We summarize the best evidence for statins in the prevention and treatment of heart failure.In patients with cardiovascular risk factors or established atherosclerotic cardiovascular disease (but without heart failure), statins reduce the risk of incident heart failure—mainly by preventing myocardial infarction although an additional benefit from reducing myocardial ischemia cannot be excluded. However, in patients with established heart failure, statins do not reduce the risk of cardiovascular death, which is mainly caused by pump failure and ventricular arrhythmias. Retrospective analyses, however, suggest that statins may reduce the rate of heart failure hospitalization and atherosclerotic events .Statin therapy should probably be continued in patients with coronary artery disease developing heart failure, although the weak evidence and small benefit may not justify the use of this treatment in very elderly patients with a short life expectancy and in which polypharmacy is a problem. Heart failure (HF) is a clinical syndrome characterized by a constellation of symptoms that may be accompanied by signs caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress . Two priHF can be prevented by treatment of risk factors such as hypertension, obesity, and diabetes. Other treatments are also effective in slowing or preventing the development of HF after cardiac damage has occurred, e.g., the use of angiotensin-converting enzyme inhibitors after myocardial infarction (MI).There is a recognized “cholesterol paradox” in this cardiac condition. That is, although raised plasma cholesterol is a causal risk factor for coronary artery disease (CAD), low serum total cholesterol is associated with poor prognosis in patients with established HF (in contrast to patients without HF) –9. The qIt is well established that HMG-CoA reductase inhibitors (statins) reduce CAD events in patients with and without diagnosed cardiovascular (CV) disease. Clinical trial outcome data have been subject exhaustively to meta-analysis that has reinforced the findings of individual studies and “filled in” any gaps in the determination of efficacy in sub-groups in the population , 23. TheSome of these trials do allow us to look at incident heart failure. Collectively, these trials provide “reasonable evidence” that statin use can prevent or delay the onset of HF –41. Thisp = 0.022). Incident HF not preceded by MI was also less common in pravastatin-treated patients (68 vs 81), although the difference was not significant (p = 0.22). This is consistent with the finding in the meta-analysis above that statins reduce HF risk through mechanisms additional to prevention of acute MI. Serial measurement of biomarkers such as NT-proBNP might have provided more support for this hypothesis but, unfortunately, NT-proBNP was measured only at 1 year after randomization in WOSCOPS [Retrospective examination of individual trials also provides supportive evidence for a beneficial effect of statins on HF prevention. In 4S, simvastatin reduced incident HF by 19% , whilst  WOSCOPS .Fig. 2InCholesterol-lowering therapy with statins is not indicated in patients with moderate to severely symptomatic HF (New York Heart Association (NYHA) class III-IV) according to the 2011 European Society of Cardiology (ESC)/EAS dyslipidemia guideline  and the Not satisfied with the above trial evidence, a number of investigators have attempted to examine if statin therapy has any role in patients with established HF by examining randomized trials in a number of meta-analyses. For example, Zhang et al. reported no significant reduction from statin therapy for all-cause death, CV death, or rehospitalization for HF, but a non-significant trend to lower non-fatal MI . NotablyStatins are believed to lower CAD by stabilizing atheromatous plaques, reduction of atheroma volume, and prevention of formation of new atherosclerotic lesions resulting in fewer MIs and less associated cardiac tissue damage. This may be the main way statins lower incident HF. We looked further at this in the long-term follow-up of WOSCOPS Fig.  where, aP = 0.79) in a meta-analysis of 23 RCTs of 42,151 participants [n = 59) and the 95% confidence interval around the estimate of treatment effect wide  [PCSK9 inhibitors have not been found to affect HF hospitalisation  . There aThere is robust evidence that in addition to lowering coronary heart disease (CHD), statins also lower risk for incident HF both in the medium and long term, although the extent of risk reduction is modest and far lower than the comparable benefits on CHD outcomes. By contrast, in patients with established HF, best evidence from two landmark trials does not support improved clinical outcomes with statins. Although statins may also lessen the chances of subsequent CAD events in HF patients , few patients with HF actually die from acute CAD events and existing evidence is far from conclusive. Nevertheless, most clinicians generally do not stop statins in patients already prescribed these drugs and who subsequently develop HF. However, more judicious use of statins in the elderly HF patient with polypharmacy and a shorter life expectancy appears to be sensible.


T2* weighted imaging. QSM values of GP and SN were 0.19 and 0.29 ppm, respectively. His twin brother showed almost the same imaging findings. Follow-up MRI revealed increase of QSM value in GP and SN.We present the first case of twins with infantile neuroaxonal dystrophy evaluating brain iron deposition using quantitative susceptibility mapping (QSM). A 6-year-old boy who was normal at birth had psychomotor regression and hypotonia from 2-years-old. Brain MRI showed low intensity areas in globus pallidus (GP) and substantia nigra (SN) on  Patients with INAD typically exhibit psychomotor regression and hypotonia before the age of 2 years and develop pyramidal and extrapyramidal features at a later stage; the neurological prognosis of these patients is poor. Genetically, 80% of children with INAD have mutations in PLA2G6.T2 and T2* weighted MRI, which indicates abnormal iron deposition. Cerebellar atrophy can also be observed and it typically precedes iron deposition. Notably, MRI may be normal at the early stage, and radiological findings and symptoms do not always correlate on conventional MRI.2Radiologically, the globus pallidus (GP) and substantia nigra (SN) of INAD patients appear hypointense on Quantitative susceptibility mapping (QSM) can be used to evaluate the behavior of biomarkers, including iron, calcium, and myelin. To the best of our knowledge, the assessment of INAD using QSM has never been reported; therefore, we believe it is valuable to present the results of our evaluation of QSM in a pair of twins with INAD.C>T mutation in p.Q173X transition and c.1634A>G mutation in p.K545R transition. They were diagnosed with infantile-onset PLA2G6-associated neurodegeneration, also known as INAD.6-year-old monozygotic twin boys were born at term with no complications. They presented with psychomotor regression and hypotonia at 2 years old, spasticity at 4 years old, and ataxia at 5 years old. Both patients had almost the same clinical course. Laboratory results were as follows: blood levels of pyruvic acid and lactate were normal, cerebrospinal fluid analysis was negative for Human T-lymphotropic virus one antibody, and direct sequencing of the PLA2G6 gene revealed c.517T1-, T2-, and T2* weighted imaging. Three-dimensional (3D) gradient multiecho was performed for QSM reconstruction with T1, T2, and T2* weighted images. 3D gradient multiecho was performed for QSM reconstruction with repetition time (TR) = 53.4 ms, echo time (TE) = 13 ms, 17.9 ms, 22.9 ms, 27.8 ms, 32.8 ms, flip angle = 10°, slice thickness = 1.2 mm, 136 slices, band width = 244 Hz/pixel, field of view (FOV) = 24 × 24 cm, matrix size = 384 × 256. QSM images were reconstructed using the morphology enabled dipole inversion method.3,4Brain imaging was performed using a 3 T MRI scanner . Patients underwent T2 weighted images as a reference. T2 weighted  using QSM. In that study, the average QSM values were 0.05 ppm in the GP and 0.04 ppm in the SN.8Our cases showed higher QSM values in the SN and GP than do normal children. In normal subjects, cerebral iron deposition increases with age, and some reports have shown correlations between age and susceptibility measured by QSM.9 Brain iron deposition has been quantified using QSM in patients with neurodegenerative diseases, such as Parkinson’s disease and multiple sclerosis, as well as other less common conditions.10,11 For example, Ishiyama et al measured QSM values in two patients with beta-propeller protein-associated neurodegeneration.12 QSM values in the GP and SN were 0.430 and 0.540 ppm in Patient 1 and 0.381 ppm and 0.425 ppm in Patient 2, respectively, and all values were higher than those for controls. It has also been reported that two patients with pantothenate kinase-associated neuropathy and PANK2 mutations have high QSM values in the GP and SN.13Quantitative imaging is an important tool that can be used as a biomarker for early diagnosis, prognostic prediction, and therapy evaluation.Our results reveal that QSM can be used to evaluate iron deposition in patients with INAD. More detailed studies are required to evaluate the correlation between the QSM value and symptoms of efficacy of therapy.T2 or T2* hypointensity of the GP and SN are the most common characteristics, while cerebellar atrophy, cerebral and cerebellar white matter abnormalities, and hypertrophy of the clava may be observed.INAD is a rare disease that causes iron deposition in the brain. On MRI, QSM showed higher iron content in the GP and SN in patients with INAD than in normal subjects, and follow-up MRI showed an increase in QSM values due to iron deposition. Therefore, QSM could be used for the quantitative assessment of disease progression and therapy response in the future.


In order to increase the responder rate to CRT, stimulation of the left ventricular (LV) from multiple sites has been suggested as a promising alternative to standard biventricular pacing (BIV). The aim of the study was to compare, in a group of candidates for CRT, the effects of different pacing configurations—BIV, triple ventricular (TRIV) by means of two LV leads, multipoint (MPP), and multipoint plus a second LV lead (MPP + TRIV) pacing—on both hemodynamics and QRS duration.Fifteen patients  with permanent AF  were selected as candidates for CRT. Two LV leads were positioned in two different branches of the coronary sinus. Acute hemodynamic response was evaluated by means of a RADI pressure wire as the variation in LVdp/dtmax.p < 0.001). Bonferroni post-hoc analysis showed significantly higher values during all pacing configurations in comparison with the baseline; moreover, higher values were recorded during MPP and MPP + TRIV than at the baseline or during BIV and also during MPP + TRIV than during TRIV. Mean QRS width decreased from 178 ± 25 ms at the baseline to 171 ± 21, 167 ± 20, 168 ± 20, and 164 ± 15 ms, during BIV, TRIV, MPP, and MPP-TRIV, respectively (p < 0.001).Per patient, 2.7 ± 0.7 veins and 5.2 ± 1.9 pacing sites were evaluated. From baseline values of 998 ± 186 mmHg/s, BIV, TRIV, MPP, and MPP-TRIV pacing increased LVdp/dtmax to 1200 ± 281 mmHg/s, 1226 ± 284 mmHg/s, 1274 ± 303 mmHg, and 1289 ± 298 mmHg, respectively (In patients with AF, the acute response to CRT improves as the size of the early activated LV region increases. A selected group of patients with systolic heart failure (HF) and prolonged QRS may benefit from Cardiac Resynchronization Therapy (CRT) , 2. HoweFifteen consecutive patients with permanent AF and indications for the implantation of a CRT-device, in accordance with the European Society of Cardiology/European Heart Rhythm Association (ESC/EHRA) guidelines , were enIn our center, the dual LV site technique is part of common practice in AF patients who are candidates for CRT. We usually optimize the best pacing site during the CRT implantation procedure by means of Q-LV and hemodynamic measurements. The implanting method was described in our previous manuscript . BrieflyPacing sites were classified as anterior, antero-lateral, lateral, postero-lateral, and posterior segments (in the left anterior oblique view) and as basal, mid, and apical ventricular segments (in the right anterior oblique view), in accordance with the scheme established by Singh et al. .Suitable pacing sites were systematically screened by measuring the local electrical delay (Q-LV) during intrinsic activation of the LV, by means of a BARD Labsystem Pro EP V2.4a , and the LVdp/dtmax by means of a Certus Pressure Wire and PhysioMon software  during all pacing configurations and during intrinsic rhythm. LVdP/dtmax at baseline and during the different pacing protocols was calculated over an interval of 15 s; premature ventricular contractions were eliminated electronically. A period of 30 s was allowed to elapse after any change in pacing settings or lead position to allow hemodynamic stabilization. To minimize the impact of respiration and physiological variation, each 15-s LVdP/dtmax value was measured during three separate recordings for each test configuration [TM 1258T, St. Jude Medical), was then implanted, usually in an anterior CS vein, and all the measurements were repeated in order to obtain all the possible combinations of pacing between the two leads. We started with BIV pacing with the proximal or distal dipole of the quadripolar lead , then TRIV , then MPP (RV + LV1 + LV2) and finally TRIV plus MPP (RV + LV1 + LV2 + LV3) in every vein . With the intention to obtain 100% of ventricular capture, the pacing protocol was set to 10 beats above the basal heart rate . Twelve-lead QRS morphology was examined beat by beat in the EP system in every pacing setting by an expert electrophysiologist to confirm continuous capture and avoid fusion beats. The first step was to place the quadripolar lead  in every single vein available for cannulation. As per protocol, in every vein we collected data on the Q-LV interval measured from the proximal dipole, defined as LV1 , and from the distal dipole, defined as LV2 (electrodes D1-M2 inter-dipole length 20 mm); we also assessed the hemodynamic effect by measuring the LVdp/dtmax at every site. A second bipolar lead, defined as LV3 . TRIV was obtained by connecting the bipolar LV lead to the atrial channel of the PSA, and by programming the atrio-ventricular delay to the minimum available value of 25 ms. The RV-LV delay was always set at 0 ms. During MPP, the LV1 and LV2 of the quadripolar lead were paced simultaneously from the LV output of the pacing system analyzer by means of a custom-made epsilon-shaped adapter. TRIV+MPP was obtained by combining the previous configurations.The two LV leads were implanted definitively, as per protocol in our center. The bipolar LV lead was connected to the atrial port of the device and programmed with the shortest available AV delay (25 ms).Our aim was to evaluate the improvement in ventricular function, as estimated by the change in LV-dP/dtmax and QRS-width from the basal measurement, obtained by switching the cardiac pacing protocol from single-site BIV, TRIV, MPP to MPP + TRIV pacing in the same subject in a one-arm (intra-patient) study. The instrumental data collected were tabulated along with topographic and protocol information and patients’ clinical characteristics.We used the “repeated measures analysis of variance” to estimate variations in within-subject measurements of LVdp/dtmax and QRS-width; the Greenhouse-Geisser adjustment was applied to degrees of freedom, and equal weights were attributed to measurements. The Bonferroni correction was used for pairwise planned comparisons between the pacing protocols.The analyses were conducted on “all measurements” collected from patients (78 measurements).The implantation of two LV leads was successfully performed in all patients. No procedure-related complications were reported. The characteristics of the patient population are shown in Table The mean procedural time was 174 ± 27 min, and the total fluoroscopy time was 36 ± 8 min. On average, 2.7 ± 0.7 veins per patient were cannulated and 5.2 ± 1.9 pacing sites were evaluated.The final positions of the LV pacing leads are reported in Table p < 0.001 followed by Bonferroni post-hoc analysis). Figure Conventional BIV pacing resulted in a 202-mmHg/s increase in LVdp/dtmax (from 998 ± 186 to 1200 ± 281 mmHg/s). TRIV pacing caused a small, non-significant, further increase to 1226 ± 284 mmHg/s, whereas MPP and MPP + TRIV increased LVdp/dtmax significantly above the BIV pacing level , MPP creates a more baso-apically oriented zone. It is interesting that the orientation of the early activated zone does not seem to matter, as both approaches result in similar hemodynamic and electrophysiological benefit in comparison with conventional BIV pacing.Finally, the observation that the combination of TRIV and MPP further improves CRT response is a further argument in favor of the idea that increasing the early activated region on the LV increases the effect of CRT. This may raise the question of what the optimal size of this early activated region may be. However, animal studies indicate that the additional hemodynamic benefit of pacing more than four sites may be small .The idea of pacing from multiple sites has already been expounded upon by various authors , 7, 19, In a study by Behar , 19 patiThe introduction of quadripolar technology has enabled a larger area to be paced from a single multipolar lead, and initial experiences documented significant improvements in hemodynamic , 9 and mThe question of whether acute improvement in LVdP/dtmax predicts long-term clinical benefit needs more evidence. However, our previous experience  indicateThe present study provides the first head-to-head comparison between the two modalities of pacing a larger area, multisite (TRIV) and multipoint pacing (MPP). The finding that MPP yields at least the same hemodynamic benefit as TRIV pacing suggests that MPP may be preferred to TRIV pacing, as the implantation technique of MPP technology is as simple as that of a bipolar LV lead and avoids placement of a second lead, with its accompanying increased risk of dislodgement.This was an acute, single-center, non-randomized study; the patient sample size was limited, and the pacing protocol configurations were conditioned by the limitations of the currently available technology. Moreover, as outlined in the methods section, due to the long protocol procedure and in order to reduce as much as possible the duration of the implant, we did not randomize the pacing protocol series. As result, the lack of a randomization of the protocol might have influenced the hemodynamics by introducing linear effects. Furthermore, the acute hemodynamic results may not lead to long-term clinical benefit. The implications of this study should be confirmed in a larger, randomized, prospective, multicenter, long-term study.Pacing from a wider area, as in TRIV and MPP, increases electrophysiological and hemodynamic benefits in comparison with standard BIV pacing, and a further improvement is achieved by TRIV + MPP. This suggests that a larger early activated region increases the efficacy of CRT. In accordance with the concept that “less is more,” it appears that MPP, which requires only one lead, is probably the most convenient technique in terms of risk/benefit ratio.


The incidence of mitral regurgitation (MR) is approximately 1.7% in the developed world, and this increases to more than 10% in patients aged over 75 years. Functional (or secondary) mitral regurgitation (FMR) is defined as poor leaflet coaptation and tethering secondary to either ischemic or non-ischemic left ventricular (LV) dysfunction and dilatation. FMR is more common than degenerative (or primary) MR and is associated with significantly worse outcomes in patients with heart failure, post myocardial infarction and following coronary artery bypass graft surgery. Patients with severe degenerative MR have excellent outcomes with surgical repair, however the benefits of surgery in FMR are less clear. Although annuloplasty is associated with a lower operative mortality compared to replacement, the recurrence rate of mitral regurgitation is high in patients with FMR and neither surgical repair or replacement have been shown to reduce hospitalisation or death in FMR. Furthermore, nearly half of patients are deemed too high risk for surgery and therefore most patients are managed conservatively and there remains an unmet clinical need. Transcatheter mitral valve interventions are an emerging alternative for those at high surgical risk. This mini review focuses on indirect mitral annuloplasty: anatomical considerations, patient selection, current devices, implantation techniques and the associated clinical outcome data. The incidence of mitral regurgitation (MR) is ~1.7% in the developed world, and this increases to more than 10% in patients aged over 75 years –4. PatieThe coronarysinus (CS) drains the majority of blood from the heart. It arises from the termination of the great cardiac vein, running through the left atrioventricular groove, emptying into the right atrium. The CS lies in close anatomical proximity to the mitral annulus  16). In. In16). Importantly, the circumflex coronary artery lies within close proximity of both the CS and mitral annulus. Studies have demonstrated that the vessel exhibits a deep course between the CS and mitral annulus in up to two thirds of patients , 20. TheThe complexity of the mitral valve apparatus necessitates patient-specific tailoring using the appropriate reparative technique because no single transcatheter technology “fits-all.” Assessment of suitability prior to annuloplasty is crucial and decision with regard to repair technique should be based on clinical and anatomical characteristics. When selecting the appropriate transcatheter therapy, it is important to first establish the primary mechanism of MR, it's severity and the imaging criteria that will predict procedural success. Traditionally, annuloplasty, either with direct or indirect percutaneous techniques are favored where annular dilatation is the predominant pathology. Surgical features of annuloplasty failure should also be taken into consideration, these include but are not limited to, increased annular dimensions (≥3.7 cm), increased systolic tenting height, complex jet(s) of mitral regurgitation and lateral wall motion abnormalities , 22. FurThe Carillon coronary sinus implant (Cardiac Dimensions) is currently the only CE approved indirect annuloplasty device undergoing clinical use. The main advantage is its simplicity and safety profile, and more than 700 procedures have been performed worldwide to date . The CarTwo clinical trials of safety and feasibility have been conducted to date. The Carillon Mitral Annuloplasty Device European Union Study (AMADEUS) study successfully implanted devices in two thirds of patients selected to undergo the procedure. Patients in the AMADEUS study had only modest reductions in MR at 6-month follow up . The TraP = 0.03), the numerical reduction of MR was even more notable in the per protocol analysis . Furthermore, no significant difference in major adverse cardiovascular and cerebrovascular events was demonstrated between the Carillon and sham control cohort. The CARILLON FDA trial (NCT03142152) of 450 patients randomized to the CARILLON device with optimal heart failure therapy vs. optimal heart failure therapy alone is currently open to recruitment in the United States.More recently, the outcomes of the REDUCE-FMR trial of efficacy and safety of Carillon implantation vs. sham control in patients with functional MR secondary to dilated ischemic or non-ischemic cardiomyopathy have been presented . The priThe ARTO system  is comprised of two anchors deployed over the lateral wall of the left atrium via the CS and in the atrial septum, connected by a tether that traverses the left atrial chamber . Erglis 2 to 68.5 ± 21.4 ml/m2, and LV end-diastolic volume index from 118.7 ± 28.6 ml/m2 to 103.9 ± 21.2 ml/m2. Mitral annular AP diameter decreased from 45.0 ± 3.3 mm to 38.7 ± 3.0 mm with an associated improvement in New York Heart Association (NYHA) functional class (p < 0.001) and reduction in mitral annular AP diameter . These changes were associated with an improvement in symptomatic status from 81.8% NHYA functional class III/IV at baseline to 60.0% NYHA functional class I/II at 2 years  trial, 11 patients underwent successful device implantation with one device displacement and one pericardial effusion requiring surgical intervention. At 30-day follow up, a decrease in regurgitant volumes from 45.4 ± 15.0 ml to 19.5±10.2 ml was demonstrated with a beneficial effect on LV volumes. LV end-systolic volume index improved from 77.5 ± 24.3 ml/mal class . Data at 2 years . Phase IThe Mitral Loop Cerclage annuloplasty system  consists of a stainless-steel tension element delivered using a multistep procedure to form a continuous loop from the coronary sinus to a basal septal perforator coronary vein and right ventricular outflow tract  13). It. It13). Implantation is performed under moderate sedation (transthoracic echocardiogram) or general anesthesia . Access is via 19 Fr sheaths in the left subclavian and right femoral vein. A dual lumen coronary sinus guiding catheter is introduced into the coronary sinus via the left subclavian and contrast injection used to identify a basal septal perforator vein through which a stiff tipped peripheral guidewire is introduced and used to traverse the septum into the right ventricular outflow tract before snaring into the femoral vein. The tension element is then connected to the guidewire using heat-shrink tubing and pulled into position through the CS into the interventricular septum before loop snaring of the distal guide wire tip from the femoral vein into the subclavian. Next, the bifid coronary sinus tricuspid valve bridge is advanced over the two free ends of the tension element and the coronary artery protection element positioned with diagnostic angiography. Tension is then applied to reduce the septal lateral distance and the tension device is locked and embedded in the subclavian pocket.First in human results demonstrate successful implantation in 4 out of 5 patients. Failure to implant in one was due to unsuitable anatomy. Of those who underwent successful implantation, one patient suffered myocardial infarction and one patient died of refractory heart failure at 6 weeks. All patients demonstrated an immediate reduction in regurgitant volume. At 6-month follow up, regurgitant volume continued to decrease in the remaining 3 patients and was associated with a reduction in left atrial and LV systolic and diastolic size. Interestingly, two patients reverted to sinus rhythm at the end of the procedure . This waCoronary sinus constriction can lead to complex torsional deformation due to the complexity of the mitral annular plane and position of the CS in relation to the mitral annulus. This has unfortunately led to the failure of two previously developed devices despite encouraging early clinical safety and feasibility data , 36. TheFunctional MR is an unmet clinical need in those on maximal medical therapy but considered too high risk for conventional surgery. Annuloplasty techniques and the associated data are promising. However, annuloplasty techniques may not be suitable for all patients. Anatomical variation between individuals may limit the clinical efficacy of this approach as indirect annuloplasty relies on the proximity of the CS to the mitral annulus. Increasing LV dilatation further increases the distance between the mitral annulus and CS potentially rendering this approach ineffective. The reduction in annular dimensions from percutaneous interventions have not been as large as suggested in the surgical literature and longer-term clinical data are required to ensure safety and efficacy of these devices due to the risk of device erosion and coronary occlusion and also to assess for recurrence of MR.The recent results of the MITRA-FR and COAPT trial have helped define a patient population in whom there is potential benefit from MitraClip implantation . The surAn increase in anteroposterior (AP) mitral annular diameter is the common final pathway in the development of functional MR and associated with worsening clinical outcomes in heart failure and post myocardial infarction. Shortening of the AP dimension is therefore critical to alleviating MR. The aim of transcatheter mitral repair is to balance the increase in peri-procedural safety (reduced risk) with a sufficient reduction in MR for it to be effective. Annuloplasty, both direct and indirect, leaflet repair and chordal repair are all viable options based upon well-established surgical techniques and a combination of these approaches may provide the most effective resolution of MR. Current predictors of MR recurrence following surgical repair include baseline LV end-diastolic diameter >65 mm, posterior mitral leaflet angle >45 degrees and mitral coaptation depth >10 mm . HoweverSR manuscript conception, design, and critical revision. BP manuscript critical revision. RR manuscript critical review and revision. TP manuscript conception, design and critical revision. HA critical revision of the manuscript. CA critical revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In chronic rheumatic mitral regurgitation (CRMR), involvement of the myocardium in the rheumatic process has been controversial. Therefore, we sought to study the presence of fibrosis using late gadolinium enhancement cardiac magnetic resonance imaging (LGE–CMR) and biomarkers of collagen turnover in CRMR. Twenty–two patients with CRMR underwent CMR and echocardiography. Serum concentrations of matrix metalloproteinase– 1 (MMP–1), tissue inhibitor of MMP–1 (TIMP– 1), MMP–1–to–TIMP–1 ratio, procollagen III N–terminal pro–peptide (PIIINP) and procollagen type IC peptide (PIP) were measured. Four patients had fibrosis on LGE–CMR. PIP and PIIINP concentrations were similar to those of the controls, however MMP–1 concentration was increased compared to that of the controls . There was increased MMP–1 activity as the MMP–1–to– TIMP–1 ratio was higher in CRMR patients compared to the controls . Myocardial fibrosis was rare in CRMR patients. CRMR is likely a disease characterised by the predominance of collagen degradation rather than increased synthesis and myocardial fibrosis.  Myocardial fibrosis can be reliably detected non–invasively using late gadolinium enhancement (LGE–CMR) or contrast enhancement cardiac magnetic resonance (CE–CMR) imaging.5Studies pertaining to the possible involvement of the left ventricle (LV) in the rheumatic process have yielded equivocal results.12In a recent study in rheumatic MR, an increase in biomarkers of collagen synthesis and degradation was reported.16Procollagen III N–terminal pro–peptide (PIIINP) and procollagen IC peptide (PIP) are released into the circulation during collagen synthesis, while the turnover of collagen is controlled by matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs).This study was part of a prospective, cross–sectional study at Chris Hani Baragwanath Academic Hospital. Patients were enrolled from January to October 2014. All patients were screened and those deemed to have moderate or severe CRMR were referred for possible inclusion in the study.2, documented ischaemic heart disease, pre–existing non–valvular cardiomyopathy, prior cardiac surgery, congenital or pericardial disease, pregnancy, severe anaemia (haemoglobin < 10 g/dl), presence of a pacemaker or defibrillator, claustrophobia, renal dysfunction , or refusal to undergo CMR.The inclusion criteria were patients aged 18 years or older with echocardiographic features of moderate or severe CRMR. Patients were excluded if they had co–morbidities, significant aortic valve disease, concurrent mitral stenosis with a valve area of less than 2.0 cmA final number of 91 patients with presumed CRMR underwent clinical evaluation, resting electrocardiogram and detailed echocardiographic assessments according to a pre–determined protocol. Of these 91 patients with CRMR, 69 were excluded due to the following: co–morbidities .The final sample comprised 22 patients. Fourteen age– and gender–matched controls were also enrolled for the biomarker arm of the study. A tolerance of five years was allowed for age matching.The baseline clinical characteristics of these individuals were recorded and they subsequently underwent comprehensive echocardiography and CMR imaging.The study was approved by the University of the Witwatersrand ethics committee. It was conducted in accordance with the principles outlined in the Declaration of Helsinki.Transthoracic echocardiography was performed on all patients in the left lateral position by experienced sonographers using a S5–1 transducer on a Philips iE33 system . Images were obtained according to a standardised protocol. The data were transferred and analysed off–line using the Xcelera workstation.All linear chamber measurements were performed according to the American Society of Echocardiography (ASE) chamber guidelines.18MR was considered rheumatic in aetiology when the morphology of the valve satisfied the World Heart Federation (WHF) criteria for the diagnosis of chronic rheumatic heart disease (RHD).For biomarker analysis, peripheral venous blood samples were drawn from 14 controls and 22 chronic rheumatic heart disease subjects at the time of echocardiographic examination. Samples were collected in a serum separator tube and allowed a clotting time of 30 min before centrifuging for 15 min at 1 000 g and the serum was stored at –80°C before analysis in a single batch.Enzyme–linked immunosorbent assays (ELISA) were used to determine the serum concentration of PIIINP , and PIP  was determined by ELISA using the USCN kit according to the manufacturer’s instructions. The minimum detectable dose of PIIINP is typically less than 25.9 pg/ml and the minimum detectable dose of PIP is typically less than 10 ng/ml. Optical density of the analytes was measured at 450 nm on a microplate reader  and concentrations were determined using a 5–PL algorithm.Multi–analyte analysis of the matrix metalloproteinase 1 (MMP–1) and tissue inhibitor of metalloproteinase 1 (TIMP– 1) was performed using the magnetic luminex screening assay  on a Bio–Plex 200  according to the manufacturer’s instructions. The minimum detectable dose of MMP–1 is typically less than 2.7 pg/ml, and for TIMP–1, less than 3.42 pg/ml. Since the actual activity of MMP–1 depends on the balance between active enzyme and inhibitor (i.e. TIMP–1), the serum MMP–1/TIMP–1 ratio was considered an index of MMP–1 activity.CMR studies were performed on a 1.5–Tesla scanner  using a six–channel phasedarray body coil. The images were obtained during patient expiratory breath–hold for approximately eight seconds and were prospectively ECG gated.23Ten minutes after the injection of 0.2 mmol/kg gadoliniumbased contrast agent , LGE–CMR images were acquired in the same long– and shortaxis position, and used in the cine imaging.Images were analysed by an independent experienced reader (RN), blinded to the echocardiographic results, with Argus software , as previously described.Ejection fraction = end-diastolic volume - end-systolic volume/end-diastolic volumeLV volumes and EF were obtained by semi–automatic tracing of contours on the short–axis images in end–diastole and end–systole, with manual corrections when required.1Statistical analysis was performed with Statistica version 12.5, series 0414 for Windows. Continuous variables are expressed as means ± SD or medians (IQRs). Categorical data are expressed as a percentage. The differences for continuous variables were calculated using the Student’s t–test or Mann–Whitney U–test when the distribution was non–normal. Chi–squared and Fisher’s exact tests were used to calculate the difference for categorical data for independent samples. Pearson’s and Spearman’s correlation coefficient were used to calculate correlations depending on whether data were normally or non–normally distributed. Biomarker levels  were log transformed before analysis when distribution was not normal. A p–value < 0.05 was considered statistically significant.The mean age of patients was 36.3 ± 13.9 years, with 81% female . All theIn this study, LGE was present in four (18%) patients with CRMR . A variePIIINP and PIP were not elevated in patients compared to controls. PIIINP concentrations were 11.8 (6.9–21.6) vs 15.7 (13.6–18.5) ng/ml (p = 0.09), while PIP levels were 780.4 (727.3–1263.7) vs 1065.1 (589.2–1252.0) μg/ml (p = 0.13) . Log MMPThe main findings of this study were: fibrosis, as assessed by LGE was uncommon in CRMR; and biomarkers suggestive of collagen degradation  were increased in CRMR, but no changes in biomarkers of collagen synthesis (PIP and PIIINP) were noted.In this study, the majority of patients with CRMR did not have LV myocardial fibrosis on LGE. There are no studies on CRMR to draw comparisons from, but the limited studies done in degenerative MR have shown the presence of fibrosis on LGE in about 30% of patients compared to only 18% in the current study.The above hypothesis is further supported on the basis of a study done by Ho et al. in hypertrophic cardiomyopathy patients, where it was noted that a pro–fibrotic state (as assessed by increased biomarkers of synthesis) preceded the development of fibrosis visible on MRI.7A higher prevalence of fibrosis is observed commonly in pressure–overload states such as aortic stenosis.14In this study, patients with CRMR had increased collagen degradation, as suggested by increase in MMP activity and normal levels of TIMPs and markers of collagen synthesis. This finding supports the lack of myocardial fibrosis observed in our study. These findings differ from the study by Banerjee et al. in 30 patients with CRMR, where they found an increased level of biomarkers of synthesis and degradation.13The use of anti–remodelling therapy was similar in our study to that of Banerjee et al.Moreover, there was increased MMP activity in their MR patients compared to mitral stenosis, as well as increased MMP–to–TIMP ratio. They acknowledge that the elevation in PIP levels was lower than anticipated in their MR cohort, and that markers of collagen degradation exceeded markers of synthesis in their patients with CRMR.The main limitation of this study was the small sample size. A larger sample size would have reduced the probability of chance accounting for the absence or presence of fibrosis. A study with a larger sample size with isolated MR and one with co–morbidities and MR may be required to account for the finding of fibrosis secondary to isolated MR. T1 mapping was not used to exclude the presence of microscopic fibrosis and LV biopsies were not performed.The occurrence of LV fibrosis by LGE imaging was low in CRMR patients. This finding corroborates the increased level of biomarkers of collagen degradation and normal levels of biomarkers of collagen synthesis. These findings may have implications in terms of therapy. Earlier surgical referral may be of benefit before dissolution of the myocardial scaffold and irreversible myocardial damage ensues, with resultant poor postoperative LV function.


Obstructive sleep apnea (OSA) causes recurrent apneas due to upper respiratory tract collapse, leading to sympathetic nervous system hyperactivation and increased cardiovascular risk. Moderate and severe forms of obstructive sleep apnea are associated with increased atrial volumes and affect left ventricular diastolic and then systolic function. Right ventricular ejection fraction can be accurately assessed via three-dimensional echocardiography, while bidimensional imaging can only provide a set of surrogate parameters to characterize systolic function . Tissue Doppler imaging is a more sensitive tool in detecting functional ventricular impairment, but its use is limited by angle dependence and the unwanted influence of tethering forces. Two-dimensional speckle tracking echocardiography is considered more suitable for the assessment of ventricular function, as it is able to distinguish between active and passive wall motion. Abnormal strain values, a marker of subclinical myocardial dysfunction, can be detected even in patients with normal ejection fraction and chamber volumes. The left ventricular longitudinal strain is more affected by the presence of obstructive sleep apnea than circumferential strain values. Although the observed OSA-induced changes are subtle, the benefit of a detailed echocardiographic screening for subclinical heart failure in OSA patients on therapy adherence and outcome should be addressed by further studies. An increase in disease prevalence has been recently detected in the general population, partly attributable to current pandemic obesity. It is estimated that 4% of middle-aged males and 2% of females suffer from OSA , a condiContinuous positive airway pressure (CPAP) therapy is still considered the gold standard treatment for moderate-to-severe OSA, but its results are limited by inadequate patient adherence to and acceptance of device therapy. A recent report has shown that only 57% of patients diagnosed with moderate-to-severe OSA initiated the recommended CPAP therapy and that only half of them continued to use the device after 1 year . Optimalp < 0.001) [p < 0.01) [Left atrial enlargement is reported in 18% of newly diagnosed OSA patients , being m < 0.01) . Several < 0.01) –14 and lp=0.001, p=0.002, respectively) [OSA is also associated with left ventricular hypertrophy, even in the absence of hypertension, obesity, and diabetes , 11 Tab. Left vectively) . The LVMctively) , 9, but ctively) , 9. Leftctively) .p=0.028) [p=0.005) [Literature reports concerning LV ejection fraction (EF) and LV fractional shortening in OSA patients are controversial. Some publications show normal LV-EF 59 ± 10%) among patients with OSA  ± 10% am, and sevp=0.005)  Table 3p=0.028 [p=0.005) .p=0.02) [p=0.002) [Previous experimental reports regarding artificially induced OSA in a canine model , 21 havep=0.02) . A recenp=0.002) , and Bagp=0.002) . The difp=0.09) [p=0.0009) but not in subjects with moderate or severe OSA [An increased AHI was associated with decreased mitral E wave  and incrp=0.09) , severalp=0.09) , 17. Survere OSA .E wave deceleration time (E-DecT) is higher in patients with OSA than in control subjects, but no significant differences regarding E-DecT were found among patients with different degrees of OSA severity . The samp < 0.01) [p < 0.001; r=0.825) [p=0.02; r=0.27) [p=0.12) [Left ventricular Tei index (LV-MPI), illustrating both systolic and diastolic functions, is higher in subjects with severe sleep apnea 0.64 ± 0.14) compared to those with mild OSA  . Two stu r=0.27) , but oth[p=0.12)  Table 5p < 0.01 As illustrated above, conventional Doppler echocardiography yields conflicting results regarding OSA impact on left ventricular diastolic function. While several Doppler parameters are not applicable in patients with atrial fibrillation, others are influenced by patient heart rate and blood pressure values or exhibit age dependency. The need of a more comprehensive echocardiographic analysis  has been recognized by current international echocardiography guidelines, which have included TDI in the diagnostic algorithms of LV diastolic dysfunction .TDI is able to detect subtle changes in systolo-diastolic ventricular function, even in patients with normal EF. The technique is limited by its angle dependence, by the need to acquire high frame rate imaging, and by the influence of myocardial translation and tethering forces. LV-S' wave velocity is an indirect marker of ventricular systolic function. Two studies found no significant difference regarding LV-S' wave velocity among patients with OSA and controls , 15, conWachter et al. found that only tissue Doppler-derived parameters  are significantly different in the presence of sleep apnea, reporting that lateral e` was significantly lower in subjects with AHI ≥ 15 (7.4 ± 2.1) than in controls (8.3 ± 2.6) . Varghesr=0.202; p=0.014) [E/e` mean ratio, an estimate of LV end-diastolic pressures, is higher in subjects with moderate-to-severe OSA than in controls , 25, 27 p=0.014) . Since Ep=0.014) . AverageRight ventricular dysfunction is a common finding in patients with OSA, and Sanner et al. showed that right ventricular failure is more frequent in patients with OSA even in the absence of any other respiratory conditions . Recent The Framingham study did not reveal any difference regarding right ventricular (RV) volumes, end-diastolic dimensions , and systolic function  between subjects with sleep-disordered breathing and controls . Due to p < 0.05) [r=0.482; p=0.0009) [r=−0.362; p=0.02) [p=0.005) [r=0.356; p=0.026) [Adequate right ventricular volume estimations are not possible without the 3D technique, and two such studies showed that patients with moderate-to-severe OSA have higher indexed RV end-diastolic and end-systolic volumes compared to controls ( < 0.05) , 31. Alt < 0.05) , Oliveir < 0.05) . A stron=0.0009) , and RV-p=0.005)  and is ar=0.40; p=0.002) [Although a recent report did not find a significant decrease in the right ventricular Tei index (RV-MPI) in patients with severe sleep apnea , a previp=0.002) . These fp=0.002) , 33. It p=0.002) . Due to p=0.002) .2D echocardiographic parameters that describe global right ventricular function include tricuspid annular plane systolic excursion (TAPSE), myocardial performance index, and right ventricular fractional area change (RV-FAC) . Howeverr=−0.285, p=0.079) [Recent results concerning the impact of OSA on RV S' are controversial, with Dobrowolski et al. stating that it does not significantly differ between patients with and without OSA . Zakhamap=0.079) .The prevalence of pulmonary hypertension among patients with OSA ranges between 12% and 70%, depending on OSA severity, PAP assessment method, time of measurement, and other possible confounding factors. Pulmonary hypertension is commonly evaluated via the modified Bernoulli equation to estimate PASP (pulmonary artery systolic pressure) , but othp=0.002) [p=0.001) and is directly correlated to AHI  [Although Altekin et al.  found nop=0.002) . Pulmonap=0.077) .Pulmonary artery (PA) stiffness can be calculated as the ratio between pulmonary artery maximal frequency shift and pulmonary acceleration time (obtained from pulsed-wave Doppler trace of pulmonary artery flow). PA stiffness appears to be correlated both with AHI and mean oxygen saturation . A recenp=0.001) [Epicardial fat thickness, an indirect marker of visceral adiposity, is significantly higher in patients with moderate or severe OSA (AHI>15). Furthermore, 24 weeks of CPAP treatment induces a significant regression of epicardial fat thickness, even in the absence of any significant changes in BMI or waist circumference . These rp=0.001) .p < 0.0001), suggesting that OSA might contribute to aortic root enlargement in such patients [A previous study showed that OSA is more frequent among patients with Marfan syndrome and found that aortic root diameter is 0.8 cm higher in OSA patients . As opposed to tissue Doppler imaging, two-dimensional speckle tracking echocardiography is not angle dependent, providing a more accurate description of global and segmental systolic function. Patients with severe OSA present significantly decreased global longitudinal strain values compared to the other groups . The samSubjects with diastolic dysfunction often have abnormal GLS even with normal LV-EF and LV volumes . In suchA recent study showed that left atrial strain rate values are significantly higher in subjects with severe OSA and found a positive correlation between AHI and LA contractile strain, which can be partially improved after 12 weeks of CPAP therapy . While sThe effect of OSA on RV function is controversial. A report by Hammerstingl et al. showed that RV global, apical, and basal longitudinal strains are correlated to the severity of OSA , but aftThere is sufficient evidence to prove that moderate and severe forms of OSA are associated with decreased ventricular function and increased atrial volume, explaining the high incidence of chronic heart failure and also atrial fibrillation in these patients. It seems that OSA begins by affecting diastolic function, leading in time to systolic dysfunction. 2D-STE is not influenced by Doppler beam angling or load dependency. Abnormal strain values, a marker of subclinical systolo-diastolic dysfunction, can be detected even in patients with normal EF and chamber volumes. However, the role of 2D-STE in OSA patients  should be addressed by further studies, as current data yield conflicting results.


Heart failure is a common presentation to the emergency department (ED), which can be confused with other clinical conditions. This review provides an evidence-based summary of the current ED evaluation of heart failure. Acute heart failure is the gradual or rapid decompensation of heart failure, resulting from either fluid overload or maldistribution. Typical symptoms can include dyspnea, orthopnea, or systemic edema. The physical examination may reveal pulmonary rales, an S3 heart sound, or extremity edema. However, physical examination findings are often not sensitive or specific. ED assessments may include electrocardiogram, complete blood count, basic metabolic profile, liver function tests, troponin, brain natriuretic peptide, and a chest radiograph. While often used, natriuretic peptides do not significantly change ED treatment, mortality, or readmission rates, although they may decrease hospital length of stay and total cost. Chest radiograph findings are not definitive, and several other conditions may mimic radiograph findings. A more reliable modality is point-of-care ultrasound, which can facilitate the diagnosis by assessing for B-lines, cardiac function, and inferior vena cava size. These modalities, combined with clinical assessment and gestalt, are recommended. Acute heart failure (AHF) is a gradual or rapid decompensation in heart failure (HF) requiring urgent management.Over one million patients are admitted for HF in the U.S. and Europe annually.32We searched PubMed and Google Scholar for articles using the keywords “heart failure” and “emergency.” We included retrospective studies, prospective studies, systematic reviews and meta-analyses, clinical guidelines, and narrative reviews focusing on diagnosis of HF including history and physical examination, biomarkers, electrocardiogram (ECG), and imaging. The literature search was restricted to studies published in English. Emergency physicians with experience in critical appraisal of the literature reviewed all of the articles and decided which studies to include for the review by consensus, with a focus on emergency medicine-relevant articles. A total of 124 articles were selected for inclusion in this review.Normal cardiac physiology is dependent on appropriately functioning ventricular contraction, ventricular wall structural integrity, and valvular competence.33An alternate way of defining this would be by the effect on ejection fraction (EF). HF with preserved EF refers to patients with an EF > 50%, while HF with reduced EF refers to patients with an EF < 40%. Borderline preserved EF is defined by HF with an EF of 41–50%.36Right ventricular failure most commonly results from LV failure. As the right side of the heart fails, increased pressure in the vena caval system elevates pressure in the venous system of the gastrointestinal tract, liver, and extremities, resulting in edema, jugular venous distension, hepatomegaly, bloating, abdominal pain, and nausea.38In AHF, peripheral vascular flow and end-organ perfusion decrease, causing the body to compensate by neurohormonal activation , ventricular remodeling, and release of natriuretic peptides.35Patients with HF are classified into one of four classes, primarily determined by daily function, using the New York Heart Association, American College of Cardiology/American Heart Association, or European Society of Cardiology Guidelines .17,18,3945Unfortunately, these classification systems are not as useful for acute exacerbation of HF, thereby limiting their applicability in the ED setting. In the ED, classification is based upon the patient’s hemodynamic status, perfusion, and blood pressure.30Due to the complex pathophysiology involved in HF and multiple phenotypes , the history and physical examination may vary. Patients with HF are heterogeneous in terms of the cardiac structure and function, the etiology of their HF, the precipitant of the AHF exacerbation, comorbidities, and current medications. Early diagnosis is vital, as a delay or misdiagnosis has been associated with an increased risk of adverse outcomes and death.58Risk factors for HF include hypertension, renal disease, heart disease, diabetes, male gender, older age, and obesity.62Acutely, the most common symptoms associated with AHF include paroxysmal nocturnal dyspnea (PND), orthopnea, and edema.67On examination, an S3 heart sound has the highest specificity, ranging from 97.7–99%, but it has only 12.7% sensitivity.65Laboratory assessment in the patient with suspected AHF can provide important diagnostic and prognostic information.72th percentile.50Troponin testing can assist in prognostication and in the detection of underlying ischemia as a potential inciting event for AHF. Elevated troponin levels are associated with higher re-hospitalization rates and 90-day mortality.Natriuretic peptides  may be a valuable adjunct when the provider is unclear of the diagnosis.81Other conditions associated with elevations in natriuretic peptide levels include pulmonary embolism, pulmonary hypertension, valvular heart disease, and acute respiratory distress syndrome. BNP levels of 100–400 pg/mL and NT-proBNP levels of 300–900 pg/mL are non-specific and may require further testing.99An ECG should be rapidly obtained to evaluate for the etiology or precipitating factors .101Imaging is an important component in the patient with suspected heart failure. The most common modality used is the chest radiograph (CXR). Several findings suggest the diagnosis of heart failure on CXR, including cardiomegaly, central vascular congestion, and interstitial edema .17,18,41105Bedside ultrasound can be valuable for diagnosing AHF, with high specificity and positive likelihood ratios . Ultraso59Assessment of EF on ultrasound may be assessed with visual assessment or quantitative measurements. Qualitative visual estimation is made by assessing the inward movement of the interventricular septum and inferior wall of the LV during systole.103Due to the heterogenous nature of heart failure, disposition may be challenging. The majority of patients presenting to the ED in the U.S. with AHF are admitted.124Heart failure is a common presentation to the ED, which can be confused with other clinical conditions. Acute heart failure refers to the gradual or rapid decompensation of heart failure, resulting from either fluid overload or maldistribution. Typical symptoms can include dyspnea, orthopnea, or edema. The physical examination may reveal pulmonary rales, an S3 heart sound, or extremity edema. Laboratory studies should include an electrocardiogram, complete blood count, basic metabolic profile, coagulation studies, troponin, brain natriuretic peptide, and a chest radiograph. Point-of-care ultrasound can facilitate the diagnosis by assessing for B-lines, cardiac function, and inferior vena cava size. Understanding the diagnostic approach can improve the diagnostic accuracy and allow for more rapid initiation of the correct intervention.


Treatment of heart failure remains one of the most challenging task for intensive care medicine, cardiology and cardiac surgery. New options and better indicators are always required. Understanding the basic mechanisms underlying heart failure promote the development of adjusted therapy e.g. assist devices and monitoring of recovery. If cardiac failure is related to compromised cellular respiration of the heart, remains unclear. Myocardial respiration depends on Cytochrome c- Oxidase (CytOx) activity representing the rate limiting step for the mitochondrial respiratory chain. The enzymatic activity as well as mRNA expression of enzyme’s mitochondrial encoded catalytic subunit 2, nuclear encoded regulatory subunit 4 and protein contents were studied in biopsies of cardiac patients suffering from myocardial insufficiency and dilated cardiomyopathy (DCM).Fifty-four patients were enrolled in the study and underwent coronary angiography. Thirty male patients (mean age: 45 +/− 15 yrs.) had a reduced ejection fraction (EF) 35 ± 12% below 45% and a left ventricular end diastolic diameter (LVEDD) of 71 ± 10 mm bigger than 56 mm. They were diagnosed as having idiopathic dilated cardiomyopathy (DCM) without coronary heart disease and NYHA-class 3 and 4. Additionally, 24 male patients (mean age: 52 +/− 11 yrs.) after exclusion of secondary cardiomyopathies, coronary artery or valve disease, served as control . Total RNA was extracted from two biopsies of each person. Real-time PCR analysis was performed with specific primers followed by a melt curve analysis. Corresponding protein expression in the tissue was studied with immune-histochemistry while enzymatic activity was evaluated by spectroscopy.p < 0.001; 7.7 ± 3.1% vs. 2.8 ± 1.4%, p < 0.0001) but no differences in subunit 2. Correlations were found between reduced subunit 2 expression, low EF  and increased LVEDD . In case of DCM less subunit 4 expression and reduced shortening fraction  was found, but enzymatic activity was higher  although myocardial oxygen consumption continued to the same extent.Gene and protein expression analysis of patients showed a significant decrease of subunit 4 (1.1 vs. 0.6, In case of myocardial insufficiency and DCM, decreased expression of COX 4 results in an impaired CytOx activity. Higher enzymatic activity but equal oxygen consumption contribute to the pathophysiology of the myocardial insufficiency and appears as an indicator of oxidative stress. This kind of dysregulation should be in the focus for the development of diagnostic and therapy procedures. Deterioration of myocardial contractility is an obvious indicator for reduced oxygen supply. In coronary heart disease, when arteriosclerotic plaque formation reduces blood flow, the reduced coronary blood supply results in ischemia and damage to the myocardium. Myocardial respiration depends on Cytochrome c- Oxidase (CytOx) activity. It represents the rate limiting step for the function of the mitochondrial respiratory chain, also known as electron transmission chain (ETC). If cardiac failure is related to the compromised cellular respiration of the heart, remains unclear. But contractility requires abundant supply of adenosine triphosphate (ATP), and this kind of “energy currency” is produced in mitochondria see Fig.  where ox“Overspending ATP” and finally metabolic break down. The CytOx (complex IV) is directly involved and has the “center stage” [The extent of ROS formation herein, determines the pathophysiological consequences. Ischemic damage and reperfusion injury of myocardium proceed with an r stage” , 5. Thisr stage” , 7. The r stage”  Fig. 2)“Overspenr stage” .Fig. 2ThInterestingly, Buchwald et al.  found inMitochondrial mtDNA mutations are known to be involved in the pathogenesis of DCM , 13. PoiThe prognosis of DCM is poor because of its progression to myocardial insufficiency. Progression results either in cardiac death or prolonged support with inotropic medication, implantation of left ventricular assist devices, or heart transplantation, respectively. Effective, early indicators are required for diagnosing heart failure and commencing justified interventions in due time. Diversely, a good prognostic parameter to start the weaning process from cardiac assist devices under intensive medical care are needed as well.3) and the other redox-active copper (CuB). Two cysteine and two histidine residues of subunit 2 are the likely ligands of CuA, forming a centre for electron transportation [2 /COX 4 gene expression, CytOx subunit 2 and 4 protein content and enzymatic activity of the holoenzyme in biopsies of DCM patients were determined. The extent of myocardial insufficiency in patients was detected by heart catheterization and LV angiography. Hemodynamic data were correlated to the biochemical findings of CytOx subunit 2 and 4 measurements.Reflecting the need of such new parameters, the present study addresses mitochondrial pathophysiology of myocardial respiration in case of myocardial insufficiency. The study addresses the question, if reduced transcription and protein translation rates of subunit 4 represents a good indicator for compromised myocardial oxygen consumption and utilization for ATP production. The mismatch between mitochondrial- and nuclear coded subunits of CytOx indicates compromised cardiac dysfunction. Subunit 2 binds to one of the copper ions (CuA) whilst subunit 1 is likely to bind the two hemes  endomyocardial specimens were obtained with a flexible Cordis bioptome from the free wall of the left ventricle, subsequently. All biopsies were snap-frozen and conserved in liquid nitrogen and stored at − 80 °C for maximum 2 months. The ESC-classification of cardiomyopathies of 2007 as well as the WHF-classification for the exclusion of inflammation and viral persistence was applied for the diagnosis of idiopathic dilated cardiomyopathy , 22. ThiThe endomyocardial biopsies used were the leftover samples from patients with suspected inflammatory disease after complete diagnostic work up. All patients gave their informed consent to use leftover samples for scientific purposes (Permission Ethics commission Az 53/18).2 subunit-II, forward 5′- AgA CgC TAC TTC CCC TAT CA -3′ and reverse 5′- ggT CgT gTA gCg gTg AAA gT − 3′ and for CytOx subunit-4 were, forward 5′- gTA CGA gCT CAT gAA AgT gTT g − 3′ and reverse 5′- ACA TAg TgC TTC TgC CAC ATg A − 3′.Total RNA was extracted from the two pooled endomyocardial biopsies by QIAGEN™ RNeasy Kit according to the manufacturers’ instructions, including a DNase digestion (Serva™). The mRNA of the COX subunits 2 and 4 from heart tissue were amplified with specific primer pairs by one step real-time PCR using an iCycler (BioRad™). Polymerase chain reaction was carried out according to the manufacturers recommendations in a total volume of 25 μl containing 2.5 μl total RNA from endomyocardial biopsies as well as 7.5 μM cytochrome c oxidase 2, cytochrome c oxidase 4 or GAPDH (housekeeping gene), specific forward and reverse Primer and 2.5 μl SYBR Green. Primer sequences for GAPDH were, forward 5′-gAA ggT gAA ggT Cgg AgT C-3′ and reverse 5′- gAA gAT ggT gAT ggg ATT TC -3′; for MT- COThe protocols for “One Step Real-time PCR” used were as follows: reverse transcription 50 °C 30 min, denaturation (95 °C for 15 min), amplification repeated 40 times (95 °C for 45 s), annealing temperature (60 °C for 45 s), extension temperature (72 °C for 45 s). A melting curve analysis was run after final amplification period via a temperature gradient from 55 to 94 °C in 0.5 °C increment steps measuring fluorescence at each temperature for a period of 10 s. All reactions were carried out in at least 5 duplicates for every sample.2 and COX 4 transcripts were calculated as the ratio between the levels of transcript and GAPDH. Using the BioRad™ iQ iCycler system software, the threshold (Ct) at which the cycle numbers were measured, was adjusted to areas of exponential amplification of the traces. The ΔΔ-method was used to determine comparative expression level by applying the formula 2(-ΔCt target - ΔCt control) as described previously [p > 0.1) between these two groups). The analysis of intraindividual variance showed no difference of COX IV expression.The relative expression of MT –COeviously . RNA conImmunohistochemical studies for the detection of the two subunits of the CytOx were performed on snap frozen biopsy specimens, conserved in liquid nitrogen. Biopsies were embedded in compound medium  and serial sections of 6 μm were subsequently placed on poly-l-lysine–treated glass slides. Fixation was achieved by 100% ice-cold acetone. Endomyocardial biopsies of a subcohort of patients were subjected to staining with monoclonal antibodies against anti-human OxPhos Complex IV  subunit 2 (clone 12C) and subunit 4 (clone 20E8C12) in a concentration of 1 μg/ml using a an avidin–biotin double sandwich technique  in combination with a monoclonal antibody against the endothelial antigen EN4  to distinguish intramyocardial vessels or capillaries. Biopsy specimens were microscopically analyzed using a Leica DMRXE microscope. Histological analysis was carried out using a digital microscope  and QUIPS analysis software . Evaluation was carried out by selecting 10 representative regions of interest (ROI) at 20-fold magnification. Relative stained area was calculated referring to the size of the biopsy.Biopsies were gently homogenized and suspended in KCl- buffer. Protein determination of myocardial suspensions were estimated by the BCA method with a NanoDrop™ instrument  using bovine serum albumin as standard. Concentration was fixed at 1 mg/ml.Measurements of oxygen consumption were performed polarographically with Hansatech Oxygraph System  using a Clark-type oxygen electrode as already described .Enzymatic activity measurements were performed spectrophotometrically. The absorption of cytochrome c at 550 nm changes with its oxidation state. Cytochrome c was reduced with 0.1 M dithiothreitol solution and then reoxidized by the cytochrome c oxidase. The difference in extinction coefficients (Δε per mM) between reduced and oxidized cytochrome c is 21.84 at 550 nm. The oxidation of cytochrome c by cytochrome c oxidase appears as a biphasic reaction with a fast initial burst of activity followed by a slower reaction rate. Initial reaction rate is measured during the first 45 s of the reaction. The decrease in absorption at 550 nm at room temperature (25 °C) was monitored with a kinetic program: Reaction was started by the addition of 50 ml of Ferrocytochrome c  as substrate. Absorption at 550 nm/minute was read immediately due to the rapid reaction rate of this enzyme. The final calculation of the sample activity in Units/ml according to: ΔA/min x Dilution × 1.1 ml (reaction volume)/ Volume of enzyme × 21.84 (Δε) and ΔA/min = A/minute – A/blank. The “Unit” is defined as 1 Unit oxidizes 1.0 mmole of ferrocytochrome c per minute at pH 7.0 (25 °C).p-value of less than or equal to 0.05 was considered significant. Linear regression analysis was also performed by SigmaStat™.Data were analyzed using the SigmaStat Advisory Statistics for scientists (SYSTAT®). For comparison of mRNA expression, CytOx levels and enzymatic activity in patients with DCM compared to controls, an unpaired, two-tailed t-test and a Mann-Whitney Rank Sum Test was used. A Fisher-test was used to demonstrate homogeneity of variances while in case of inhomogeneity, a Welch-test was performed. A 2  and COX 4 (nuclear encoded subunit) in endomyocardial biopsies (EMB) of patients with non- viral, non- inflammatory and non- familial idiopathic DCM and compared to controls. Hemodynamics of 54 patients were studied. Thirty patients were classified as DCM according to international criteria [In this study, we have investigated the mRNA expression of MT –COcriteria , 22. In 2 measurements, were found   and LVEDD  as well as shortening fractions  . The age of patients neither correlate to the MT- CO2 mRNA nor with COX 4 mRNA data. For this reason the found alterations were age- independent. Even in the group of DCM the reduced SF correlated to the reduced COX 4 expression .A significant decrease of COX 4 mRNA expression and protein content but no significant changes in correlating MT- COp = 0.643, n.s.). However, enzymatic activity of CytOx in case of DCM was approximately 3fold increased  was throughout the same, but COX 4 was down-regulated and protein content of subunit 4 was also reduced in cases of myocardial insufficiency. This effect is age- independent. The complex IV in the ETC is involved in the electron transfer to dioxygen via subunit 4 that determines the subsequent respiratory activity of the tissue [In our study, gene expression of mitochondrial encoded subunit 2  underwent heart catheterization. Thirty patients suffering from reduced LV ejection fraction below 45% and an enlarged left ventricular enddiastolic diameter bigger than 56 mm were considered to be myocardial insufficient. In biopsies of all patients the activity of Cytochrome c-oxidase  was measured. Furthermore, the subunit mRNA expression and protein content of the mitochondrial encoded catalytic subunit II (MT-CO2) and nuclear encoded regulatory subunit 4 (COX 4) were detected. Patients with myocardial insufficiency showed a significant decrease in COX 4 but not in MT-CO2. Correlations were found between COX 4 expression and EF% and LVEDD. Therefore, it is concluded that reduced COX 4 leads to impaired activity of Cytochrome c oxidase, subsequent reduction in mitochondiral respiration and hence myocardial insufficiency.


In patients with repaired tetralogy of Fallot (TOF), a better understanding of the impact of surgical pulmonary valve replacement (PVR) on ventricular mechanics may lead to improved indications and outcomes. Therefore, we used cardiovascular magnetic resonance (CMR) feature tracking analysis to quantify ventricular strain and synchrony in repaired TOF patients before and after PVR.Thirty-six repaired TOF patients (median age 22.4 years) prospectively underwent CMR a mean of 4.5 ± 3.8 months before PVR surgery and 7.3 ± 2.1 months after PVR surgery. Feature tracking analysis on cine steady-state free precession images was used to measure right ventricular (RV) and left ventricular (LV) circumferential strain from short-axis views at basal, mid-ventricular, and apical levels; and longitudinal strain from 4-chamber views. Intraventricular synchrony was quantified using the maximum difference in time-to-peak strain, the standard deviation of the time-to-peak, and cross correlation delay (CCD) metrics; interventricular synchrony was assessed using the CCD metric.Following PVR, RV end-diastolic volume, end-systolic volume, and ejection fraction declined, and LV end-diastolic volume and end-systolic volume both increased with no significant change in the LV ejection fraction. LV global basal and apical circumferential strains, and basal synchrony improved. RV global circumferential and longitudinal strains were unchanged, and there was a varied impact on synchrony across the locations. Interventricular synchrony worsened at the midventricular level but was unchanged at the base and apex, and on 4-chamber views.Surgical PVR in repaired TOF patients led to improved LV global strain and no change in RV global strain. LV and RV synchrony parameters improved or were unchanged, and interventricular synchrony worsened at the midventricular level. Young children undergoing surgical repair of tetralogy of Fallot (TOF) have excellent short-term survival ; howeverA better understanding of the effects of surgical PVR on ventricular function may lead to improved indications and outcomes for the procedure. In particular, areas that merit further investigation are regional ventricular mechanics and synchrony. In repaired TOF patients, right bundle branch block is nearly universal and several studies have documented dyssynchronous ventricular contraction –12. MoreFeature tracking is an image processing technology that quantifies myocardial tissue deformation, and has been increasingly employed to aid cardiac resynchronization therapy , 16. ThiOur group previously published a prospective, randomized study comparing 2 techniques for surgical PVR: PVR alone versus PVR plus RV remodeling with the resection of scar tissue . No sign2, RV ESV index ≥70 ml/m2, RV EF ≤45%, LV EDV index ≤65 ml/m2, RV outflow aneurysm, or a clinical criterion such as exercise intolerance, symptoms and signs of heart failure, or cardiac medications. Exclusion criteria included any of the following: severe RV outflow obstruction, severe RV hypertension with RV pressure ≥ systemic pressure, and contraindications to preoperative CMR. Patients were randomized to PVR alone or a combination of PVR with RV remodeling surgery. The study protocol included a pre-operative and a 6-month post-operative CMR study.Subjects in this study were all participants in a previously reported prospective, randomized, single-center trial comparing 2 techniques for surgical PVR . These pFor the current study, we analyzed the database of the prospective trial, selected only those patients with TOF, and performed feature tracking analysis of the CMR images. The Boston Children’s Hospital Committee on Clinical Investigation granted permission for this study and waived the requirement for informed consent.The CMR protocol used for patients with repaired TOF has been previously published . BrieflyFeature tracking analysis for determination of strain was performed using commercially available software , as previously described . CircumfVarious ventricular synchrony parameters based on feature tracking measurements have been reported; however, there is no consensus on the optimal approach. Hence, we used 3 techniques that have been reported in the literature as measures of ventricular synchrony , 25, 26.p-value ≤0.05 was considered statistically significant. The intraclass correlation coefficient (ICC) and mean difference were used to assess intraobserver and interobserver agreement.All collected data were tested for normalcy using the Shapiro-Wilk test. Continuous data are presented as median (range) and mean ± standard deviation. A two-tailed paired t-test was used to compare pre- and post-PVR strain and synchrony parameters. A Of the 64 patients in the initial prospective trial, 36 had a diagnosis of TOF as well as pre- and post-operative CMR studies with suitable image quality for strain analysis. These patients constitute the study group, and their demographic and clinical data are summarized in Table Key diagnostic testing results pre- and post-PVR are shown in Table Global strain values pre- and post-PVR are shown in Fig. The impact of PVR on segmental strain in the LV and RV is shown in Fig. Synchrony parameters derived from the segmental strain versus time curves pre- and post-PVR are shown in Table For the RV, both of the time-to-peak parameters showed significantly improved synchrony at the base and worsened at the apex and longitudinally. At the mid location, there were no significant synchrony changes.In addition to the synchrony parameters reported above, the raw time-to-peak strain values (rather than differences) for each segment were compared pre- and post-PVR. This analysis provides information on how PVR affects the timing of contraction relative to the cardiac cycle rather than assessing synchrony per se. All LV segments with a statistically significant change in time-to-peak strain following PVR were increases and these were 2 of the 6 longitudinal and 7 of 16 circumferential segments Fig. . Similarp = 0.002), as a result of slightly earlier LV peak strain. There was no change in the interventricular CCD at the base , the apex , or the 4-chamber view .Interventricular synchrony was assessed by comparing the global strain versus time curves for the LV and RV on each of the 4 views, and calculating the CCDs. The LV peak strain preceded RV peak strain in 128 of 144 segments (89%) pre-PVR and in 127 of the 144 segments (88%) post PVR. The interventricular CCD significantly increased after PVR at the mid-ventricular level  had RV-to-pulmonary artery conduit dysfunction, and were divided into those with predominant pulmonary stenosis (n = 18) and those with predominant PR (n = 13). For the PR subgroup, PVR led to not only improved LV circumferential strain, as it did in our patients with surgical PVR, but also improved longitudinal strain. This difference in longitudinal strain response may be related to the fact that even in the PR subgroup, there was some degree of pulmonary stenosis, more than in the current study population. There was no change in RV circumferential or longitudinal strain with transcatheter PVR in the PR subgroup, in agreement with our results for surgical PVR.Only a few other reports have measured changes in strain that accompany PVR. A similar study from our group examined the impact of transcatheter pulmonary valve implantation on strain assessed by CMR feature tracking . All patPrior studies assessing the impact of PVR on ventricular synchrony are also scarce. Lurz et al. examined 20 patients with RV-to-pulmonary artery conduit obstruction, most with TOF, before and after transcatheter PVR . Based oThe clinical implications of improved LV circumferential strain and synchrony following PVR are uncertain but there are some data to suggest that this may be beneficial. Impaired LV systolic function in repaired TOF patients is fairly common , 34. BotSeveral limitations of this study are worth noting. Assessments were performed at a mean of 7 months following PVR. Available data suggests that RV volumes and, thus, EF remain stable between 1 and 5 years after PVR . NeverthIn this cohort, surgical PVR in repaired TOF patients resulted in improved LV global strain and no change in RV global strain. LV synchrony parameters improved or were unchanged, RV synchrony effects varied by location, and interventricular synchrony was largely unchanged. Future studies should address longer-term changes in strain and synchrony following PVR and their relationship to clinical outcomes.


The characterization of the pathological substrate and/or mapping of the clinical ventricular tachycardia in patients with left ventricular assist device may represent a challenge, due to the risk of entrapment of the intracardiac catheter into the inflow cannula. Hereby, we present the technique of a fast and safe mapping using a 20‐poles catheter which allowed the identification of the critical isthmus during ventricular tachycardia. The patient had a history of anterior myocardial infarction with severe left ventricular dysfunction (EF 20%). Under general anesthesia, left ventricle was approached via trans‐septal puncture. Using a 20‐poles catheter , a high‐density map was built with the EnSite Precision™ Mapping System . During sinus rhythm, a large myocardial scar (<0.2 mV) on the anterior and septal LV wall was documented, but no late potentials were recorded. A clinical VT (CL [cycle length] 400 ms), hemodynamically tolerated, was induced. An activation map of the VT was attempted Figure  with the2Ventricular tachycardia recurrences often complicate the course of patients with left ventricular assist device (LVAD). Transcatheter ablation, as shown by a recent multi‐center study,Dr Paolo della Bella is consultant for Abbott and Biosense webster companies. Research grant from Biotronik, Biosense Webster, Abbott and Boston Scientific.NT and KO: performed the case and helped to draft the manuscript. AF, FC, PDB: acquired, analyzed the data, and drafted the manuscript.


Heart failure predisposes to an increased risk of silent cerebral infarction, anddata related to left ventricular ejection fraction are still limited. Ourobjective was to describe the clinical and echocardiographic characteristics andfactors associated with silent cerebral infarction in patients with heartfailure, according to the left ventricular ejection fraction groups. Aprospective cohort was performed at a referral hospital in Cardiology betweenDecember 2015 and July 2017. The left ventricular ejection fraction groups were:reduced (≤ 40%), mid-range (41-49%) and preserved (≥ 50%). Allpatients underwent cranial tomography, transthoracic and transesophagealechocardiography. Seventy-five patients were studied. Silent cerebral infarctionwas observed in 14.7% of the study population  and was more frequent in patients in the reduced left ventricularejection fraction group (29%) compared with the mid-range one . There were no cases of silent cerebral infarction in the group ofpreserved left ventricular ejection fraction. In the univariate analysis, anassociation was identified between silent cerebral infarction and reduced  and preserved  left ventricular ejection fraction and diabetes mellitus. In patients with heart failure andwithout a clinical diagnosis of stroke, reduced and mid-range left ventricularejection fractions contributed to the occurrence of territorial and lacunarsilent cerebral infarction, respectively. The lower the left ventricularejection fraction, the higher the prevalence of silent cerebral infarction. It is believed that reduced blood flow may favor theformation of spontaneous echo contrast, intracavitary thrombi and consequentcardioembolic events.6 However,data explaining the stroke mechanism in HF in patients with LVEF are stilllimited,7 and data relatedto stroke and mid-range LVEF are scarce.Ischemic stroke is a common complication of HF regardless of the Preserved (pLVEF) orreduced (rLVEF) Left Ventricular Ejection Fraction (LVEF).The objective of this study was to describe the clinical and echocardiographiccharacteristics and factors associated with silent cerebral infarction in patientswith HF according to the LVEF groups.8 with patients who had signs and symptoms of HF, relevantstructural heart disease (left ventricle (LV) body mass index ≥ 115 g in menand ≥ 95 g in women, or left atrial dilatation ≥ 40 mm) and ordiastolic abnormality . The LVEF groups were characterized as follows: rLVEF (≤40%), mid-range LVEF  and pLVEF (≥ 50%).9 The diagnosis of Atrial Fibrillation(AF) was based on information available in medical records and theelectrocardiogram.This is a prospective cohort performed at a referral hospital for the care ofpatients with HF in the city of Salvador, state of Bahia, Brazil, between December2015 and July 2017. The diagnosis of HF was made according to the recommendations ofthe European Society of Cardiology (ESC),The cranial tomography was performed in all the patients to identify infarctionsin the brain parenchyma . The reports were analyzed by aneurologist, blinded to the patients' clinical data. These examinations wereperformed using a 1385 Toshiba Medical Systems Corporation device, .10 A commercially availabledevice was used ,equipped with a 5 MHZ transducer with a multiplanar transesophageal probe.Subsequently, the images were recorded in a pen drive and reviewed by anechocardiographist.The examinations were performed by two experienced echocardiographists, asrecommended by the American Society of Echocardiography (ASE).The measures analyzed by the Transthoracic Echocardiogram (TTE) were: diastolicand systolic diameter of the LV, anteroposterior diameter of the LA, aortic rootdiameter, interventricular septum and posterior wall thickness. These analyseswere obtained in the parasternal short axis and the parasternal long axis planesusing the M-mode. The calculation of the LVEF was carried out using the LVmodified biplane Simpson's method.11To perform the Transesophageal Echocardiography (TEE) images, the patient wasplaced in the left lateral decubitus position, and the left arm was extendedover the head. The exams were performed under topical anesthesia with xylocainespray at 10% and under intravenous sedation. The presence of spontaneous echocontrast and intracavitary thrombi were observed. The intracavitary thrombus wasdefined as an echodense intracardiac mass, and the spontaneous echo contrast wasidentified through its typical swirling movement, resembling smoke.t test, according tothe variable distribution. Pearson's chi-square test or Fisher's exact test wasapplied for association measures. Values were considered statisticallysignificant when p ≤ 0.05 and the confidence interval ≥ 95%.The collected data were processed using the Statistical Program for SocialSciences (SPSS), version 21.0. For data analysis, descriptive statistics wereused , mean and standarddeviation. The Kolmogorov-Smirnov was used in the normality test. The means andproportions were evaluated by Student's Seventy-five patients were studied. Comparisons of clinical and echocardiographicparameters are described in 12In our study, patients with rLVEF had silent cerebral infarction in the territoryregion, and those with mrLVEF had silent cerebral infarction of the lacunar type.There was no silent cerebral infarction in patients with pLVEF. It was demonstratedthat the lower the LVEF, the higher the prevalence of silent cerebral infarction. Aprevious study showed that reduced LVEF values are associated with patients withsilent stroke (p = 0.030).13 In the study by Kozdag etal.,12 with 72 patientswith ischemic dilated cardiomyopathy, the prevalence of silent cerebral infarctionwas 39%. However, it is worth mentioning that the high prevalence of silentinfarctions in these studies was probably the result of increased HF severity in thestudied populations.The prevalence of silent cerebral infarction in this study was considered small whencompared to other studies of HF patients. In a study of 117 patients with HFevaluated for heart transplant, the prevalence of ischemic stroke was 34%.14found that abnormalities in early LV diastolic filling were commonly observed indiabetic patients, and the proposed mechanism includes, among other factors,microvascular disease, which may justify the data found in our study.Another important finding was the association between diabetes mellitus and silentcerebral infarction. Chen et al.15A recent study clearly demonstrated that the clinical characteristics of mrLVEF areintermediate between pLVEF and rLVEF, or close to pLVEF or rLVEF, and suggest thatmrLVEF is a transitional stage from pLVEF to rLVEF, or from rLVEF to pLVEF, ratherthan a distinct HF class.16However, data are still limited regarding these patients.In the case of patients with mrLVEF, silent cerebral infarctions were reported to beof the lacunar type, usually associated with cerebral small vessel disease, buteventually of embolic etiology.17Patients in the LVEFp group did not show silent cerebral infarction, differently froma study on LVEF groups, in which the rates of stroke or transient ischemic attackwere slightly higher in patients with pLVEF vs. patients with rLVEF and mrLVEF. Itis worth mentioning that AF was more common in these patients with pLVEF, althoughthe AF was associated with an increased risk of stroke or transient ischemic attack,regardless of LVEF status.In patients with heart failure and without a clinical diagnosis of stroke, thereduced and mid-range left ventricular ejection fractions contributed to theoccurrence of territorial and lacunar silent cerebral infarction, respectively. Incases of preserved left ventricular ejection fraction, there was no prevalence ofsilent cerebral infarction; reduced left ventricular ejection fraction and diabetesmellitus were associated with embolic cerebral infarction, and the lower the leftventricular ejection fraction, the higher the prevalence of silent cerebralinfarction. Further studies are required to elucidate the mechanisms of silentcerebral infarction in the left ventricular ejection fraction groups.The study was carried out in a single center, with a small sample and there wereno analyses of intra- and interobserver variability between theechocardiographists.