reserve. The magnitude of ventricular remodeling advances in line with progressive ventricular geometric changes including myocardial hypertrophy and chamber dilatation with accompanying functional deterioration  were also obtained. LV pressure waveform input and pressure derivative (dP/dT) were superimposed on the electrocardiogram (ECG) trace in real time along with data regarding heart rate (HR) and body temperature (ºC).Seven weeks after experimental MI, the mice were anesthetized with intraperitoneal injection of ketamine (50 μg/g body weight) and xylazine (5 μg/g body weight). A 1.4 Fr Millar Mikro-tip Catheter Transducer  was inserted through right common carotid artery cutdown into the LV cavity. The LV pressure signals were ported to the Vevo770 Ultrasound System in real time. Simultaneously, M-mode echocardiogram was obtained from parasternal short axis view. LV systolic pressure (SP) and LV end diastolic pressure (LVEDP) were measured. The maximum values of the first derivatives of the ascending (+) and descending (−) left ventricular pressure , LV hypertrophy [LVPW(d)], and systolic performance (%FS and %Vcf) in MI (n = 5) and sham (n = 5) groups Figure A. ProgreThis small MI model was previously reported by us as an experimental model to induce ventricular remodeling without initial hemodynamic deterioration . After 7max and (−)dP/dTmax were significantly higher in the sham group than in the MI group ; further difference was observed with the 10 μg/kg/min of dobutamine infusion , suggesting that both systolic and diastolic ventricular reserve capacities were significantly diminished in MI compared with sham. Three of 5 MI mice developed hemodynamic instability at 20 μg/kg/min of dobutamine infusion. Of these 3, 2 mice subsequently died of cardiovascular collapse. Echocardiographic measurements at 7 wk were not included in Figure At 7 weeks after MI, echocardiography and cardiac catheterization were performed simultaneously at rest and with continuous intravenous infusion of dobutamine (first 5 and then 10 μg/kg/min) under ketamine/xylazine anesthesia Figure . Heart rIWS changes in both MI and sham groups, before and after dobutamine stimulation (5 and 10 μg/kg/min), are shown in Figure We also measured peak systolic wall stress (PS-WS) and end diastolic wall stress (ED-WS) before and after dobutamine infusion in both groups Figures B and C. × HR). Figure × HR and IWS, both in sham-operated and MI hearts .Increased IWS in dobutamine-stimulated condition in the MI group appeared to be primarily related to increased heart rate and higher PS-WS when compared with the sham group. Thus, we calculated the “IWS index” by multiplying PS-WS with heart rate as a marker for IWS, and examined whether IWS correlates well with calculated IWS index  including the effect of heart rate and inotropic state of the ventricular myocardium, whereas one-spot measurement of PS-WS and ED-WS only reflects maximum and minimum wall stress during a cardiac cycle, respectively. We hypothesized that increase in IWS indicates failure of myocardium to counteract increased ventricular workload. We have measured IWS in the mouse model in various physiological and pathological conditions to validate this hypothesis. Unchanged IWS observed in sham operated mice may imply that the contractile reserve of ventricular myocardium can absorb the increased cardiac output, whereas increased IWS after MI suggests that ventricular workloads exceeds intrinsic myocardial contractile reserve. Thus, we postulate that IWS is a reliable physiological marker in indicating a balance between external ventricular workload and intrinsic myocardial contractile reserve.“Wall stress theory” is an important concept in understanding the process of cardiac hypertrophy in response to increased hemodynamic loading . When thSystolic wall stress has been studied extensively as a clinical marker for myocardial reserve. Systolic wall stress reflects the major determinants of the degree of LV hypertrophy and plays a predominant role in LV function and myocardial energy balance . It has in vivo. In this study, we have proposed unchanged IWS as a marker of sufficient myocardial contractile reserve, since increased wall stress demands higher myocardial oxygen consumption. Indeed, systolic wall stress does not increase with strenuous isometric exercise in healthy young athletes . Alt. Alt5]. We have demonstrated a very good correlation between IWS and the product of PS-WS and HR (“IWS index”) in both MI and sham-operated hearts Figure . This foThere are certain limitations in this study. First, wall stress measurement is reliable when there is an equal wall thickness with symmetrical structure. Obviously, with the creation of small MI, there is an asymmetry of LV myocardium in both structure and consistency (myocardium vs. scar tissue). However, the scar tissue is small and restricted to the LV apex (approximately 14% of entire LV myocardium ). In facIWS can be estimated by obtaining IWS index, which is calculated non-invasively by simultaneous M-mode echocardiogram and cuff blood pressure measurement, i.e., PS-WS instead of ES-WS and heart rate. This will provide a sensitive way to detect subclinical borderline failing myocardium in which the decline in LV myocardial contractile reserve precedes apparent LV dysfunction. This method may be clinically useful to address LV myocardial reserve in those patients who are not amenable to perform on exercise stress test, such as immediate post-operative patients under mechanical ventilation, critically ill patients with questionable LV dysfunction, and patients with primary muscular disorders and general muscular weakness .The authors declare that they have no competing interests.HD prepared and participated in all animal studies, completed histology and molecular studies, critically analyzed the data, performed statistic analysis, and completed all figures. HR assisted in all aspects of the animal experiments and independently performed echocardiography. EG performed the surgical procedures for experimental MI and invasive cardiac catheterization. RAE and SGG critically read the manuscript and helped to revise the text. TT originally created the concept of IWS, designed the experimental plans, supervised all laboratory activities, assessed the data with co-authors, and drafted and revised the manuscript. All authors read and approved the final manuscript.


Duchenne (DMD) and Becker (BMD) muscular dystrophy (MD) are inherited X-linked disease characterized by progressive skeletal muscle degeneration and myocardial involvement and caused by a mutation on dystrophin gene Xp21). Dystrophin is a sarcolemal protein that links the cytoskeleton to the basal lamina and is essential for maintenance of the muscular membrane integrity during muscular contraction. In a previous study, our group described for the first time, in a small group of 10 patients, that CMR can identify myocardial fibrosis (MF) and may be useful for detecting the early stages of cardiomyopathy in MD [. DystropWe enrolled 76 pts, 70 pts with DMD and 6 BMD. Mean age was 13.1 ± 4.4 years. 74 patients underwent 2 CMR exams within a mean of 2.3 years, performed on a 1.5-T Siemens Avanto . Breath-hold LV short-axis and long-axis images were obtained by 2-pulse sequences at the same locations, allowing precise comparisons between LV function  and myocardial structure , acquired with the following parameters, respectively: TR 2.0/ 9.0, TE 1.07/ 5.0; flip angle 69/50; cardiac phases 20/1; VPS 8/16 to 32; matrix 192 x 162 / 256 x 192; ST 8/8 mm; gap 2/2 and FOV 32 to 38/32 to 38 cm; TI none/150 to 390 ms; receiver bandwidth 930/150 Hz; number of excitations 1/1; acquisition every other heartbeat for MDE.The images were analyzed by two experienced observers. End-systolic LV volume, end-diastolic LV volume and LV ejection fraction were measured by the Simpson method using Argus software, Siemens. For the MDE short axis images, we evaluated the MF mass per patient, using a 5 standard deviation thresholding technique, on a CMR42 software, version 3.4.2 . Normal LVEF was defined as above 50%. Test of Wilcoxon was used for comparison of myocardial fibrosis between baseline and follow-up CMR studies.Two patients died before the follow-up CMR. For all 74 patients, MF increased significantly from 11.3 ± 12.2 g on the baseline CMR to 15.9 ± 15.4 g, p<0.001. The number of segments with MF increased from 3.7 ± 3.3 to 5.1 ± 3.6, p<0.001. In a sub-group with LV dysfunction (n=11) MF increased from 26.9 ± 13.0 g to 35.5 ± 20.2 g, p=0.021. In a sub-group of patients with normal LVEF and no fibrosis (n=21) on the baseline CMR, MF progressed from 0 g to 1.5 ± 3.7 g, p=0.08.Myocardial fibrosis detected by CMR progressively increases in patients with Duchenne and Becker muscular dystrophy over a period of 2.3 years. The progression occurs not only in patients with more advanced cardiomyopathy and LV dysfunction, but also in patients with normal function and no myocardial fibrosis at the baseline CMR.Self Funding


Accidental malpositioning of a right ventricular (RV) electrode has not been previously reported in the context of cardiac resynchronization therapy (CRT).The case of a 75-year old male patient with dilative cardiomyopathy, left ventricular (LV) ejection fraction 23%, New York Heart Association functional heart failure status stage III, left bundle branch block (LBBB) with QRS width of 136 ms, and misplacement of the RV lead to the LV apex during implantation of a CRT defibrillator is described.Following unremarkable implantation, routine interrogation of the CRT device on the first day after the implantation revealed uneventful technical findings. The 12-lead surface electrocardiogram (ECG) showed biventricular stimulation featuring a narrow QRS complex with incomplete right bundle branch block (RBBB) and R>S in V1. The biplane postoperative chest X-ray was graded normal. On routine follow-up one month later, a transthoracic echocardiogram revealed an increased ejection fraction of 51% but the RV lead was placed in the LV apex. An additional transesophageal echocardiogram exhibited an Eustachian valve guiding the lead via the patent foramen ovale through the mitral valve into the LV apex. Operative revision was scheduled and the active fixation lead was uneventful removed from the LV. A new electrode was inserted and placed in the RV apex.Accidental malplacement of the RV electrode to the LV may be difficult to diagnose in the context of CRT patients as a stimulated biventricular ECG with incomplete RBBB appearance is expected in this situation. Careful analysis of lateral radiographic views during the operation is important to ensure correct lead positioning. As timely revision is the preferred procedure, early routine transthoracic echocardiography may be considered for detection of malplacement. In most cases, implantation of pacemaker or defibrillator leads is a straightforward routine procedure. In selected patients difficulties may be caused by congenital variants , angioloA 75-year-old caucasian male patient with a diagnosis of dilative cardiomyopathy (echocardiographic biplane ejection fraction (EF) 23%) had sinus rhythm with left LBBB ECG Figure a-b QRS c-d with One month later on follow-up, the patient reported a marked improvement of his exercise capacity (NYHA II). Electrode values remained stable. An unscheduled echocardiogramm (Philips iE33) revealed a marked reduction of left ventricular dimensions with an improved monoplane ejection fraction (51%). However, through the mitral valve leaflets a thick electrode proceeded into the apex of the left ventricle. An additional transesophageal echocardiographic examination demonstrated the coronary sinus (CS) electrode in place (Figure After studying the literature and informing the patient about possible consequences a revision procedure was performed. The RV electrode was easily removed from the left ventricle but could not be safely placed in the right heart without a sheat. A new electrode was advanced and fixed at the base of the right ventricle. Postprocedure chest x-ray Figure c-d, ECG This was a clinical study and no experimental work. No ethical committee had to be involved. Everything happened in the compliance with the Helsinki Declaration.Inadvertent placement of a transvenous RV electrode in the left ventricle has been described by several case reports and reviews ,7. ElectIn patients with right ventricular apical pacing postprocedure ECG is diagnostic in most patients revealing a RBBB with positive deflection in lead V1 and a negative deflection in lead I. Typically, RV pacing results in a LBBB with negative deflection in V1 and positive in I. This finding has a good sensitivity for malposition or perforation of the RV electrode . HoweverRV malplacement may be detected by postero-anterior and lateral chest radiographs in particular if the tip shows a posterior orientation ,6,9. HowElectrodes in the arterial circulation without adequate anticoagulation may cause cerebral and systemic embolism ,7,13 or Inadvertent malposition of an RV lead in the left ventricle may be difficult to diagnose in patients with CRT devices. Lateral radiographic views during the operation should be used to ensure correct lead positioning. In biventricular stimulation, ECG criteria commonly used in RV stimulation are not applicable. In case of electrode malplacement, early operative revision seems to be the favorite strategy. There should be a low threshhold performing routine transthoracic echocardiography days or a few weeks after the CRT device implantation procedure.Written informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available by the Editor-in-Chief of the journal.RV: Right ventricle; CRT: Cardiac resynchronisation therapy; LV: Left ventricle; EF: Ejection fraction; CRT-ICD: Cardiac resynchronisation therapy - implantable cardioverter defibrillator; NYHA: New York Heart Association; LBBB: Left bundle branch block; ECG: Electrocardiogram; RBBB: Right bundle branch block; TEE: Transesophageal echocardiogram; PFO: Patent foramen ovale.The authors declare that they have no competing interests.RD conceived, designed and drafted the manuscript, assisted in the operation and was the consultant in charge of the patient’s care. UW was the principal operating cardiologist and collected various imaging data. MZ was primarily involved in the clinical and scientific discussion of the case. All three authors revised the manuscript and made intellectual contributions.


Severe aortic valve stenosis (AVS) can cause an exercise-induced reflex syncope (RS). The precise mechanism of this syncope is not known. The changes in hemodynamics are variable, including arrhythmias and myocardial ischemia, and one of the few consistent changes is a sudden fall in systemic and pulmonary arterial pressures (suggesting a reduced vascular resistance) followed by a decline in heart rate. The contribution of the cardioinhibitory and vasodepressor components of the RS to hemodynamics was evaluated by a computer model. This lumped-parameter computer simulation was based on equivalent electronic circuits (EECs) that reflect the hemodynamic conditions of a heart with severe AVS and a concomitantly decreased contractility as a long-term detrimental consequence of compensatory left ventricular hypertrophy. In addition, the EECs model simulated the resetting of the sympathetic nervous tone in the heart and systemic circuit during exercise and exercise-induced syncope, the fluctuating intra-thoracic pressure during respiration, and the passive relaxation of ventricle during diastole. The results of this simulation were consistent with the published case reports of exertional syncope in patients with AVS. The value of the EEC model is its ability to quantify the effect of a selective and gradable change in heart rate, ventricular contractility, or systemic vascular resistance on the hemodynamics during an exertional syncope in patients with severe AVS. Exertional syncope, a syncope present during increased heart workload due to increased muscle work, is an important complication of advanced aortic valve stenosis (AVS) . The mecA consistent change in hemodynamics during exertional syncope is systemic hypotension, a reduction in both systolic and diastolic blood pressure. Changes in heart rate are variable, ranging from insignificant to sinus bradycardia or even sinus node arrest –5. SigniThe triggers for the reflex syncope are not completely understood –8. Most Cardiac syncopes can be due to arrhythmias  or due to structural diseases of the heart or major blood vessels. The most common cause of a cardiac (cardiovascular) syncope is an arrhythmia, for example, a bradycardia or a tachycardia .Patients with severe AVS are more prone to exertional syncope than healthy individuals. Firstly, severe AVS limits the ability of the cardiovascular system to maintain an adequate perfusion of the brain during increased muscle work. Secondly, these patients may have developed compensatory changes  that increase the chances of left ventricular dysfunction with or without myocardial ischemia or arrhythmias (bradycardias or tachycardias) during increased muscle work. To summarise, exertional syncope in a patient with severe AVS is caused by different mechanisms  and conc an improved subcircuit controlling ventricular contractility that gives an ejection fraction value of 70% for a normal heart; a heart model with severe AVS, moderately decreased left ventricular contractility, and systolic insufficiency (as a complication of compensatory ventricular hypertrophy). The simulated left ventricle still has a preserved but limited capacity to respond to inotropic mechanisms, thus more closely resembling the clinical conditions of a patient with AVS that develops exertional syncope; the ability to simulate different patterns of the RS during exercise by selectively activating or inactivating the vasodepressor reflex (loss of venoconstriction) or the cardioinhibitory reflex (reduced left ventricular contractility or reduced heart rate).We studied the differential effects of arrhythmia  or reduced stroke volume  in the presence of syncope-related homeostasis failure of the cardiovascular system with venous pooling of blood and decreased peripheral resistance. The lumped-parameter computer model of this cardiovascular system was based on equivalent electronic circuits (EECs). For the presented study we upgraded an existing EEC model of the cardiovascular system with AVS –16. The In addition, the results of the simulation were analyzed with the pressure-volume (P-V) loop diagrams of left ventricular work.Analyses are performed by developing an equivalent electronic circuit (EEC) by using Electronics Workbench (EWB) Personal version 5.12 –16. In tCompared to the earlier EECs –16, the Decreased left ventricle contractility is achieved by decreasing the nominal gain from 100 to about 20 . AVS is Results are shown graphically, as the time course of equivalent variables. Thus, electrical variables: voltage, current, resistance, capacitance, and charge, correspond to physiological variables: pressure, blood flow, resistance, capacitance, and volume (for details refer to –16). The50 s–70.5 s: sedentary, normal  conditions;70.5 s–110.5 s: development of decreased LV contractility in sedentary conditions;110.5 s–150.5 s: development of decreased LV contractility and severe AVS in sedentary conditions;150.5 s–240.5 s: decreased-LV contractility and AVS, and MAoP reset and peripheral resistance decreased by 50% during physical exercise;240.5 s–550 s: failure of homeostasis due to activation of the reflex syncope response during physical exercise . This is achieved by differentially switching off the negative feedback circuits controlling heart frequency, left ventricular contractility, and venous tone. Figures In all simulations, the sequence of parameter change (in the five time sequence sections) is as follows:The time course of AoP, MAoP, CO, CVV, Sy, and LAtP during simulation as described above is shown in Failure of homeostasis results in a dramatic change of almost all variables; their steady state is established at about 500 s of simulation time . A decreNormal, sedentary  conditions : note that peak LVP is reached in less than 0.1 s, indicating a relatively high rate of LV contraction. SVLV is 87 mL, EF is 63%, and diastolic LVP is slightly negative. Accordingly, the P-V loop diagram shows relatively low ventricle volume and low ventricular diastolic pressure.Decreased LV contractility in sedentary conditions : maximum LVP is almost normal, but peak LVP is reached in more than 0.1 s, indicating a relatively low rate of LV contraction. EDVLV and ESVLV are strongly increased, SVLV only slightly decreased, but EF strongly decreased to about 30%. Diastolic LVP is positive. Accordingly, the P-V loop diagram is shifted to the right, to an increased ventricular diastolic pressure and a relatively high ventricle volume.Decreased LV contractility and AVS in sedentary conditions simulate the conditions of an AVS related systolic ventricular dysfunction : an aortic-ventricular pressure gradient (about 50 mm Hg) shows up. Maximum LVP is almost 170 mm Hg, but peak LVP is reached in more than 0.1 s, indicating a relatively low rate of LV contraction. EDVLV and ESVLV further increased, SVLV maintained, and EF strongly decreased to about 25%. The P-V loop diagram is shifted strongly to the right and upwards, to a relatively very high ventricle volume and systolic pressure.Decreased LV contractility AVS and MAoP reset, and peripheral resistance decreased by 50% during physical exercise : the aortic-ventricular pressure gradient is increased to about 70 mm Hg. Maximum LVP is almost 190 mm Hg and peak LVP is reached in about 0.1 s, indicating an improved rate of LV contraction. EDVLV and ESVLV decreased, SVLV is about 107 mL, and EF 56%. Accordingly, the P-V loop diagram is shifted to the left and upwards, to a relatively low ventricle volume and high ventricle systolic pressure.The time course of AoP, MAoP, LVP, LAtP, and CO during one cardiac cycle and the corresponding P-V loop diagram, are shown in Various types of homeostasis failure are also shown in steady state (after about 540 s of simulation time) as the time course of AoP, MAoP, LVP, LAtP, and CO during systole and part of diastole (543.7 s–544.3 s). All data are shown in columns (a)–(d) , includiIf heart rate is 120/min and Sy is 1 FGU , the P-VIf the heart rate is 45/min and the Sy is 0.5 FGU, the P-V loop diagram is shifted to extreme right, but maintains its width. EDVLV is strongly increased, increasing also SVLV. If in this condition the Sy is increased to 1.5 FGU, the P-V loop diagram is shifted to the left, increasing its width: EDVLV is decreased, but SVLV increased, as is also shown in the time course of ventricular volume and pressure.Technical details important to be considered in simulations have already been discussed . Note thCompared to earlier AVS simulations , in the a flow-dependent decrease in pulmonary vascular resistance is not simulated; the control of peripheral (arteriolar) resistance is not included into the negative feedback.It should be noted that at any heart rate, the duration of systole is constant, 0.2 s. Therefore, if heart rate is increased, only the duration of systole is decreased. Atria do not contract. It should also be noted that in the present circuit:In principle, it would be possible to include both features. However, this would contribute considerably to the complexity of the circuitry, without contributing very much to the understanding of underlying physiological mechanisms.Despite the model's deficiencies described above, the negative feedback  seems to be quite similar to that controlling the human cardiovascular system –19. AfteBy using the present model various physiological and clinical conditions have been simulated . Our unpuplished data also show that, by a suitable modification of the ventricle circuit, even the cardiac aneurysm can be simulated quite satisfactorily. In the present EEC, blood inertia is not simulated; therefore, the aortic dicrotic notch—as simulated in —is absenHemodynamic changes effected by AVS were simulated by Korürek et al. . This moCompared to the simulations described above , 21, theThere are only a few published reports of exercise-induced syncope in patients with aortic stenosis , 3–5. CoOur model demonstrates the changes in hemodynamics (a reduction in both systolic and diastolic blood pressure) when the capacity of the heart to maintain a sufficient cardiac output is reduced either due to arrhythmia or to reduced contractility. Therefore, the results of the model are qualitatively in agreement with the published data , 3–5. SiThe presented lumped-parameter EEC model can differentially simulate the effect of cardioinhibitory and vasodepressor component of the RS response, and the simulated hemodynamic data are in agreement with patient data recorded during exercise-induced syncope. To our knowledge, this is the first reported computer simulation of an exercise-induced RS in patients with severe AVS.


We present the case of a 35-year-old man affected by the late juvenile form of galactosialidosis. He was known for a moderate pericardial effusion which remained unchanged in the last 12 months. Last follow-up transthoracic echocardiographic examination showed a bulging of the posterior and lateral wall of the left ventricle. This finding has never been described before in galactosialidosis.  Galactosialidosis is a very rare form of lysosomal storage disease, whose prevalence is unknown. It is inherited in an autosomal recessive way. It is caused by a combined deficiency of beta-galactosidase and neuraminidase. The combined deficiency has been found to result from a defect in protective protein/cathepsin A, an intralysosomal protein which protects these enzymes from premature proteolytic processing . Based on the age of onset and severity of the disease, galactosialidosis is divided into three clinical subtypes .All patients have clinical manifestations typical of lysosomal storage disorder, such as coarse facies, cherry-red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile form of galactosialidosis shares some features with the early infantile form although the signs and symptoms are somewhat less severe and begin later in infancy. This form is characterized by short stature, dysostosis multiplex, heart valve problems, and hepatosplenomegaly. Other symptoms seen in some individuals with this type include intellectual disability, hearing loss, and a cherry-red spot. Children with this condition typically develop symptoms within the first year of life. The life expectancy of individuals with this type varies depending on the severity of symptoms. The juvenile/adult form of galactosialidosis has signs and symptoms that are somewhat different than those of the other two types. This form is distinguished by difficulty coordinating movements (ataxia), muscle twitches (myoclonus), seizures, and progressive intellectual disability. People with this form resembles those with the other forms in having dark red spots on the skin (angiokeratomas), abnormalities in the bones of the spine, “coarse” facial features, a cherry-red spot, vision loss, and hearing loss. The age at which symptoms begin to develop varies widely among affected individuals, but the average age is 16. This form is typically associated with a normal life expectancy.We present the case of a 35-year-old man affected by the late juvenile form of galactosialidosis. He presented mental and growth retardation, coarse facies, and chronic renal failure in haemodialitic treatment. He has been known for one year for pericardial effusion, which remained stable at periodic transthoracic echocardiographic examinations (TTEs). Last follow-up TTE showed a bulging of the posterior and lateral wall of the left ventricle which had a wide neck and a thin wall. It was not possible to discriminate between left ventricle aneurysm and pseudoaneurysm. The patient underwent a cardiac magnetic resonance (CMR). CMR showed a moderate circumferential pericardial effusion with fibrin exudates Figures  and 3. TThe bulging has a wide neck, which is typical of aneurysm. In the medium segment of the left ventricle, where it originates from the posterior and lateral walls, myocardial tissue is thickened and vacuolated. This appearance could be related to the presence of vacuolated cells, which is well described in other organs in patients affected by galactosialidosis .The presence of vacuolated cells could make the wall of the diverticulum less resistant, which could be the cause of its expansion under the left ventricular pressure. This hypothesis could also explain the presence of a thinner wall, which is derived from the stretched tissue with vacuolated cells. The variability in neck diameter during systole and diastole indicates the muscular origin of the diverticulum.The typical cardiac finding in galactosialidosis is valve involvement. Our patient showed only mildly myxomatous valves without any significant valve dysfunction. Pericardial effusion is not described in the literature, but it could be related to the previously described peritoneal effusion. The more striking finding is the presence of the cardiac bulging, which remained stable in a 12-month followup.To our knowledge this is the first report of a cardiac bulging in galactosialidosis. This case is only hypothesis originating since we did not performen domyocardial biopsy taking in account the high risk of free wall rupture of the left ventricle, but we will follow up the patient with a CMR with spectroscopy.The video shows short axis cine MR from apex to base with evidence of the left ventricular diverticulum.Click here for additional data file.


Echocardiography remains the most frequently performed cardiac imaging investigation and is an invaluable tool for detailed and accurate evaluation of cardiac structure and function. Echocardiography, nuclear cardiology, cardiac magnetic resonance imaging, and cardiovascular-computed tomography comprise the subspeciality of cardiovascular imaging, and these techniques are often used together for a multimodality, comprehensive assessment of a number of cardiac diseases. This paper provides the general cardiologist and physician with an overview of state-of-the-art modern echocardiography, summarising established indications as well as highlighting advances in stress echocardiography, three-dimensional echocardiography, deformation imaging, and contrast echocardiography. Strengths and limitations of echocardiography are discussed as well as the growing role of real-time three-dimensional echocardiography in the guidance of structural heart interventions in the cardiac catheter laboratory. The beginning of the twenty-first century in cardiovascular imaging has been dominated by one theme: “multimodality.” It is currently the buzz word of imaging, as the “traditional” techniques of echocardiography and nuclear cardiology have been complimented by the more “modern” techniques of cardiovascular magnetic resonance (CMR) and cardiac-computed tomography (CCT). Cardiovascular imaging has seen an unprecedented growth in demand, fuelled by technological advances and wider availability of these modalities . Each ofEchocardiography has witnessed dramatic improvements in technology over the past 25 years. Aside from the plain chest X-ray, it remains the primary—and thus most frequently performed—cardiac imaging investigation. A wealth of structural  and haemodynamic  information can be ascertained from one examination. From the one-dimensional M-mode echocardiogram to real-time three-dimensional imaging, an echocardiographic study in 2013 can reveal physiology and pathology in detail previously unimaginable.The numerous modalities within echocardiography furnish the scanning sonographer or physician with a wide array of technologies for complete assessment of cardiac morphology and function. The high temporal resolution of M-mode echocardiography permits accurate depiction of rapidly moving structures and retains relevance in today's practice. 2D transthoracic echocardiography (TTE) forms the basis of visual assessment of cardiac chambers and valves and permits identification of structural abnormalities. Doppler echocardiography, comprising spectral Doppler (pulsed wave and continuous wave) and colour Doppler imaging, identifies the direction, velocity, amplitude, and timing of blood flow through the heart. This information has an enormous number of uses—Doppler echocardiography remains the cornerstone of evaluating the severity of stenotic and regurgitant valve diseases, estimating LV filling pressures , detection of intracavity and subvalvular obstruction in hypertrophic cardiomyopathy, and for identification of intracardiac shunts . Transoesophageal echocardiography (TOE) permits detailed views of most cardiac structures and has a very wide number of indications, from exclusion of atrial appendage thrombus prior to cardioversion through to investigation of suspected cardioembolic stroke . In mostStress echocardiography (SE) has progressed significantly over the past three decades to become one of the most widely utilised imaging techniques for evaluation of patients with known or suspected coronary artery disease (CAD). Once heavily criticised for being too “operator dependent,” several technical advances have dramatically improved the accuracy—and reduced variability—of SE. These include firstly the advent of tissue harmonic imaging, which was shown to improve diagnostic accuracy for detection of CAD over fundamental frequency imaging in exercise  and dobuSE has numerous advantages as a stress technique but also some disadvantages. Its advantages include the ubiquitous availability of echocardiography machines and thus the low infrastructure cost, lack of exposure to ionising radiation, safety, multiple stressor options  or pharmacological (inotropes or vasodilators)), portability, and the substantial supporting evidence base accrued over the past 20 years. The option of performing physiological stress is important, as this should always be the preferred stress technique in an attempt to reproduce patient's symptoms and also determine their functional aerobic capacity. Disadvantages include a lower sensitivity than perfusion techniques and suboptimal image quality in some patients despite use of ultrasound contrast.In the United Kingdom, SE is now—along with myocardial perfusion scintigraphy and CMR—recommended over exercise electrocardiography (ex-ECG) for the investigation of patients with chest pain suspected to be angina pectoris . A randoThere is also now growing appreciation of the potential clinical value of SE for “noncoronary” applications see , in partExercise SE is also helpful in certain patients with mitral valve disease. Patients with mitral stenosis (MS) who have symptoms disproportionate to the degree of MS at rest  should undergo exercise SE—an increase in mean transmitral gradient to >15 mm Hg or pulmonary artery pressure to >60 mm Hg is an indication for valve intervention . The dynAside from valvular heart disease, exercise SE can also be used in patients with hypertrophic cardiomyopathy to reveal dynamic left ventricular outflow tract obstruction  18]. Fi. Fi18]. Three-dimensional (3D) echocardiography is widely perceived as a novel technique, but the initial work on 3D echocardiography dates back three decades , 21. How3D-TTE has numerous proven uses in clinical practice. It has been shown to be superior to 2D-TTE and equal to CMR for assessment of ventricular volumes , cardiacThe most significant advance, however, has been in 3D-TOE . Real-tiThe complex orientation of myocardial fibres—radial, circumferential, and longitudinal—has been recognised for a long time. The theory that tissue motion, as opposed to endocardial excursion, is important in assessment ventricular function is also not new—M-mode echocardiography was used to relate myocardial velocity to ventricular function in the 1970s .E/E′ ratio [E′ is the early motion of the mitral annulus back towards the cardiac base from the apex). The longitudinal function of both ventricles is also assessed with TDI, where S′ represents the peak systolic velocity of the left or right ventricle. These parameters have become routine measurements in clinical practice due to a combination of their reproducibility and diagnostic and prognostic importance.Tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) are techniques that permit detailed analysis of regional as well as global cardiac function through unique temporal and spatial data processing. TDI deliberately filters out the low amplitude, high frequency signals from the blood-pool in order to allow analysis of the high amplitude, and low frequency signals from myocardium itself . TDI is E′ ratio  (where E−1)). In normal myocardial segments, there is shortening in systole (negative strain and strain rates) and lengthening in diastole (positive strain and strain rates) as cardiomyocytes return to their resting state [STE is based on the principle of following (or tracking) the unique “speckle pattern” of a myocardial segment through the cardiac cycle see . One advng state .A wealth of data has been accumulated on the potential clinical value of strain and strain rate assessment in a number of cardiac diseases . Normal Potentially of great clinical relevance is the fact that STE can reveal subclinical LV dysfunction in hearts with apparently normal systolic function, as measured by EF, and thus could have a role in detecting cardiac involvement in systemic diseases , unusualUltrasound contrast agents (UCAs) consist of gas-filled microspheres which display unique acoustic properties when exposed to ultrasound waves. Contrast bubbles resonate when exposed to an ultrasound wave. This is predominantly a nonlinear oscillation  at the ultrasound frequencies used in diagnostic imaging. Microbubbles are several million times more effective at scattering sound than red blood cells, resulting in a greatly enhanced “blood pool” signal . The bloThe first generation UCAs consisted of air surrounded by an albumin shell . UnfortuThere is ample evidence demonstrating that UCAs improve estimation of global  and regiThe majority (90%) of the blood within the myocardial walls reside within capillaries . Thus thThe advances in 3D echocardiography—in particular the advent of a fully sampled matrix array transducer allowing real-time 3D-TOE—has brought the echocardiologist to the forefront of catheter-lab-based procedures in structural heart disease. Real-time 3D-TOE is now considered by many a pre-requisite for guidance of percutaneous treatment of aortic stenosis ), mitral regurgitation , closure of the left atrial appendage and of atrial septal defects (ASDs and PFOs). The incremental value of 3D-TOE over 2D-TOE during TAVI procedures was recently demonstrated in a large single-centre study . Indeed,Intracardiac echocardiography (ICE), performed in the catheter laboratory using single-use percutaneous 2D probes introduced transvenously , is also widely used to guide interventions . Its bigThe echocardiologist performing such studies needs to have a sound grasp of normal cardiac and valvular anatomy and combine quick thinking with speedy manual dexterity. This skill set is not necessarily acquired during conventional training. He/she may be called upon to provide urgent information in case of sudden unexplained patient deterioration . The need for such individuals is likely to be restricted to tertiary units, but in large centres one can imagine such a person spending a significant amount of time in the cardiac catheter laboratories. Appropriate training will be required to ensure that we produce cardiologists capable of performing such studies—hence one can envisage the birth of a super-speciality of “interventional echocardiology.”Echocardiography does have certain limitations, which merit discussion. The greatest advantage of cross-sectional imaging  over echocardiography is the information available on extracardiac structures. The aorta, aortic arch, pulmonary artery, and pulmonary veins are far more clearly seen by these modalities and are often poorly seen or not seen at all by echocardiography. Thus, assessment of pulmonary veins in patients awaiting an atrial fibrillation ablation procedure, assessment of the aortic arch and descending thoracic aorta in patients with chronic aortic dissection or coarctation, and serial assessment of patients with previous coarctation repair, for example, will generally be performed by CMR or CCT. Echocardiography can also suffer from poor image quality, despite the use of ultrasound contrast agents. This is most often seen in patients who are extremely underweight or overweight, but also in patients with chronic airways disease or chest wall deformities . Patients on intensive care units, who are frequently supine and may be mechanically ventilated, also often have challenging TTE images, although TOE can resolve such difficulties. Echocardiography permits accurate assessment of myocardial structure, function and perfusion. Echocardiography is thus in itself a multimodality imaging technique. The field of echocardiography is diverse and encompasses numerous individual techniques—some with established clinical value, whilst others show much promise in research. The expanding role of echocardiography within current clinical practice is underpinned by continual technological advances and justified by the accumulating evidence of clinical value of these techniques when utilised in daily practice.


Further to MitraClip implantation, several additional approaches are developing, to better match with the extreme variability of mitral valve disease. Not only repair is evolving, initial steps towards percutaneous mitral valve implantation have already been undertaken, and initial clinical experience has just started.Mitral valve regurgitation (MR) is often diagnosed in patients with heart failure and is associated with worsening of symptoms and reduced survival. While surgery remains the gold standard treatment in low-risk patients with degenerative MR, in high-risk patients and in those with functional MR, transcatheter procedures are emerging as an alternative therapeutic option. MitraClip Mitral valve regurgitation (MR) is the most prevalent valvular heart disease in the community, its prevalence increasing along with population aging and heart failure.P < 0.0001). Mean follow-up was 6 years. The 10-year survival rate after mitral valve repair was 57%, identical to that of the normal age- and sex-matched US population. Five-year survival was 68% among patients with NYHA class III–IV compared with 85% among those with NYHA class I–II (hazard ratio class III–IV versus class I–II: 2.65). The numbers of observed events for mitral reoperation, heart failure, bleeding, and stroke were 552 of 14,604 (3.7%), 2,681 of 14,604 (18.4%), 1,051 of 14,604 (7.2%), and 1,131 of 14,604 (7.7%), respectively. Advanced preoperative symptoms were strongly associated with 5-year readmission for congestive heart failure after successful mitral valve repair .The Euro Heart Survey dataP = 0.016). Age stratification revealed a significantly better 5-year survival for patients between the ages of 70 and 75 years of 58.6%, compared with 52.9% at the age of 75 to 80 years, and 47.9% at the age of >80 years. Associated co-morbidities  were associated with an increased risk of late death.Seeburger et al. recently reported the single-center experience with 2,053 elderly (defined as 70 years or older) patients who underwent mitral valve (MV) surgical procedures with or without associated procedures.These data support the evidence that comorbidities are the real burden in the successful treatment of elderly patients undergoing MV procedures. In this setting a number of minimally invasive transcatheter techniques are emerging to treat MR in high-risk and elderly patients, as an alternative to conventional surgery. Mitral transcatheter interventions carry the hope of minimizing risks while preserving clinical efficacy of surgical repair and replacement. As such, transcatheter interventions may improve outcomes by reducing risks in elderly patients, with reduced left ventricular function or with co-morbidities, and could open the way for earlier interventions, particularly in the field of FMR.13Multiple technologies and diversified approaches are under development. They can be categorized based on the anatomical and pathophysiological addressed target.All these procedures act directly at the leaflet level with the final goal of improving leaflet coaptation and reduce the effective regurgitant orifice.MitraClip®System . It is the most widely used transcatheter mitral device . The MitraClip system was almost directly derived from the surgical edge-to-edge techniqueThe most advanced technology under this category is the The first MitraClip procedure was performed about 10 years ago.European guidelines assigned an indication class IIb, level of evidence C, signifying that MitraClip may be considered in patients with symptomatic severe MR despite optimal medical therapy, who are judged inoperable or at high surgical risk by a heart-team, and with life expectancy greater than 1 year.A different approach to obtain transcatheter leaflet repair is off-pump adjustable chordal implantation, for which several devices are currently under development.Babic device The MitraFlex  places an anchor in the inner LV myocardium and another on the leaflet via a thoracoscopic transapical approach and connects the two with a synthetic chord; it can also perform an edge-to-edge repair at the same time.The NeoChord The V-Chordal The Percu-Pro  is a space-occupying “buoy” anchored at the LV apex through a transseptal approach that should fill the gap between leaflets. The Thermocool irrigation ablation electrode  delivers, in the context of degenerative disease, radiofrequency energy to the leaflets to provoke shrinking and reduced motion.27Alternative techniques for leaflet repair have been proposed. The Annuloplasty is a fundamental step to achieve effective and durable results after surgery.The coronary sinus (CS) encircles the posterior mitral annulus, and it may allow devices to be delivered to affect indirectly the posterior mitral annulus geometry. Although the CS approach is a consolidated procedure, it has important limitations: the CS is variably located at a certain distance from the mitral annulus (frequently increased in case of severe MR with annular dilation),33CARILLON  is composed of two nitinol anchors  and proximal anchor in the proximal CS) linked by a bridge element PTMA 37A previously investigated device was the Edwards Mitral Cerclage  creates a loop around the mitral annulus and left ventricular outflow tract (LVOT), entering through the CS ostium, passing through the anterior interventricular vein and returning near the CS ostium, perforating the myocardium either coming out in the right ventricle and passing through the anterior tricuspid commissure, or directly coming out through the septum in the right atrium; the loop is then tightened and secured near the CS ostium.A more aggressive concept has been developed by the National Institute of Health. The These technologies force septo-lateral annular reduction through the approximation of two devices connected by a bridge. The reduction of this dimension is expected to be particularly important for MR reduction and in the functional setting.39Ample PS3 System  consists of a CS anchor (“T bar”) and an interatrial septal anchor at the level of the fossa ovalis linked by an adjustable bridge; the device is designed for specific septal-lateral reduction at the P2 level. Clinical experience is limited to a temporary implant in two patients, in whom the device appeared safe and effective.40The i-Coapsys  is the percutaneous version of the surgical Coapsys, a surgical device to reshape the left ventricle. Large-scale data from the surgical RESTOR-MV trial suggest that, besides the MR reduction, the Coapsys can produce a significant LV restoration effect,The Myocor BACE  is a wide band with an inflatable chamber that is slipped externally around the base of the beating heart without cardiopulmonary bypass. The chamber can be inflated by saline through subcutaneous ports, and their volume can be adjusted intra- and postoperatively, thus remodeling the mitral valve annulus and sub-valvular apparatus. The surgical device seems effective in functional MR reduction,The Mardil The implantation of devices directly into the mitral annulus more closely reproduces surgical annuloplasty. Only the posterior annulus is usually targeted, since the anterior annulus remains a more challenging structure due to the close vicinity of the aortic valve. Annular calcification, circumflex artery, and the potential for leaflet damage remain of concern for direct annuloplasty approach.Accucinch System  is designed to implant a series of anchor elements under the posterior mitral annulus, in the sub-valvular space, from trigone to trigone. All anchors are connected by a cable that is used to cinch the annulus and the basal portion of the left ventricle. The Accucinch is delivered through a retrograde transfemoral route. The feasibility and the safety of the device have been shown in 10 patients, with no conversion to surgery and no 30-day major events; however, mitral regurgitation reduction was inconsistent, most probably due to the challenge of implanting the anchors from trigone to trigone and close enough to the annulus .The Mitralign device  also uses a transfemoral retrograde approach to deliver pairs of pledgets connected with a suture. Each pledget pair can be cinched to achieve selective plications of the annulus. More than two pairs of pledgets can be implanted along the posterior annulus. A prospective, single arm feasibility and safety study is on-going to obtain CE mark. Available data reported that 36 patients have been enrolled, and 24 treated; 5 of them have reached 1 year follow-up. Although final results are not yet available, in the first 15 patients no procedural death and one pericardial tamponade occurred. After 1 year an average reduction of one grade of MR was observed along with minimal reduction in LV dimensions .The Cardioband System  is a transcatheter-implantable surgical-like ring  and thrombus formation.QuantumCor is composed of a malleable radiofrequency probe with seven electrodes. Available preclinical data on sheep showed significant antero-posterior annular reduction together with some degree of MR decrease and no sign of damage of surrounding structures.46The ReCor  device is a balloon catheter with a cylindrical piezoelectric ceramic transducer located towards the distal end, introduced in the left atrium through transseptal approach. The transducer converts electrical energy to acoustic energy, which is then delivered radially through a balloon inflated with a contrast-saline mixture at the mitral valve annulus site, without contact. In a series of 33 dogs, one death due to energy-induced ventricular fibrillation occurred and modest annular diameters reduction was observed, although no nearby structure was damaged.47The Paravalvular leakage is a complication of prosthetic valve implantation occurring in 5%–15% of cases. Surgical re-operation is associated with higher morbidity and mortality and does not always guarantee a definite solution since prostheses detachment recurrence is not infrequent.Although it remains more challenging than aortic leak closures, in recent years transcatheter mitral leak closure had emerged as a new valid option. Procedural success rate has improved over the years, ranging from 60% to 90% in the different series, with different kinds of Amplatzer occluders .49Although repair is currently the leading method to treat mitral valve regurgitation in surgical practice, replacement is associated with a number of potential advantages, particularly suitable for a transcatheter approach: the procedure can be more reproducible; it can be applied to the majority of patients, and may provide more predictable results. However, mitral valve anatomy brings unique and complex features that make transcatheter valve implantation much more challenging than in the aortic position. The mitral annulus is asymmetrical, non-tubular, and frequently not calcified, so that the main problem for any kind of mitral prosthesis remains anchoring, since radial force would not be effective and could cause serious complications. Left-ventricle outflow tract obstruction and aortic valve deformation  are also major concerns. Moreover, leaks in the mitral position would be poorly tolerated, both hemodynamically and in terms of hemolysis because of the elevated pressure gradients. Mitral valve implantation is not yet routinely available in the clinical setting, but several devices are currently under development.CardiAQ  prosthesis has been the first to reach human implantation in 2012, although only one case has been reported so far . It is transseptally delivered and self-anchoring without the need of radial force. The first patient showed early good implantation and hemodynamic result, but died after 3 days due to multi-organ failure. Autopsy did not reveal any prosthesis issue.The Lutter prosthesis  has been successfully implanted transapically in numerous porcine models. The latest version of the prosthesis is made of a flat ring  connected at a 45° angle to the tubular stent that accommodates a 28-mm trileaflet bovine pericardial valve; between the base of the stent and the apex, neo-chordae act as ventricular fixation system. A waterproof membrane is sutured in the atrial ring and over the ventricular component to guarantee sealing, minimize paravalvular leakage, and allow easier repositioning. In the latest animal series the prosthesis was implanted with optimal results and without any complications in 5/6 animals.50The Tiara  is a transapical self-expandable valve; its atrial portion is designed specifically to fit the saddle-shaped mitral annulus: the D-shape matches the natural shape of the mitral orifice and prevents impingement of the left ventricular outflow tract (LVOT). The ventricular portion of the device comprises a covered skirt to prevent paravalvular leak and three anchoring structures to capture the fibrous trigones of the posterior mitral leaflet. First, the atrial portion is deployed and oriented; the valve is then pulled downward to seat the atrial flange firmly on the floor of the atrium, and the three ventricular anchor structures are deployed. Finally the ventricular skirt and valve leaflets are released from the catheter, allowing the device to begin functioning. In all stages until the final step of ventricular deployment, the valve is retrievable and repositionable. Tiara valves were implanted with early successful results in 29/36 domestic swine.The Endovalve-Herrmann prosthesis  is implanted from the left atrium via a right mini-thoracotomy on a beating heart. The device is a foldable nitinol structure that attaches to the native valve with specially designed grippers, is fully valve sparing, and repositionable before release. Animal modelshave been successful, and a true percutaneous version is planned.The CardioValve  is also currently delivered off-pump through the left atrium and is currently in preclinical animal development and valve in ring (ViR) procedures are performed routinely (on an off-label basis). The previously implanted bioprosthesis or ring provides an ideal support for the successful implantation of the currently available transcatheter aortic valve prostheses, which commonly use radial force . Most prData from the Global Registry recently  reported a 30-day and 1-year mortality of 12% and 25%, respectively, and an impressive improvement in symptoms early after the procedure. The most used access has been the transapical (85%), but transatrial, transjugular, and transfemoral approaches have also been performed.Transcatheter mitral valve repair with the MitraClip System has proved excellent safety results and good efficacy results in high-risk patients and is already a real alternative to surgery in such a population. Furthermore, MitraClip is evolving as a device therapy for congestive heart failure, targeting patients who were not referred for surgery in the past.To expand further the field of transcatheter mitral valve treatment, several devices, addressing many different anatomical and pathophysiological concepts , are under development.Transcatheter mitral techniques should be considered the natural and inevitable evolution of mitral surgery. In the context of such a wide spectrum of different available therapies, the patient-centered care and the heart-team approaches are fundamental to provide effective and individualized treatments.


Pulmonary hypertension (PH) leads to progressive right ventricular (RV) dilatation, hypertrophy, and systolic dysfunction. PH is also associated with the presence of late gadolinium enhancement in the interventricular septum (IVS). Post-contrast T1 mapping is a previously validated non-invasive technique for the quantification of extracellular volume increase as a surrogate of diffuse interstitial fibrosis. The aim of our study was to evaluate the presence of septal fibrosis in PH patients with T1 mapping, and to investigate potential correlations with RV performance and hemodynamic status.24 patients with known or suspected PH of various etiologies (excluding left heart disease) were included in the study. Cardiac magnetic resonance (CMR) was performed on a 3-T scanner and the IVS T1 time was quantified offline by an independent and blinded observer on a Look-Locker sequence acquired 5-15 minutes after the infusion of 0.19±0.03 mmol/kg of gadopentetate dimeglumine. End-diastolic RV free wall thickness was measured on a cine sequence at the left ventricular outflow tract view. Twenty (83%) patients additionally underwent right heart catheterization. Using Pearson r coefficients, septal T1 times were correlated with RV volumes and ejection fraction as derived from CMR, and cardiac output and pulmonary pressures and vascular resistance obtained invasively.The mean age was 53.8±11.9 years and 29.2% of the patients were males. PH (mean pulmonary artery pressure >25 mmHg) was present in 92%. In patients with PH, the etiology was pulmonary arterial hypertension in 63.6% (36.4% idiopathic PH), connective tissue disease in 9.1%, lung disease in 18.2%, and miscellaneous in 9.1%. Patients with shorter IVS T1 times showed more severe RV dilatation, RV hypertrophy and systolic dysfunction (Figure A reduction in post-contrast T1 times in the IVS, possibly indicating increased interstitial fibrosis, correlates with RV structural and functional impairment and hemodynamic severity in PH. T1-mapping may constitute a novel approach for the evaluation of cardiac adaptation to pressure overload.None.


Enlarged Virchow-Robin spaces (EVRS) are considered to be a sign of cerebral small vessel disease. Hypertension is an important risk factor for cerebral small vessel disease, whereas ambulatory blood pressure (BP) is the strongest predictor of hypertension-related brain damage. However, the association between ambulatory BP levels and EVRS has never been investigated. The aim of this study was to determine the association between ambulatory BP levels and EVRS. In 143 first-ever lacunar stroke patients, we performed 24-h ambulatory BP monitoring after the acute stroke phase. On brain MRI we counted EVRS in the basal ganglia and the centrum semiovale. We graded the number of EVRS at each level into a three-category severity scale. We assessed the association between BP levels and EVRS by ordinal regression analysis. After adjusting for age, sex, extensive white matter lesions, and asymptomatic lacunar infarcts, higher day systolic , day diastolic  and 24-h diastolic  ambulatory BP levels were associated with EVRS at the basal ganglia level. No relation was found between ambulatory BP levels and EVRS in the centrum semiovale. Higher day ambulatory BP levels are associated with EVRS in the basal ganglia. This association was independent of the presence of extensive white matter lesions and asymptomatic lacunar infarcts. Our results imply that basal ganglia EVRS should be regarded as a separate manifestation of BP-related brain damage. Virchow-Robin spaces are perivascular spaces that surround the perforating vessels in the brain. These perivascular spaces are continuous with the perivascular space around the arteries in the subarachnoid space and likely play a role in the drainage of interstitial fluid from the brain , 18. WheEVRS are considered to be a sign of cerebral small vessel disease since they are associated with the lacunar stoke subtype, white matter lesions and asymptomatic lacunar infarcts , 19. HypFor a lacunar stroke research project, we prospectively recruited patients who presented with a first-ever lacunar stroke at Maastricht University Medical Centre, the Netherlands, from May 2003 to January 2008 and at Orbis Medical Centre Sittard, the Netherlands, from September 2004 to April 2007. The present study was a sub-study of this lacunar stroke research project. As described earlier , we defiMR images  were obtained within 6 months after stroke (mean 40.6 ± 42.6 days). We performed standard axial T2-weighted fast spin echo  and axial fluid attenuated inversion recovery (FLAIR)  images, all with slice thickness of 5 mm and gaps of 0.50 mm. We defined EVRS as round, oval, or linear-shaped structures that follow the orientation of the perforating vessels with a diameter <3 mm, a smooth margin, and absence of mass effect. On T2-weighted MR images, EVRS have a signal intensity equal to cerebrospinal fluid and (if visible) they appear hypointense on FLAIR images without a hyperintense rim to distinguish them from cavitated lacunar infarcts . EVRS weAmbulatory BP monitoring  was performed after the acute stroke phase, between 1 and 6 months post-stroke (mean 101.2 ± 42.3 days). Measurements over a 24-h period were obtained every 15 min during the day 07:00–23:00 hours) and every 30 min during the night (23:00–7:00 hours). Patients continued their prescribed medication, and we registered the use of antihypertensive drugs. Patients kept a record of rising and retiring times [:00 hoursn (%), as mean ± SD for parametric data, or as median (range) for nonparametric data. Differences between groups were determined using Chi-square (χ2) test or one-way ANOVA where appropriate. We assessed the relationship between the various BP levels and EVRS by ordinal regression analysis adjusting for age and sex (model 1). We tested whether age was an effect modifier of the association between BP and EVRS by adding the relevant interaction term into the model. As p values of the interaction term for each of the BP variables were all >0.05, we further omitted the term. We then adjusted for the presence of asymptomatic lacunar infarcts and extensive white matter lesions (model 2). Extensive white matter lesions were defined as (early) confluent deep white matter hyperintensities (Fazekas score 2 and 3) and/or irregular periventricular hyperintensities extending into the deep white matter (Fazekas score 3) on FLAIR and T2-weighted images. We used these Fazekas scores because they are histopathologically related to cerebral small vessel disease [p < 0.05.Statistical analysis was performed using SPSS . Data are presented as  disease . Finallyp < 0.001) and more often male . By applying the same criteria, we recruited 29 patients from Orbis Medical Centre Sittard (number and characteristics of non-included patients were not listed), which totals 143 patients.Of 281 first-ever lacunar stroke patients at Maastricht University Medical Centre, 35 were excluded because of carotid artery stenosis or possible cardioembolic source , 116 refused to participate or had contra-indications for MRI and 16 were excluded because of inadequate MRI or ambulatory BP monitoring data, leaving 114 patients for the present study. Included subjects were younger .Table Ambulatory BP levels for the three EVRS categories at the BG are presented in Table Ambulatory BP levels for the three EVRS categories at the CSO are also presented in Table We studied the association between BP analyzed as a continuous variable, using ambulatory BP monitoring, and EVRS. We found that higher day systolic, day diastolic, and 24-h diastolic ambulatory BP levels are associated with higher numbers of EVRS in the BG in first-ever lacunar stroke patients. This association was independent of age, sex, the presence of extensive white matter lesions, and the presence of asymptomatic lacunar infarcts.Recently Zhu et al. found an association between the severity of EVRS (in both the BG and CSO) and hypertension in a large population-based cohort of elderly individuals . PreviouSimilar to other studies , 19, 31,Elevated BP causes endothelial dysfunction , 27. RecMost ambulatory BP-monitoring studies report an association between white matter lesions and/or lacunar infarcts and day as well as night BP , 22, 26.The main strength of our study is that we used ambulatory BP monitoring instead of office BP measurements. Furthermore, we collected a homogeneous group of lacunar stroke patients, for which there was no other cause than cerebral small vessel disease. In this group, EVRS are more prevalent than in the general population, which makes this group very suitable for studying the association between BP and EVRS. However, our study also has some limitations. First, we found a linear relation of higher age and higher numbers of EVRS. After correction for age, the associations of BP levels and EVRS were significant, indicating that the association is not completely determined by an age effect. However, it is impossible to completely cancel out other age-related effects on BP. Second, our patient selection favors younger, less disabled patients, able to undergo MRI. However, this selection bias would probably lead to an underestimation of the association between EVRS and BP levels. Third, this is a cross-sectional study. Results of ambulatory BP monitoring represent the actual BP level without accounting for BP level, course, duration, and treatment in the past. Besides, we cannot account for a possible effect of the symptomatic lacunar infarct on BP levels, although we performed ambulatory BP monitoring after the acute stroke phase. Longitudinal studies are needed to investigate the progression of EVRS in relation to BP levels. Fourth, we did not use diffusion-weighted imaging to confirm the acute lacunar infarct, and therefore we cannot exclude that we erroneously classified an asymptomatic lacunar lesion as the symptomatic one. However, because all patients had a distinct clinical lacunar stroke syndrome, we feel that this did not lead to unrightfully included patients.In conclusion, we found an independent association between higher day systolic and diastolic BP levels and the number of EVRS in the BG. Our results imply that EVRS are a separate manifestation of BP-induced brain damage and support the hypothesis that EVRS in the BG should be regarded as a separate manifestation of cerebral small vessel disease.