In a chronic closed-chest model we assessed whether cardiac function is preserved in TLR4-deficient mice (C3H/HeJ) following MI/R, and whether myocardial and systemic cytokine expression differed compared to wild type (WT).It has been reported that Toll-like receptor 4 (TLR4) deficiency reduces infarct size after myocardial ischemia/reperfusion (MI/R). However, measurement of MI/R injury was limited and did not include cardiac Infarct size (IS) in C3H/HeJ assessed by TTC staining after 60 min ischemia and 24h reperfusion was significantly smaller than in WT. Despite a smaller infarct size, echocardiography showed no functional difference between C3H/HeJ and WT. Left-ventricular developed pressure measured with a left-ventricular catheter was lower in C3H/HeJ . Serum cytokine levels and myocardial IL-6 were higher in WT than in C3H/HeJ (p < 0.05). C3H/HeJ MI/R showed increased myocardial IL-1β and IL-6 expression compared to their respective shams (p < 0.05), indicating TLR4-independent cytokine activation due to MI/R.does not preserve myocardial function. The change in inflammatory response, secondary to a non-functional TLR-4 receptor, may contribute to the observed dichotomy between infarct size and function in the TLR-4 mutant mouse.These results demonstrate that, although a mutant TLR4 signaling cascade reduces myocardial IS and serum cytokine levels, it  Activation of Toll-like receptor 4 (TLR4) initiates a sequential activation of IL-1 receptor-associated kinases (IRAKs), tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6), nuclear factor κB inducing kinase (NIK), and the IκB kinase complex (IKKs). IKK activation induces phosphorylation and degradation of IκB followed by activation of nuclear factor κB (NFκB) .Innate immunity is involved in myocardial ischemia/reperfusion (MI/R) injury, specifically through activation of TLR4, which was originally proposed to solely recognize lipopolysaccharide (LPS) . Other cIt has not been shown that a reduction in infarct size in the TLR4-deficient mice results in improved hemodynamics and cardiac function. The expression of cytokines after MI/R is unclear with conflicting reports ,9. ThereInfarct size in C3H/HeJ mice was significantly reduced at 30.1 ± 4.8% of the area at risk  after 60 min of ischemia . Echocardiography detected no difference in ejection fraction (EF) between sham-operated WT (n = 14) and C3H/HeJ (n = 7) mice . 24 h following MI/R  and relaxation (- dp/dtmin) showed a tendency towards impaired LV function in C3H/HeJ mice , resulting in similar myocardial levels of TNF and IL-1β in both strains. With the onset of reperfusion in TLR4-deficient mice, cytokine and chemokine signaling is disturbed because of the non-functional TLR4-receptor. This can result in decreased chemotaxis of leukocytes. Alteration in the inflammatory response to myocardial infarction may account for the observed discrepancy between infarct size and cardiac function for the TLR4 deficient mice.in vivo myocardial function and protection from cardiac myocyte apoptosis after MI/R. It is unclear, if TLR4 deficiency ameliorates reperfusion injury due to blunted systemic inflammatory response as shown by our present study but leads to myocardial dysfunction due to apoptosis in addition to TLR4 independent cytokine expression.A recent study has shown that TLR4 in cardiac myocytes mediates survival through MyD88 and NOS2 using TLR4 -/- cardiac myocytes in comparison to wild type in a model of serum deprivation induced apoptosis . Other sIn this study, mice were sedated with propofol i.p. for induction of MI/R. Propofol was chosen because of its lack of preconditioning effects. However, we found a significant decrease in heart rate only in WT, probably an effect of propofol which has been also reported in C57Bl/6 mice . With thTLR4 contributes to myocardial infarction by inducing a systemic and a myocardial cytokine response after MI/R. It has to be considered that TLR4-independent pathways are also activated due to MI/R and contribute to myocardial dysfunction. The targeted pharmacologic inhibition of TLR4 in the clinical setting of myocardial ischemia and reperfusion could initially lead to a smaller infarct, but an altered inflammatory response could have unexpected effects on cardiac function and long term infarct healing. Thus, further investigations are needed to elucidate the role of TLR4 in infarct size, modulating inflammatory responses and its impact on cardiac function.®, Abbott GmbH, Wiesbaden, Germany) with 1 L*min-1 O2 flow. After sufficient anesthesia depth was confirmed by squeezing the paws, animals were placed in a supine position for intubation on a water warmed plate. Body temperature and electrocardiography (ECG) were monitored and surgery was performed, as described previously [-1, 200 μl tidal volume). A left parasternal incision through the third and fourth rib was made. The chest walls were separated with retractors to achieve a good visualization of the heart. The pericardium was then gently opened and the heart was rotated on its longitudinal axis to identify the LAD with a mini tip cotton applicator . A U-shaped 8-0 tapered needle was cautiously passed underneath the LAD 1 mm distal from the tip of the left auricle. The 8-0 prolene suture was cut at the needle side and both ends were threaded through a 1 mm section of a PE 10 tube. Both ends of the suture were tightened to confirm the correct position of the suture by observing paleness of the distal myocardium. The following procedure was modified according to Nossuli et al. [2.A chronic, closed-chest model of MI/R was utilized in order to exclude that any inflammatory reaction following MI/R is due to the surgical trauma itself. Male, 8–12 weeks old C3H/HeJ (n = 15) and WT  were anesthetized with isoflurane 2.5 Vol.% , allowing spontaneous breathing, and were placed in a supine position on a warming plate beneath a heating lamp to maintain body temperature, which was monitored with a rectal probe. The ECG was monitored to document ST-segment elevation . The former skin incision was reopened and after dissecting the loop, tension was carefully applied to the loop to achieve and maintain a significant ST-elevation. After 60 minutes, the loop was relaxed and it was taken care of monitoring a resolution of the ST-segment elevation as a sign of reperfusion. The loop was placed back into the subcutaneous tissue and the skin was closed. Sham-operated mice underwent the same procedure except for pulling the loop to induce myocardial ischemia/reperfusion. The time course of the MI/R protocol is summarized in figure For MI/R experiments, mice were sedated with propofol i.p.  was injected into the left atrium 24 h following MI/R to determine the area at risk (AAR) [sk (AAR) . Hearts C3H/HeJ (n = 6) and WT (n = 6) were anesthetized and heart function was assessed 24h following MI/R, as described before . In brieA practiced, single, blinded observer performed echocardiographic analyses. End-diastolic measurements were obtained at the peak of the R-wave, whereas end-systolic measurements were obtained at the time of minimum internal chamber dimensions. The acquired sequential 2D short-axis cineloops of the left ventricle were used to measure left-ventricular volumes at end-diastole and end-systole and ejection fraction (EF).max, -dP/dtmin).Hemodynamic measurements of LV function were obtained immediately following echocardiography after 24 h of MI/R. LV function was assessed using a 1.4-Fr Mikro-tipped Millar catheter as described previously . BrieflyC3H/HeJ and wild type mice underwent either MI/R (n = 5) or sham (n = 6) procedure to evaluate if differences in post-MI/R myocardial edema could contribute to myocardial dysfunction. Body weights were assessed and hearts excised after 24 h of MI/R or corresponding time in sham and rinsed shortly with PBS. Left ventricular and total heart weights were determined. Afterwards, hearts were dried at 80°C for 40 min. to determine dry weights. Ratio of left-ventricular wet to dry weights as well as ratios of wet to body weight were calculated.To determine TNF, IL-1β and IL-6 protein expression after 2 hours of reperfusion, snap-frozen myocardial tissue was homogenized and incubated on ice for 5 min in 1 mL of ELISA buffer containing PBS, Triton X-100 , PMSF  and protease inhibitors . Samples were incubated on ice for 20 min, homogenized and centrifuged for 15 min at 4°C at 16,100 g. The supernatant was used for measuring myocardial TNF, IL-1β and IL-6 protein levels with ELISA .Blood was taken after 2 hours of reperfusion. Serum was assayed for levels of TNF, IL-1β and IL-6. A standard commercially available sandwich ELISA  with a polyclonal antibody, specific for the murine recombinant cytokine, was used.All values are expressed as mean ± SEM. Student's t-test was used for comparison of myocardial infarction size and cardiac function between groups. A one-way ANOVA for repeated measurements was used for heart rate. A Mann-Whitney rank sum test was used for comparison of hemodynamic values. One-way ANOVA on Ranks was used for comparison of heart weights. One-way ANOVA was used for comparison of cytokine levels followed by a Holm-Sidak pairwise multiple comparison. Differences among experimental groups were considered significant with p < 0.05.SK carried out the ischemia/reperfusion experiments, analyses of infarct sizes, heart weights and drafted the manuscript. AG carried out the echocardiography, hemodynamic measurements and drafted the manuscript. HS carried out the ischemia/reperfusion experiments and analyses of infarct sizes and heart weights. KT carried out analyses of echocardiographic images. PK carried out cytokine measurements. AH participated in the design of the study, interpretation of data and revised the manuscript. CG participated in the design of the study and revised the manuscript. AAK participated in the design of the study, interpretation of data, revised and helped to draft the manuscript. GB conceived of the study, and participated in its design and coordination and helped to draft the manusript. All authors read and approved the final manuscript.


Left ventricular free wall rupture (LVFWR) is a fearful complication of acute myocardial infarction in which a swift diagnosis and emergency surgery can be crucial for successful treatment. Because a significant number of cases occur subacutely, clinicians should be aware of the risk factors, clinical features and diagnostic criteria of this complication. We report the case of a 69 year-old man in whom a subacute left ventricular free wall rupture (LVFWR) was diagnosed 7 days after an inferior myocardial infarction with late reperfusion therapy.  An asymptomatic 3 to 5 mm saddle-shaped ST-segment elevation in anterior and lateral leads, detected on a routine ECG, led to an urgent bedside echocardiogram which showed basal inferior-wall akinesis, a small echodense pericardial effusion and a canalicular tract from endo to pericardium, along the interface between the necrotic and normal contracting myocardium, trough which power-Doppler examination suggested blood crossing the myocardial wall. A cardiac MRI further reinforced the possibility of contained LVFWR and a surgical procedure was undertaken, confirming the diagnosis and allowing the successful repair of the myocardial tear. This case illustrates that subacute LVFWR provides an opportunity for intervention. Recognition of the diversity of presentation and prompt use of echocardiography may be life-saving. Left ventricular free wall rupture (LVFWR) is a dramatic complication of acute myocardial infarction (AMI) and is presumably responsible for as much as 20 to 30% of all infarct related deaths -4. GivenHistorically, the first clinical reference to post-infarction left ventricular wall rupture was reported by William Harvey in 1647 .We describe the case of a 69 year-old patient with sub-acute "contained" LVFWR which was successfully treated through surgical correction. The diagnosis was preliminarily established by bedside transthoracic echocardiography, driven by an unexpected change on a routine ECG.The patient was a 69 year-old caucasian male with recently diagnosed diabetes and a history of non-disabling stroke several years before. There was no record of hypertension, hypercholesterolemia, tobacco use or previously known coronary artery disease. Importantly, he was not taking any cardiovascular medication, including ASA.The patient first presented to the emergency department of a referral hospital complaining of lower chest pain and vomiting. The ECG showed no signs of acute ischemia and, as biomarkers of myocardial necrosis tested negative, the patient was discharged with no further evaluation. During the next days, chest pain persisted and, on day five after the initial symptoms, he went back to the emergency. At that time the ECG showed inferior pathological Q waves, slight (~1 mm) ST-segment elevation and biphasic T waves on the inferior leads and a test for cardiac troponin I was positive. The patient was admitted with the diagnosis of subacute inferior myocardial infarction with recurrent angina and anti-thrombotic and anti-ischemic medications (including low molecular weight heparin and GP IIb/IIIa inhibitors) were started. Due to the persistence of chest pain the patient was referred for urgent coronary catheterization, which was performed at our institution on day five after symptom onset. Angiography showed a critical stenosis of the right coronary artery with TIMI 2 grade flow, with no other significant coronary lesions. An angioplasty procedure with deployment of a drug-eluting stent was successfully undertaken and the patient transferred to the CCU for routine monitoring.On day seven after the first chest pain episode, clinicians were surprised by a new and persistent 4 to 5 mm ST-segment elevation affecting leads V1 to V5, I and aVL Figure . There wAs previously mentioned, mechanical complications of acute MI, including LVFWR, apparently tend to become less frequent in day-to-day practice, at least in part due to the our growing ability to deliver safe and effective reperfusion therapies  to a wide range of MI patients.The time frame for the occurrence of LVFWR may vary widely. In the pre-thrombolytic era incidence peaked between days 5 and 7 after the MI, but rupture has been reported to occur as late as one month or even beyond -11.th decade or later), female gender, hypertension without left ventricular hypertrophy, delayed or no reperfusion, the anterior location of the AMI, no prior angina, a first myocardial infarction, poor collateral circulation to the infarct related area, use of NSAIDs or steroids during the acute phase, and high serum levels of C-reactive protein [Traditionally, factors considered to increase the risk of LVFWR would include advanced age  era, female sex has still been reported to be an independent predictor of LV rupture ,12.Despite being theoretically more probable in the inferior-lateral wall, it seems that the fact that anterior infarcts are more common, renders anterior wall ruptures more frequent . Howeverany reperfusion is better than no reperfusion. However, perhaps particularly in elderly patients, the relation between the use and the timing of thrombolytic treatment (which is the most widely used reperfusion strategy) and the risk of LV rupture, has been matter of concern [post-hoc analysis of pivotal clinical trials [et al. found no significant differences in the incidence of LVFWR in patients treated with a rt-PA based regimen within the 6 to 12 hour period after symptom onset and those randomized to the active treatment arm between 12 and 24 hours. However, there was a significant interaction between the assignment to active treatment and the time of rupture occurrence, as thrombolysis appeared to accelerate rupture events, typically to within 24 h after treatment [p = 0.05), this study might have been underpowered to evaluated the benefits of PCI in isolated hard endpoints such as MI-related death.Despite age and general clinical status would have made this patient eligible for on site reperfusion therapy, absence or delay of timely reperfusion (owing to late diagnosis) was perhaps the major risk factor for LVFWR. The reported decrease in the incidence of MI-related cardiac rupture in the thrombolytic and subsequently in the d-PCI era is relatively consistent. Regarding the absolute risk of mechanical complications, there is general agreement in that  concern ,18. This concern . Althougl trials ,20, neitl trials , Becker reatment . Severalreatment , diminisreatment , and digreatment -25. Whetreatment . The relreatment . In thisWhen the acute form of LVFWR occurs, it usually results in an abrupt haemodynamic collapse with cardiac tamponade and electromechanical dissociation. Death ensues in a matter of minutes to hours in the large majority of cases, as cardiopulmonary resuscitation maneuvers are uniformly unsuccessful.Less frequently, in up to one third of the cases, the rupture can be sealed by the epicardium or by a haematoma on the epicardial surface of the heart, forming a "LV diverticulum" or contained myocardial rupture. This situation represents a subacute pathologic condition standing somewhere between free rupture into the pericardial cavity and formation of a pseudoaneurysm ,27-29. TMyocardial free wall rupture should be suspected in patients with recent MI who have recurrent or persistent chest pain, sometimes of the pericardial type, haemodynamic instability, syncope , and pericardial tamponade. New ST segment changes ("saddle shaped ST-segment elevation") may be the chief clinical manifestations ,17. In fIn a scenario of relatively low threshold for clinical suspicion, the unexpected ECG changes were the key to the diagnosis. Otherwise, patient was only to be exposed to the natural history of the disease which, at this point, may be rather unpredictable -17. In oIn those who are haemodynamically unstable, which was not the case of our patient, right heart catheterization will usually provide useful information and may help in the differential diagnosis with other life threatening complications, such as VSD. In the typical patient, right atrial pressure will be comparable to pulmonary capillary wedge pressure .Emergency pericardiocentesis has the potential for the identification of haemopericardium and relief of cardiac tamponade. Despite rarely seen in the acute MI setting, cardiac tamponade may be caused by serous or serohaemorrhagic pericardial effusions; also, the risk of chamber puncture and the theoretical possibility of "thrombus displacement" and "decompression" of the contained rupture, can, not only hamper the diagnostic accuracy of pericardiocentesis, but also make it potentially harmful. Given these considerations, we strongly feel that this procedure should not be "routinely" used as a diagnostic tool and should be kept for situations of absolute need for tamponade relief .If a mechanical complication is suspected, emergency bedside transthoracic and/or contrasted transesophageal echocardiograms are considered the gold standard diagnostic tools .Pericardial effusion is the most common finding, usually with echodense intrapericardial echoes. The absence of pericardial effusion in a patient with AMI excludes the diagnosis of myocardial rupture, but its presence as an isolated finding in this context does not definitively confirm the diagnosis. Right atrial and right ventricular wall compression as well as Doppler signs of a compromised ventricular filling, can also be identified by 2D echocardiography. Direct signs of rupture like a myocardial tear, as in this case, will be seen only occasionally ,17. In aIn our case, Doppler examination suggested an abnormal intramyocardial tract, but could not definitely demonstrate active bleeding into the pericardium. The detection of blood flow at the site of rupture may not be feasible in many cases, as the myocardial tear is most often anfractuous and sometimes covered by thrombi and thus blood flow velocities may be low. Despite the potential ability of contrast echocardiography to decrease the number of false-positive diagnoses -35 – by The role of new imaging techniques in this setting, such as cardiac MRI, although promising, remains observational and anecdotic -38. TriaDespite cases of a fairly good long term survival following a conservative approach have been described ,17, theret al., in a retrospective analysis, reported much poorer results with a survival rate of only 10% [One prospective study reported a 44% survival rate among MI patients with confirmed or strongly suspected LVFWR who survived resuscitation maneuvers after electromechanical dissociation (EMD) or presented only with hypotension without EMD  and wereonly 10% . Intra-aonly 10%  but someonly 10% ,15.The very high surgical risk, which can be unacceptable if the procedure is to end up as "blank" sternotomy, is the major drawback posed to surgeons. Thus, all efforts should be made to confirm the diagnosis in order to reduce the number of false positives. The goals of surgery are to stop bleeding, to relieve cardiac tamponade and to prevent a second rupture. When possible, off-pump sutureless techniques using biocompatible glues and patches to cover the necrotic/ruptured area are increasingly being preferred to infarctectomy and direct myocardial suture, and are thought to yield better results ,15,39,40Despite high perioperative mortality rates (33 to 55%), a rather well preserved post-procedure left ventricular function, as well as a fairly good functional long term prognosis are increasingly being reported ,39-41.This case illustrates that LVFWR is not always fatal especially in patients with the subacute form of presentation, which occurs in about one third of the cases. The diagnosis can be made accurately using bedside echocardiography, as long as clinicians are aware of the risk factors, clinical signs and other subtle manifestations, such as ECG changes. Because the clinical course is unpredictable, excessive confidence in the stability of the patient can be misleading and even fatal. Considering that surgery yields fairly good immediate and long term results, we feel that surgical treatment should be promptly advised to most patients regardless of the clinical status, unless the diagnosis is doubtful and the surgical risk is unacceptably high.PCI – Percutaneous InterventionCRP – C-Reactive ProteinMRI – Magnetic Resonance ImagingNSAIDs – Non-Steroid Anti-Inflammatory DrugsThe author(s) declare that they have no competing interests.LR was responsible for the initial clinical assessment of the patient and diagnostic workup, performed the literature review and wrote the manuscript. MJA performed the bedside echocardiogram, participated in the drafting, and revised the manuscript for important intellectual content. JF and CA participated in the clinical assessment of the patient and diagnostic workup, and revised the manuscript for important intellectual content. RC revised the document for important intellectual content. MC performed the transesophageal echocardiogram. NJT performed the cardiac MRI. MA performed the surgical procedure. JAS gave final approval to the manuscript. All authors read and approved the final manuscript.Movie 1 – 2D-Echo: Subcostal view showing echodense pericardial effusion. Echoes correspond to blood cloths and/or fibrin.Click here for fileMovie 2 – 2D-Echo: Parasternal short axis view showing a myocardial tear in the left ventricular inferior wall.Click here for fileMovie 3 – 2D-Echo: Two-chamber view showing the myocardial tear in the left ventricular inferior wall. Note that it is particularly evident during diastole.Click here for fileMovie 4 – 2D-Echo: Magnified two-chamber view showing the myocardial tear in the left ventricular inferior wall. Note that it is particularly evident during diastole.Click here for fileMovie 5 – 2D-Echo: Apical two-chamber view with Power-Doppler suggesting blood flow across the inferior myocardial wall.Click here for file


Reduced exercise capacity is a key symptom and an independent determinant of mortality in patients with heart failure. We analyzed the running activity of hamsters with cardiac dysfunction after myocardial infarction.In 39 male Syrian hamsters aged 10 to 12 weeks, a myocardial infarction (MI) was produced by permanent ligation of the left coronary artery. Spontaneous running activity in a wheel was monitored daily. After four weeks, left ventricular (LV) hemodynamics (catheter tip manometry) were measured at baseline and during inotropic stimulation . LV infarct size was quantified using planimetry.Four weeks post MI, daily running distance was reduced stepwise in animals with small (4–15 % of LV: 9.8 ± 3.4 km/d) and large (> 15 % of LV: 7.5 ± 3.5 km/d) MI, compared to sham-operated hamsters (11.5 ± 1.5 km/d). Similar reductions were observed in maximum speed and distance of longest running period. MI size influenced daily running distance, maximum speed, and longest running period . MI size also impaired LV systolic and diastolic function under isoprenaline stimulation.The results suggest that myocardial infarction reduces running capacity and isoprenaline stimulated LV function in hamsters, mimicking impaired exercise performance in patients with heart failure. Analysis of running activity in hamsters with myocardial infarction offers a unique opportunity for non-invasive and serial functional assessment of heart failure in the experimental setting. Heart failure (HF) is a clinical syndrome in which the heart loses its ability to pump blood efficiently . A key cIn animals, myocardial dysfunction can be induced by a large number of different methods reflecting the different etiologies of HF in the clinic. Among those, the post myocardial infarction (MI) model in rodents, originally introduced by Pfeffer et al. , has beeIn the present study, we quantified daily wheel-running performance in hamsters with and without myocardial infarction. Unlike other rodents, the hamster has a genetic drive to run long distances spontaneously, which avoids variability in exercise performance due to learning and training effects. Our results suggest that, similar to the clinical situation, the degree of cardiac dysfunction in hamsters can be quantitatively assessed using activity in the running wheel. The hamster post MI model therefore offers a unique experimental setup to study the functional aspects of HF serially and non-invasively.The current study was performed as part of K.H.'s DVM thesis at Aventis Pharma, Frankfurt am Main, Germany. The animal experiments were performed in accordance with Aventis Laboratory Animal Science and Welfare guidelines and the German law for the protection of animals.Male Syrian hamsters were purchased from Harlan-Winkelmann GmbH  and arrived in the animal care facilities at the age of 8–10 weeks. The animals were housed individually in cages which were permanently equipped with a running wheel (diameter 17 cm). A 12:12-h light-dark cycle was kept throughout the experimental period. Ambient temperature and humidity were kept constant at standard conditions. Food pellets and water were provided ad libitum.The wheel-running activity was monitored continuously in 5 min segments by electromagnetic induction using a specialised data acquisition system , connected to a personal computer. Microsoft Excel was used for data processing. After an acclimatisation period of at least ten days, baseline data were taken as the mean of 3 days. After surgical induction of the myocardial infarction , the hamsters were taken back into their cages and wheel-running activity was followed up for four weeks. Hamsters were considered active when more than 20 rotations per 5 min were recorded. Using the raw wheel rotation data, the following parameters were calculated: total daily running distance (in km), maximum running speed (in km/h) and longest running period (in km). In order to account for inter-day variability, daily data were averaged for statistical analysis over three days at baseline and weekly post MI. In addition, in order to assess the fragmentation of the running behavior, daily activity records (actograms) were produced from the day before the terminal experiments, i.e., approximately 4 weeks post MI.The animals were anesthetized with isoflurane (3 % v:v) plus fentanyl  and artificially ventilated (60 times 1.2 mL room air per minute). After opening the chest through the third intercostal space, a myocardial infarction was produced by permanent ligation of the left coronary artery, approximately 5 mm distal to its origin from the aorta. Animals randomly assigned to sham underwent the identical experimental procedure except that no ligation of the coronary artery was produced. Recovery of the animals from the operation was supported by local anesthesia at the sites of incision  and buprenorphin  at the end of the procedure. In addition, the animals were supplemented with furosemide, , metamizol , and enrofloxazine  via the drinking water for the first 5 post-operative days.At two weeks post MI, a transthoracic echocardiography (M-mode) was performed on all hamsters  under light anesthesia (1.5 vol% isofluran). Left ventricular dimensions as well as end diastolic septal and posterior wall thicknesses were measured in a parasternal short axis view at the level of the papillary muscles, according to the leading-edge convention of the American Society of Echocardiography. LV fractional shortening (FS) was calculated as: FS = (EDD – ESD)/EDD where EDD and ESD represent LV end-diastolic and end-systolic dimension, respectively.At four weeks post MI, the hamsters were again anesthetized with isoflurane (1.5 % v:v) plus fentanyl (33 μg/kg i.p.) and artificially ventilated. A catheter tip-manometer  was introduced into the left ventricle via the carotid artery. Heart rate, left ventricular pressure, its derivative dP/dt and the relaxation constant τ [In a pilot study, we had found that mortality was extremely high in hamsters with MI sizes > 30 % of the LV (details not shown). We therefore arbitrarily defined the middle value between 0 and 30 %  as the threshold MI size to distinguish between the small and large infarct size groups. Because we expected a large variability in running performance after the first operation, it was predefined to perform statistical testing at baseline and at the end of the experiments . Differences between groups were tested for significance by two-way ANOVA, followed by Bonferroni posttests. Correlations between MI size (as independent variable) and running parameters or hemodynamic indices (as dependent variables) were calculated using a linear model. Data are reported as mean +/- SD, unless otherwise stated. A p value of less than five per cent was considered significant.The time course of daily distance, maximum speed, and longest running period at baseline and during the post MI period are shown for the three groups in figure Another aspect of daily activity is illustrated by the actograms from all individual animals at four weeks post MI figure . There wThe left ventricular systolic, but not diastolic diameter was increased in hamsters with large MIs. The end diastolic wall thicknesses were reduced in the groups with small or large MIs, compared to the sham group. Fractional shortening was significantly reduced in the animals with MI, compared to sham table .LV hemodynamics during the terminal experiments are shown in table MI size was a significant predictor of daily running activity, as demonstrated in figure The present study demonstrates that activity in the running wheel is reduced in hamsters with chronic myocardial infarction, corresponding to impaired exercise performance in patients with HF. Therefore, analysis of running activity in hamsters with cardiac dysfunction offers a unique opportunity for non-invasive and serial functional assessment of experimental heart failure.Whereas in the clinical setting the degree of exertional dyspnea (assessed using the NYHA classification or quantified with spiroergometry) has been established as both a marker of severity and a predictor of mortality in heart failure, the effect of myocardial infarction on spontaneous exercising has not yet been investigated in animals. In the present study, we used the post MI model to induce cardiac dysfunction because MI is the most frequent single cause for HF in patients . OriginaCompared to an amazing average daily running distance of approximately 13 km at baseline, post MI heart failure resulted in reduction of up to 50 per cent, depending on the MI size. Similarly, both peak running speed and endurance were reduced by approximately 25 and 50 per cent, respectively. We estimate that this reduction can be compared to a clinical severity of NYHA class II-III. Moreover, in our experimental series, several animals were dyspneic and not able to run at all after the MI operation  and did not survive the four weeks follow-up. These hamsters were noted to have very large MIs upon necropsy (> 30 per cent) and were therefore not included in the statistics.Penev et al. have previously performed an analysis of age-related fragmentation of running activity in hamsters . They diThe correlations between infarct size and either running activity or hemodynamic parameters were found to be relatively weak in the present study, and were not observed within the groups. This observation is not surprising, though, given that in patients, infarct size and degree of cardiac dysfunction do not correlate well with heart failure symptoms. Obviously, the extent of heart failure as a clinical syndrome is determined by additional factors, such as the level of neuro-endocrine activation, myocardial remodeling, or the duration of the disease.While myocardial infarction and aging undoubtedly have an influence on wheel running activity in hamsters, the level of physical activity may also have an impact on cardiovascular function and prognosis. In humans, a sedentary life style is an accepted cardiovascular risk factor, and physical activity can improve outcome in patients with heart failure . SimilarIn contrast to hamsters, voluntary wheel running in rats is characterised by a large variability, both over time and inter-individually . MoreoveThe author(s) declare that they have no competing interests.


Insufficient data describe the relationship of hemodynamic parameters to left ventricular (LV) diastolic flow propagation velocity (Vp) measured using color M-mode Doppler echocardiography.An in vitro LV model used to simulate LV diastolic inflow with Vp measured under conditions of varying: 1) Stroke volume, 2) heart rate (HR), 3) LV volume, 4) LV compliance, and 5) transmitral flow (TMF) waveforms (Type 1: constant low diastasis flow and Type 2: no diastasis flow).Univariate analysis revealed excellent correlations of Vp with stroke volume (r = 0.98), LV compliance (r = 0.94), and HR with Type 1 TMF (r = 0.97). However, with Type 2 TMF, HR was not associated with Vp. LV volume was not related to Vp under low compliance, but inversely related to Vp under high compliance conditions (r = -0.56).These in vitro findings may help elucidate the relationship of hemodynamic parameters to early diastolic LV filling. The flow Vp of early diastolic LV inflow measured using color M-mode Doppler echocardiography (CMD) has been recognized as a useful measure of LV relaxation. -4 Vp by We used a customized commercially-available LV model , which was modified to facilitate ultrasound interrogation by placing echo-transducer ports at the side of the LV apex and left atrium. The LV diaphragm, made of silicone rubber, had a hemi-ellipsoid shape . The normal baseline LV volume contained 150 ml of saline. The hydraulic chamber surrounding the LV diaphragm was filled with distilled water. The LV diaphragm was contracted and expanded by a computer-programmed piston pump which controlled the volume of the hydraulic fluid. Pericardial bileaflet bio-prosthetic valves (diameter = 21 mm) were mounted at the aortic and mitral valve sites. Aortic, LV, and left atrial pressure, and aortic or mitral flow rate were monitored during experiments.Aortic and mitral waveforms were programmed to mimic various physiological conditions. We programmed two different types of transmitral waveforms: Type 1 (with constant low velocity diastasis flow) and Type 2 . The transducer (2.5 MHz) was positioned at the LV apex site. The distance between transducer and mitral valve was 7.6 cm. The CMD red-blue interface  velocity was set at 92 cm/sec to avoid signal "bleeding". CMD sweep speed was 200 mm/sec. The echocardiography machine settings were kept constant during all experiments. All CMD images were recorded on an optical disc or CD-ROM, and off-line analysis was performed using commercial software (EchoPac for Vivid 7). The Vp was measured as the slope of the first aliasing velocity from the mitral annulus to 4 cm distal in the left ventricle in early diastole. Vp measurements were performed 10 times for each flow condition.-3; 10 ml air, 9.75 × 10-3; 20 ml air, 16.34 × 10-3; 30 ml air, 17.05 × 10-3; and 40 ml air, 19.92 × 10-3.The following ranges of hemodynamic variables were studied: 1) stroke volume (SV): 50, 60, 70, 80, and 90 ml; 2) heart rate (HR): 40, 50, 60, 70, and 80/min; 3) baseline LV volume (LVV): 130, 150, 180, 200, and 200 ml; 4) LV compliance: five conditions; and 5) transmitral flow (TMF) waveforms (Type 1: featuring constant low diastasis flow between early and late diastolic waves and Type 2: featuring no diastasis flow). LVV was changed by adding distilled water to, or sucking hydraulic liquid from, the hydraulic chamber. Adding 0, 10, 20, 30, or 40 ml of air into the hydraulic chamber and sucking the same volume of hydraulic liquid from the hydraulic chamber changed LV compliance – specifically, the greater the volume of air, the greater the LV compliance. Baseline conditions were: Type 1 waveform, SV = 70 ml, HR = 60/min, LVV = 150 ml, and an LV compliance with 0 ml of air in the hydraulic chamber. LV compliance was calculated as volume change divided by pressure change during the period from the LV-left atrial pressure crossover-point to the minimum LV pressure in early diastole. The LV compliance (ml/mmHg) under 5 experimental conditions was calculated as follows: 0 ml air, 8.32 × 10Vp measurements were made using commercially available software. Vp was measured on two separate occasions on 26 images stored on disc by one reader to estimate intra-reader measurement variability. A second observer, blinded to the measurements made by the first reader, also measured Vp on these 26 images to calculate inter-reader variability.t test and univariate regression analysis. All calculated P values were two-tailed, and a value of P < 0.05 was considered to indicate statistical significance.The association of hemodynamic parameters with Vp was analyzed using Student's paired The mean difference (+ or - SD) of Vp measurements for the same reader was 1.56 ± 0.88 cm/sec (2.0 ± 1.1% mean intra-reader variability). The mean difference (± SD) of Vp measurements between two readers was 1.79 ± 1.16 cm/sec (2.2 ± 1.4% mean inter-reader measurement variability).SV  and LV compliance  both showed excellent correlations with Vp Figures  and 3. WMany investigators have studied diastolic suction. They have characterized diastolic suction as ventricular filling under zero source pressure for filling or peak diastolic negative pressure. The elastic recoil of the relaxing ventricular wall is considered to be the source of the ventricular suction force ,6. CourtUsing computer simulations, Lemmon showed that the effect of delayed relaxation was to decrease the early filling propagation, and this decrease was larger when the stiffness of the ventricle was increased . VierendThe difference in HR relationship to Vp with our two transmitral waveform models (Type 1 and Type 2) may be due to the fact that the waveform program software automatically modifies transmitral velocity-time integral to be equal to the aortic velocity-time integral. There is no in vivo study confirming a HR effect on Vp. However, some previous clinical studies and human or canine studies employing atrial pacing demonstrated that increasing HR was not associated with a change in mitral peak E velocity on pulsed wave Doppler -18. ChenSteen reported, in a mechanical LV model similar to ours, that a larger ventricle had a higher Vp than did a smaller ventricle for the same transmitral peak E wave velocity . The difOur hydraulic LV model had various limitations in simulating the human left ventricle. Specifically, the LV had negligible mass, no papillary muscles and, higher volume compared with the normal human left ventricle, and lacked the LV twisting motion and left atrial contraction with changes in left atrial volume. Also, during LV filling, the position and size of the mitral valve annulus were fixed in our model.We used a mechanical LV model to study how Vp measured by color M-mode Doppler echocardiography varied with changes in stroke volume, heart rate, LV volume, LV compliance, and mitral waveform. Our results documented important relationships between various physiologic parameters and Vp. These studies of Vp should help to elucidate the physiology of early diastolic LV filling. Further studies are needed to investigate the relationship between factors such as left atrial pressure, severity of mitral regurgitation, and mitral annulus size and Vp.Drs. Toshihiro Ogawa, Ajit Yoganathan, Cheryl Nordstrom, Julius Gardin, and Renee Bess all declare that they have no competing interests. Dr. David Walker and Mr. Lawrence Scotten state that during the time of the performance of these studies, they were employees of Vivitro Systems, Inc., which was the manufacturer of the in vitro flow model (Superdup'r SD1002) used in this study.


Diagnosis and differential diagnosis require a careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography. Current management recommendations include empirical, nonspecific and mainly supportive measures. The exact prognosis remains unclear. The extent of cirrhotic cardiomyopathy generally correlates to the degree of liver insufficiency. Reversibility is possible , but further studies are needed.Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes, and macroscopic and microscopic structural changes. The prevalence of cirrhotic cardiomyopathy remains unknown at present, mostly because the disease is generally latent and shows itself when the patient is subjected to stress such as exercise, drugs, hemorrhage and surgery. The main clinical features of cirrhotic cardiomyopathy include baseline increased cardiac output, attenuated systolic contraction or diastolic relaxation in response to physiologic, pharmacologic and surgical stress, and electrical conductance abnormalities . In the majority of cases, diastolic dysfunction precedes systolic dysfunction, which tends to manifest only under conditions of stress. Generally, cirrhotic cardiomyopathy with overt severe heart failure is rare. Major stresses on the cardiovascular system such as liver transplantation, infections and insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can unmask the presence of cirrhotic cardiomyopathy and thereby convert latent to overt heart failure. Cirrhotic cardiomyopathy may also contribute to the pathogenesis of hepatorenal syndrome. Pathogenic mechanisms of cirrhotic cardiomyopathy are multiple and include abnormal membrane biophysical characteristics, impaired  Despiirrhosis -19.In the absence of consensus definitions, the term "cirrhotic cardiomyopathy" is defined at present as: 1) baseline increased cardiac output but blunted ventricular response to stimuli, 2) systolic and/or diastolic dysfunction, 3) absence of overt left ventricular failure at rest, 4) electrophysiological abnormalities including prolonged QT interval on electrocardiography and chronotropic incompetence ,20-22. NWithout firm diagnostic criteria, the exact prevalence of cirrhotic cardiomyopathy remains unknown. Its estimation is a difficult task as the disease is generally latent and shows itself only when the patient is subjected to stress such as body position changes, exercise, drugs, hemorrhage and surgery. The prevalence of liver cirrhosis is also difficult to estimate, because many persons with compensated cirrhosis do not exhibit signs or symptoms of the disease and because noninvasive studies lack sensitivity to detect cirrhosis at early stages. Moreover there is tremendous geographical variability of cirrhosis worldwide, depending on the prevalence of the causative factors such as viral hepatitis B and C, chronic alcoholism, iron overload, autoimmune liver disease, etc.However, we believe that at least one feature of cirrhotic cardiomyopathy, such as electrocardiographic QT prolongation or diastolic dysfunction, is present in the majority of patients with cirrhosis who have reached Child-Pugh stage B or C (representing moderately or severely advanced liver failure). Moreover, diastolic dysfunction is probably present in virtually all patients with cirrhotic cardiomyopathy, and simple echocardiographic indices such as the E/A ratio may detect diastolic dysfunction even at rest. Indeed, once cirrhosis has advanced to a moderate stage, with the accumulation of peripheral edema or ascites, it appears that some element of diastolic dysfunction is universally present. For now, tests of diastolic function by echocardiography or dynamic magnetic reasonance cardiac imaging may therefore represent the best available screening test to diagnose the syndrome.Many aspects of cardiac contraction have been described to be abnormal in cirrhosis, including histology and structure, chronotropic, systolic and diastolic function, and electrophysiological changes.Functional and structural changes in the cardiac chambers have been seen in the left heart, rather than the right. Most studies have found dilatation of the left atrium, and hypertrophy or dilatation of the left ventricle. The right atrium and right ventricle generally have normal dimensions and wall thickness in the absence of the uncommon syndrome of portopulmonary hypertension. Histological changes of cirrhotic cardiomyopathy include myocardial fibrosis, subendocardial edema, and nuclear and cytoplasmic vacuolation of cardiomyocytes [reviewed in ,4,7. Howβ-adrenergic agonist isoproterenol is attenuated in cirrhotic humans and rats [The chronotropic response to the and rats ,23. Cardand rats ,7,22. Stand rats ,14-19. FIn contrast, some element of diastolic dysfunction appears to be more common. Indeed, some authorities contend that some degree of diastolic dysfunction is present in virtually every patient with cirrhosis -18,22. DElectrophysiological changes including prolonged repolarization and impaired cardiac excitation-contraction coupling have been demonstrated in cirrhotic patients -28. RepoIn addition to QT prolongation, Henriksen and colleagues have recently reported that cirrhotic patients show a dispersion of the normal interval between the onset of electrical systole (the electrocardiographic QRS complex) and mechanical systole itself . In otheThe exact mechanism leading to these electrophysiological changes is unclear. In clinical studies, severity of liver disease and circulatory dysfunction are related to prolonged QT interval. Moreover, these changes disappear after liver transplantation in most patients -28. StudOvert heart failure is rare because of the peripheral vasodilatation characteristic of cirrhosis, in effect "autotreating" the ventricle by systemic vasodilatation reducing afterload, and compensatory diminution of inhibitory influences such as the cardiac muscarinic system ,34. AlthStresses such as liver transplantation, infection and procedures such as insertion of transjugular intrahepatic portosystemic stent-shunts (TIPS) can convert latent to overt heart failure. Indeed, heart failure is responsible for 7–15% of mortality following liver transplantation , and in vs large volume paracentesis for treatment of ascites, reported that 12% of the TIPS group developed heart failure compared to none in the paracentesis group [TIPS are often used to treat recurrent or intractable variceal bleeding, or ascites. The abrupt shift of a significant portion of the mesenteric venous blood directly into the systemic venous circulation through these portosystemic shunts dramatically increases the cardiac preload. Several studies have reported abnormal cardiac response to this abrupt increase in preload -44. Theris group . Recentlis group  demonstris group .Recent studies suggest that cirrhotic cardiomyopathy may contribute to the pathogenesis of hepatorenal syndrome (HRS) precipitated by spontaneous bacterial peritonitis -51. Thesβ-adrenergic receptor signalling pathways, altered cardiomyocyte plasma membrane physicochemical properties, and overactivity of negative-inotropic factors such as nitric oxide, carbon monoxide and endocannabinoid systems [There is no direct genetic predisposition to cirrhotic cardiomyopathy. The pathogenic mechanisms of cirrhotic cardiomyopathy include impairment of stimulatory  systems ,22.β-adrenergic receptor system. When stimulated by norepinephrine or other catecholamines, the β-adrenergic receptor-ligand complex couples with G-protein to stimulate membrane-bound adenylate cyclase, generating cAMP which phosphorylates several proteins leading to intracellular calcium fluxes. The calcium then causes actin-myosin cross-linking, and thus cellular contraction [Heart cell contractility is mainly determined by the stimulatory traction .β-adrenergic signaling pathway and lipid composition of the membrane bilayer [β-adrenergic receptors [Cardiomyocyte plasma membranes isolated from a rat model of cirrhosis show multiple defects in the  bilayer ,54. Due  bilayer ,54. Decreceptors .Other mechanisms include increased inducible nitric oxide synthase (iNOS) activity with overproduction of NO -57, and via CB1 receptors contributes to blunted contractile responsiveness to β-adrenergic stimulation [Myocardial endocannabinoid production may be increased in response to stresses such as increased heart rate and hemodynamic overload ; these smulation .To date, there is no single diagnostic test that can identify patients with this condition. The heart produces and releases peptide hormones such as natriuretic peptides, and in other conditions, increased release of these hormones indicates cardiac stress or distress. For example, levels of brain natriuretic peptide, also called B-type natriuretic peptide (BNP), are elevated in systolic and diastolic dysfunction, ventricular hypertrophy and myocardial ischemia ,65. In cβ-adrenergic receptors in the cirrhotic heart. Recently, Torregrosa et al. [Some studies have used the measurement of systolic time intervals as a noninvasive tool to evaluate ventricular contractile performance in cirrhosis. The preejection period (PEP) to left ventricular ejection time (LVET) ratio is an important parameter for assessing left ventricular contractile function. In cardiomyopathy of all types, PEP is prolonged and LVET is shortened; thus, PEP/LVET is increased . Howevera et al.  studied Many cardiac conditions resulting in mild or moderate left ventricular failure may mimic cirrhotic cardiomyopathy. Patients with liver disease may also have concomitant primary cardiac diseases such as ischemic heart disease, hypertensive cardiomyopathy or alcoholic cardiotoxicity. Whether patients with cirrhosis are somehow protected from developing coronary atherosclerosis remains unclear. Although this was formerly accepted as dogma, more recent evidence suggests that cirrhotic patients can indeed manifest severe coronary artery disease . In WestA careful assessment of patient history probing for excessive alcohol, physical examination for signs of hypertension such as retinal vascular changes, and appropriate diagnostic tests such as exercise stress electrocardiography, nuclear heart scans and coronary angiography will help distinguish these conditions from cirrhotic cardiomyopathy.The exact prognosis of cirrhotic cardiomyopathy remains unclear. The weight of evidence indicates that the clinical features of the syndrome become more prominent or worsen in parallel with progression of liver failure [reviewed in ,22. In oThe optimum management of cirrhotic cardiomyopathy has not been established since there are neither "gold standard" diagnostic criteria nor specific treatments at present, recognition of cirrhotic cardiomyopathy depends on a high level of awareness for the presence of this syndrome, particularly in patients with advanced cirrhosis who undergo significant surgical, pharmacological or physiological stresses.If heart failure becomes overt, the usual treatments should be initiated as for all forms of congestive heart failure, including bedrest, oxygen, diuretics and careful preload reduction by drugs ,73.β-adrenergic receptor is desensitized in cirrhotic cardiomyopathy, inotropic β-agonists such as isoproterenol and dobutamine may not benefit patients with cirrhotic cardiomyopathy. In this regard, previous studies have demonstrated markedly attenuated vascular responses to isoproterenol and dobutamine in cirrhotic patients without overt evidence of heart failure [Because the  failure ,74.β-blockade remain generally untested in humans or animals with cirrhosis. Henriksen and colleagues have reported that acute administration of a single dose of the β-blocker propranolol improves the prolonged electrocardiographic QT interval in cirrhotic patients [i.e., reduced left ventricular chamber sizes and wall thickness. However, while diastolic function improved slightly, these did not reach statistical significance. The authors suggested, quite reasonably, that a more prolonged course of treatment might have allowed such changes to reach significance. In any case, angiotensin/aldsterone inhibitors appear to be a very promising potential treatment for cirrhotic cardiomyopathy and need further study.There remains a significant paucity of human or animal data about specific pharmacological treatments ,75. Specpatients , but whepatients . Much fupatients  recentlyet al. [Orthotopic liver transplantation (OLT) remains the gold standard of curative therapy in most liver diseases. Even though the immediate perioperative stresses, particularly increased arterial pressure (thus increased afterload) associated with this operation may unmask latent or overt myocardial dysfunction ,79, yet et al.  in a proet al. . These ret al. .Consensus definition criteria, specific diagnostic tests, the exact prevalence of this syndrome and appropriate management strategies are all unresolved questions requiring further study.Cirrhotic cardiomyopathy is the term used to describe a constellation of features indicative of abnormal heart structure and function in patients with cirrhosis. These include systolic and diastolic dysfunction, electrophysiological changes and macroscopic and microscopic structural changes. The functional changes often require a significant stress challenge  to become manifest. To date, there is no single diagnostic test that can identify patients with this condition. Reversibility is possible , but further studies are needed.


Subaortic and midventricular hypertrophic cardiomyopathy in a patient with extreme segmental hypertrophy exceeding the usual maximum wall thickness reported in the literature is a rare phenomenon.A 19-year-old man with recently diagnosed hypertrophic cardiomyopathy (HCM) was referred for sudden death risk assessment. The patient had mild exertional dyspnea , but without syncope or chest pain. There was no family history of HCM or sudden death. A two dimensional echocardiogram revealed an asymmetric type of LV hypertrophy; anterior ventricular septum = 49 mm; posterior ventricular septum = 20 mm; anterolateral free wall = 12 mm; and posterior free wall = 6 mm. The patient had 2 types of obstruction; a LV outflow obstruction due to systolic anterior motion of both mitral leaflets (Doppler-estimated 38 mm Hg gradient at rest); and a midventricular obstruction (Doppler-estimated 43 mm Hg gradient), but without apical aneurysm or dyskinesia. The patient had a normal blood pressure response on exercise test and no episodes of non-sustained ventricular tachycardia in 24-h ECG recording. Cardiac MRI showed a gross late enhancement at the hypertrophied septum. Based on the extreme degree of LV hypertrophy and the myocardial hyperenhancement, an implantation of a cardioverter-defibrillator was recommended prophylactically for primary prevention of sudden death.Midventricular HCM is an infrequent phenotype, but may be associated with an apical aneurysm and progression to systolic dysfunction (end-stage HCM). Midventricular hypertrophic cardiomyopathy (HCM) is an infrequent phenotype, but may be associated with an apical aneurysm and progression to systolic dysfunction (end-stage HCM) .A 19-year-old man with recently diagnosed HCM was referred for sudden death risk assessment. The patient had mild exertional dyspnea , but without syncope or chest pain. There was no family history of HCM or sudden death. The patient's blood pressure was 130/70 mmHg and a grade 3–4/6 systolic ejection murmur was present at the apex. ECG showed a left ventricular (LV) hypertrophy with strain pattern. A two dimensional echocardiogram revealed an asymmetric type of LV hypertrophy; anterior ventricular septum = 49 mm; posterior ventricular septum = 20 mm; anterolateral free wall = 12 mm; and posterior free wall = 6 mm  .Movie representing 2 types of obstruction. This movie shows a three-chamber view with a combination of 2 different flow jets, one in the mid of left ventricle and the other in the outflow tract.Click here for file


Advances in pacemaker technology in the 1980s have generated a wide variety of complex multiprogrammable pacemakers and pacing modes. The aim of the present review is to address the different rate responsive pacing modalities presently available in respect to physiological situations and pathological conditions. Rate adaptive pacing has been shown to improve exercise capacity in patients with chronotropic incompetence. A number of activity and metabolic sensors have been proposed and used for rate control. However, all sensors used to optimize pacing rate metabolic demands show typical limitations. To overcome these weaknesses the use of two sensors has been proposed. Indeed an unspecific but fast reacting sensor is combined with a more specific but slower metabolic one. Clinical studies have demonstrated that this methodology is suitable to reproduce normal sinus behavior during different types and loads of exercise. Sensor combinations require adequate sensor blending and cross checking possibly controlled by automatic algorithms for sensors optimization and simplicity of programming. Assessment and possibly deactivation of some automatic functions should be also possible to maximize benefits from the dual sensor system in particular conditions. This is of special relevance in patient whose myocardial contractility is limited such as in subjects with implantable defibrillators and biventricular pacemakers. The concept of closed loop pacing, implementing a negative feedback relating pacing rate and the control signal, will provide new opportunities to optimize dual-sensors system and deserves further investigation. The integration of rate adaptive pacing into defibrillators is the natural consequence of technical evolution. The advances in pacemaker technology in the 1980s have generated a wide variety of complex multiprogrammable pacemakers and pacing modes. Pacing systems can be classified as (1) single lead ventricular, such as VVI or ventricular demand; (2) atrial based, single lead, such as AAI or atrial demand; or dual chamber, such as DDD, which senses and paces from atrial and ventricular chambers. These pacing modalities may or may not be rate adaptive or sensor-driven. In the pacemaker code, rate adaptive pacemakers are designated with a fourth letter R, for example a rate adaptive DDD becomes DDDR. Rate adaptive pacemakers are useful for patients who cannot increase their heart rate appropriately on exercise.The goal of new technologies is to come as close as possible to sinus node electrical activity, combining the need of regular ventricular rate to a better quality of life. In this context the clinical benefit of increasing ventricular rate, and consequently cardiac output, during physical activity in patients with “chronotropic incompetence” consequent to Sick Sinus Syndrome or advanced AV block, has been established by different studies -7.The ACC/AHA guidelines  define cMany studies have shown that during exercise, an increase in the pacing rate provided by VVIR, VDD, DDD or DDDR modes augments the cardiac output, achieved workload, and duration of exercise more than does fixed-frequency VVI pacing in patients with both normal or impaired LV function -7,12-15.When patients with complete AV block exercise, the sinus rate is significantly higher with VVI pacing than during dual chamber or VVIR modes, a response possibly reflecting the increased activity of the sympathetic nervous system when pacing is set on VVI mode -19. IndeIn patients with atrial chronotropic incompetence, VVIR and DDDR pacing modes are clearly superior to the DDD mode in terms of exercise performance, because the sensor increases the pacing rate according to metabolic needs. Most studies -21. on pMoreover, preliminary data suggest that rate adaptive AAIR and DDDR modes may be more efficacious in preventing atrial arrhythmias than their non rate adaptive counterparts in Sick Sinus Syndrome -24. DDDRRate-adaptive pacing has been designed to increase heart rate according to metabolic needs during physical, mental or emotional activity.  Rate responsive pacemakers control heart rate by sensing physiological or nonphysiological signals other than atrial rate.Ideally the rate adaptive sensors should reproduce the sinus node as close as possible; therefore some definite properties must be accomplished: (1) the chronotropic output should respond as promptly as the normal sinus node. (2) Sensors should perform a highly specific and sensitive detection of the need of increasing heart rate. (3) These latter have also to be proportional to metabolic demand. (4) Rate decay during recovery after exercise should match metabolic needs ; (5) it should ideally operate in a closed loop system, making rate adaptive pacing also insensitive to inputs not heart related. Finally, (6) dedicated sensors should avoid undesiderable overpacing and the need of complex programming.Different parameters have been investigated for controlling the pacemaker rate: oxygen saturation , venous Activity sensors are the older and more widely used. The working modality is based on the relationship between activity and heart rate. Activity may be acknowledged either by a piezoelectric crystal, which recognizes the muscular pressure waves, produced by physical activity and convert them to an electrical signal sent to the pacemaker, or by an accelerometer that identifies the postural changes and the body movements related to physical activity.Activity sensors offer rapid response to exercise by assessing body vibrations or movements. A rapid response plays an important role in “burst activity” during daily life. Fast reaction to termination of short exercise and technical simplicity that allows for instance to tailor the rate response (RR) to the single patient with proper treadmill protocols,  represenMetabolic sensors, based on QT interval, minute ventilation (MV) or peak endocardial acceleration, provide pacing rates more closely and specifically related to physical and mental stress requirements.Minute ventilation, the product of respiratory rate and tidal volume, is a physiological indicator that has been shown to be correlated with metabolic demand ,39. ThisLimitations of the MV sensor include the lower reliability in patients with obstructive pulmonary disease, false positive reaction in hyperventilation or interference with cardiac monitors  and postMore recently, a sensor that assesses mechanical vibrations generated by the myocardium during the isovolumetric contraction phase , has been developed. A micro accelerometer is housed inside a rigid, perfectly hermetic capsule inserted in the tip of a standard unipolar pacing lead. The rigidity of the capsule prevents the generation of artifacts that may arise from compression of the electrode by the cardiac muscle during contraction. Therefore, the sensor is only sensitive to the inertial forces generated by myocardium movements. An associated electronic circuit pre-processes the signal to ensure its correct transmission trough the catheter.Experimental and clinical trials have shown that ∆PEA is correlated with dP/dT max ,45,46 anPEA sensor is usually combined with activity sensors, however, in view of its rapid and appropriate heart rate response in different conditions, the possibility to use PEA sensor as a single sensor should also be considered.As previously described no single sensor can reproduce sinus node behavior in all the different activities of daily life. To overcome these limitations a possible option is to combine two different sensors. Rate modulation has to be considered at three different levels: (1) short term response for effort or emotions; (2) medium term adaptation for circadian variation of heart rate during day- and night-time; and (3) long term regulation to obtain different rate variations according to rest and activity periods .Combining different sensors might more closely mimic intrinsic heart rate, if the chosen sensors are complementary. The most common combination include association of an activity sensor giving a rapid response for light or for short duration exercise, and a metabolic sensor, e.g. QT interval or minute ventilation (MV) that provides a delayed but proportional and stable acceleration to sustained exercise and deceleration during recovery . AnotherIndependently of the choice of sensors and mode of integration, algorithms for sensors optimization determine the performance of dual sensor rate adaptive pacemakers. Combining sensors with different rate responses requires adequate blending of respective sensor activities. Blending can be performed at signal production. The resulting signal transmitted to the algorithm is a mixture of a percentage of activity sensor signals (0%…10%) with an inverse percentage of non activity sensor signals (100%…0%). This blending modality is used for instance in the Vitatron device, combining QT interval and activity in 5 different possibility. This blended signal is transmitted to the algorithm working with a variable automatic slope .Another possibility for sensor blending is priorization as in Medtronik Kappa 400: the activity sensor initially accelerates from the lower rate to a plateau (programmable 90-95 b/min). The rate returns to the lower rate if activity stops, or is proportionally increased from the plateau up to the sensor maximal programmed rate, if the minute ventilation sensor activates. MV sensor is then in charge during the recovery rate decrease.Sensors cross checking are used to avoid inappropriate rate increase. During crosscheck both sensors can control each other and the pacing rate will only be changed if both or a predominant sensor agrees. For example, after administration of a drug that shortens the QT interval, a QT interval sensor would indicate the need for rate increase, but the pacing rate would not change because the activity sensor is not activated. Conversely, passively tapping on the device would activate the activity sensor and indicate a rate increase, but the pacing rate would not be modified because the QT-interval sensor would not be activated by this manouver.2 consumption measurement during physical exercise (cardiopulmonary stress test) should be used. Alternatively an algorithm computing the best correlation between heart rate and metabolic needs, such as  Pacing Rate Profile Software (PRPS), ought to be used [Algorithms for sensors optimization determine the performance of dual-sensor rate-adaptive pacing systems. Automatic setting has been developed in complex pacemakers to simplify programming and optimize time. It is necessary for physicians to be able to verify that rate adaptive pacemakers respond correctly, according to the patient’s need. Nevertheless, even though these systems are generally reliable , manual  be used .Future devices may provide the opportunity to use physiologic sensors to monitor cardiac function and to adapt pacemaker function to assist therapy for associated disorders. Multisensor devices can be used for cardiac rehabilitation in pacemaker dependent patients, particularly the elderly and affected by cardiopulmonary disease. These patients deserve a physically and psychologically autonomous life style, which may be accomplished by using two rehabilitation methods: (1) the set up of appropriate rate response; and (2) the institution of aerobic training programs  for in- Moreover, the integration of rate adaptive pacing into biventricular pacemakers and implantable defibrillators is a natural consequence of technical evolution. The rationale for the use of rate adaptive pacing in implantable defibrillators is the same as for pacemaker.  In normal heart, an increase in oxygen uptake from 3 to 50 mL/kg per minute in a healthy subject is due to an increase of oxygen extraction rate, stroke volume (by a factor of 1.5) and heart rate (by a factor of 3). This allows a 4-5 fold increase in cardiac output compared to resting values. In the large majority of patients receiving an implantable defibrillator, the contractility reserve is limited. Therefore, an increase in cardiac output is strictly related to the possibility of increasing heart rate. Concomitant therapy with beta blockers, amiodarone or other antiarrhythmic drugs may also impair the chronotropic response. This makes the issue of chronotropic competence crucial in patients with biventricular stimulation and implantable defibrillator despite the fact that only 20% of these latter need primarily a cardiac pacing .The concept of closed loop pacing should be the next step in future technical developments. Sensors that could be used in a closed loop system, indicating whether heart rate is adequate to a given metabolic situation, are endocardial accelerometers and sensors using impedance derived ventricular signals. It might take some time to test technical feasibility and clinical reliability of those closed loop systems before they will be implemented in cardiac pacemakers and implantable defibrillators or biventricular pacemakers.


Cardiac resynchronisation therapy (CRT) using biventricular (BIV) pacing has proved its effectiveness to correct myocardial asynchrony and improve clinical status of patients with severe congestive heart failure (CHF) and widened QRS. Despite a different effect on left ventricular electrical dispersion, left univentricular (LV) pacing is able to achieve the same mechanical synchronisation as BIV pacing in experimental studies and in humans. This results in clinical benefits of LV pacing at mid-term follow-up, with significant improvement in functional class, quality of life and exercise tolerance at the same extent as those observed with BIV stimulation in non randomised studies. Furthermore these benefits are obtained at lesser costs and with conventional dual-chamber devices. However, LV pacing has to be compared to BIV pacing in randomised trials before being definitely considered as a cost-effective alternative to BIV pacing. Despite advances in drug treatment, congestive heart failure (CHF) remains a major health care problem associated with a poor quality of life and a high mortality rate. During the past decade, cardiac resynchronisation therapy (CRT) using biventricular (BIV) pacing emerged as a promising technique improving quality of life, exercise tolerance and mortality -3, and iMany other arguments support the concept that LV univentricular pacing by reversing intraventricular dysynchrony is sufficient in humans to improve LV function and clinical status at the same extent and at a lower cost-effective ratio than BIV pacing and this is in accordance with the fact that intraventricular asynchrony seems more relevant that interventricular asynchrony to predict prognosis in patients with dilated cardiomyopathy .The first clinical series with CRT were performed empirically using BIV pacing . However2 (2.46 ml/mn/kg), in 6 minute walk distance (47 m) and a decrease in quality of life score (8.1) during the active pacing period in the group of patients with the longest  QRS duration (above 150 ms) [2 by 26 %) and norepinephrine level by 37% [Whether or not these hemodynamic benefits result in sustained improvement of clinical status during permanent LV stimulation has not been extensively investigated until now. However, some studies reported significant improvement in both exercise tolerance and quality of life at mid-term  follow-up during chronic LV pacing ,19 or fa 150 ms) . In anot 150 ms) . Our perl by 37% .Are these clinical effects correlated with improvement in myocardial synchrony? This is an important issue on a physiopathological point of view and for the selection of candidates for LV pacing. In an interesting experimental study using a canine model of cardiac failure and left bundle branch block, Leclercq et al examined mechanical and electrical synchrony during right atrial, LV and BIV stimulation; as expected, electrical dispersion decreased during BIV pacing whereas it increased during LV pacing; however, despite this opposite action upon electrical phenomena, the same improvement in mechanical coordination within the LV, measured by tagged magnetic resonance imaging, was observed with LV and BIV pacing, and this was correlated with improvement in hemodynamics (25 % increase in dP/dt and aortic pulse pressure) . SimilarBy comparison to BIV pacing, LV pacing offers several technical and economical advantages : 1) if insertion of a third lead (the right ventricular one) is not the most difficult part of the operative procedure, it could prolong significantly its duration and the X-ray exposure; 2) the presence of 3 leads instead  of 2 induces certainly more adverse events and increases the risk of venous thrombosis or mechanical complications; 3) more importantly, uniLV pacing needs only a less complex to program and less often subject to dysfunction conventional dual-chamber  pacemaker. Finally, BIV pacing is more expensive than LV pacing as it implies implantation of a supplementary right ventricular lead and of a specific and more costly device: in Europe, the extra cost could be approximately evaluated at 30 % and this must be taken in account in the context of the growing “epidemic” of heart  failure consecutive to demographic ageing and of the control of medical expenses in many countries.So, at this time, there are no arguments in favour of the hypothesis that, for patients with severe CHF and enlarged QRS duration, BIV pacing would be significantly more effective than LV pacing in terms of mechanical coordination, hemodynamic and clinical benefits. However, our knowledge about the effects of LV pacing still suffers some limitations: the present studies are only observational and non-randomised. Furthermore, it seems, as shown during acute hemodynamic studies, that in some patients LV pacing would not be as effective as BIV pacing , and this could perhaps be the case in patients with a dysfunctional right venricle but no study have focused on this topic at this time. Finally  and unlike BIV pacing ,23, no s


Heart failure as a result of a variety of cardiac diseases is an ever growing, challenging condition that demands profound insight in the electrical and mechanical state of the myocardium. Assessment of cardiac function has largely relied on evaluation of cardiac motion by multiple imaging techniques. In recent years electrical properties have gained attention as heart failure could be improved by biventricular resynchronization therapy. In contrast to early belief, QRS widening as a result of left bundle branch block could not be identified as a surrogate for asynchronous contraction.The combined analysis of electrical and mechanical function is yet a largely experimental approach. Several mapping system are principally capable for this analysis, the most prominent being the NOGA-XP system. Electromechanical maps have concentrated on the local shortening of the reconstructed endocardial surface from end-diastole to end-systole. Temporal analysis of motion propagation, however, is a new aspect. The fundamental principles of percutaneous catheter based activation and motion assessment are reviewed. Related experimental setups are presented and their main findings discussed. The evaluation of cardiac motion has traditionally been based on cine-angiography and echocardiography. Both methods being essentially two-dimensional share inherent limitations, as approximations are needed to quantify basic parameters like stroke volume and ejection fraction. Since the mid-1990s a non-fluoroscopic navigation technique entered the catheterization suites around the world . ShortlyThe therapeutic options to treat advanced heart failure today include resynchronization therapy. Further insight into the mechanisms underlying asynchronous contraction due to different myocardial alterations can be expected from combined activation and motion analysis. Other experimental approaches like localized stem cell or growth factor application ,9 may utWith the development of magnetic resonance tissue tagging an elegant method for a truly three-dimensional analysis and quantification of local myocardial function is now available . From MRFor each point engaged by the mapping catheter the exact location in three-dimensional space is recorded. The series of locations of a single cardiac cycle makes up an elliptical shaped path with the major axis pointing towards the apex. With the recording of consecutive cycles, the trajectory takes up a helical shape. Each cycle gives rise to one loop of the helix . This phThe myocardium as a continuous structure transmits local deformation to neighboring areas. Any locally measured myocardial velocity therefore reflects active as well as passive motion. Obtaining strain data from closely spaced points by subtracting motion components from adjacent points can theoretically overcome this problem. Practically, spacing between points is random thereby introducing a varying error. Furthermore, spatial resolution of magnetic catheter tracking and beat-to-beat variability  is compaTo overcome this problem, the NOGA-system employed a local shortening formula that averaged the change in distance between an index point and all its recorded surrounding points from late diastole to maximum systole . To accoThe exact influence of tethering is unknown and is dependent on the elastic properties of the myocardium. Insights gained from angiography show that motion of hypo- or akinetic areas is dramatically reduced also in a static frame of reference. Therefore delineation of these areas is possible without strain analysis and correlates with bipolar voltage amplitude recorded at these sites . A methoStable contact of the catheter tip with a particular endocardial point during the cardiac cycle is of paramount importance when using the positional information for quantitative analysis of the myocardial contraction. In early studies Ben-Haim et al.  and GepsFor practical purposes certain approaches should be avoided for cardiac motion mapping. By bending the catheter by 180 degrees, i.e. using loops, the tip may loose contact with the endocardium during systole when the proximal shaft is shifted by contraction of the apex. The transseptal approach via the mitral valve is complicated by the mitral leaflets, papillary muscles, and tendons. A direct approach with little twisting of the catheter should be preferred.Several criteria as published by Koronowski et al.  had to bFor the analysis of motion timing some of the strict criteria can be modified. Reproducing the morphology of the intracardiac electrogram during consecutive beats is sufficient to ensure an unchanged position during diastole. Small beat-to-beat variations in the catheter tip trajectory are negligible since the absolute velocities remain almost unchanged.As for the assessment of motion, timing ideally is calculated from local data. Strain rate being the time derivative of strain is used in conjunction with MRI . CalculaOther parameters derived from absolute displacement or strain analysis have been proposed. Zwanenburg et al.  used theWhen compared with myocardial motion, defining an activation-time seems trivial. But we encounter analogous problems. In the experimental setting, intracellular recordings exactly define activation by the upstroke of the membrane potential. When compared with unipolar recordings obtained from the surface of homogeneous myocardial slabs a good approximation is the time at maximum down-slope of the unipolar electrogram ,21. UnipEarly studies of combined activation and motion analysis concentrated on a limited area of the left ventricle. Prinzen et al.  measuredA replacement of epicardial contact mapping could be the use of magnetocardiography sensor arrays. Using this approach electrical potentials on the epicardial surface are calculated from signals recorded on the patient's skin. This method was adopted by Jeremic et al.  and promToday, the most dedicated platform to assess left ventricular mechanics is the NOGA-XP ,2 systemThe Ensite Array and NavX technologies  ,34 that The Realtime Position Management system  ,36 utiliMismatches between cardiac activation and motion propagation are of growing interest in the evaluation of heart failure patients who are candidates for resynchronization therapy. In addition, the role of this mismatch in the evolution of heart failure is largely unknown.Electromechanical remodeling in the ischemic heart has probably fundamental differences to the process occurring in idiopathic dilated cardiomyopathy. A change of activation and motion propagation may as well serve as a sensitive surrogate for the state of the disease and consequently as a marker for reverse remodeling. The latter is of importance in the delivery of stem cells or growth factors which is feasible using NOGA ,9,37,38.Activation and motion mapping is a valuable extension of currently available mapping techniques. Several catheter tracking systems meet the technical prerequisites to establish motion analysis. Most of the necessary online tools to sample catheter motion have already been included in the NOGA-XP system. Studies are warranted to define the role of activation and motion propagation in the definition of heart failure and cardiac remodeling. Being largely experimental today, the step from bench to bedside seems possible in the near future.


Cardiac dysfunction after right ventricular (RV) apical pacing is well known but its extent, time frame of appearance and individual effect on left ventricular (LV), RV systolic and diastolic parameters has not evaluated in a systematic fashion.Patients with symptomatic bradycardia and ACC-AHA Class I indication for permanent pacemaker implantation (PPI) were implanted a single chamber (VVI) pacemaker. They were followed prospectively by echocardiographic examination which was done at baseline, 1 week, 1 month and 6 months after implantation. Parameters observed were chamber dimensions (M-line), chamber volumes, cardiac output (modified Simpson's method), systolic functions  and diastolic functions( isovolumic relaxation time & deceleration time) of left and right heart.Forty eight consecutive patients  implanted a VVI pacemaker were enrolled in this study. The first significant change to appear in cardiac function after VVI pacing was in diastolic properties of RV as shown by increase in RV isovolumic relaxation time (IVRT) from 65.89±15.93 to 76.58±17.00 ms,(p<0.001) at 1week and RV deceleration time (DT) from 133.84±38.13 to 153.09±31.41 ms, (p=0.02) at 1 month. Increase in RV internal dimension (RVID) from 1.26±0.41 to 1.44±0.44, (p<0.05) was also noticed at 1 week. The LV diastolic parameters were significantly altered after 1 month with increase in LV-IVRT from 92.36±21.47 to 117.24±27.21ms, (p<0.001) and increase in LV DT from 147.56±31.84 to 189.27±28.49ms,(p<0.01). This was followed by LV systolic abnormality which appeared at 6 months with an increase in LVPEP from 100.33±14.43 to 118.41±21.34ms, (p<0.001) and increase in LVPEP/LVET ratio from 0.34±0.46 to 0.44±0.10, (p<0.001)]. The reduction in LV EF was manifested at 6 months falling from 61.82±10.36% to52.52±12.11%, (p<0.05) without any significant change in the resting cardiac output.The present study shows that dysfunction of right ventricle is the first abnormality that occurs in VVI paced patients, which manifests by 1 week followed by LV dysfunction which starts appearing by 1 month and the diastolic dysfunctions precede the systolic dysfunction in both ventricles. Single chamber right ventricular apical pacing (VVI) continues to be the predominant pacing mode in the developing countries primarily due to economic constraints, despite the well-known advantages of dual chamber pacing. Pacemaker induced myocardial dysfunction has been recognized for a long time and the effect of single chamber right ventricular (RV) apical pacing (VVI) on left ventricular (LV) functions has been studied previously, yet  there remain some unexplored areas such as the chronology of events to occur -8. MajorAll consecutive patients undergoing VVI pacemaker implantation having a class I indication according to AHA guidelines  were incA thorough clinical evaluation and resting 12-lead electrocardiogram (ECG) were done at admission, on day 7 after PPI and on follow up at 1 month and 6 months. Patients were discharged with a programmed pacing rate of 70/mt. At follow up visits, patients were evaluated for any evidence of a new onset dyspnea attributable to pacemaker syndrome, in the absence of any recognizable recent myocardial infarction, anaemia, respiratory illness and new LV ejection fraction of less than 50% ,11. The Baseline echocardiographic evaluation was done within 24 hours of hospital admission with the temporary pacemaker rate being kept at 70/mt. In the event of intact atrio-ventricular (AV) conduction, echocardiography was done on right ventricular temporary pacing at a rate 10 beats higher than the  intrinsic sinus rate. Echocardiography was repeated at day 7, 1 month and 6 months after implantation.  Each measurement was taken in three consecutive paced beats not preceded by a sinus P wave and the average was considered as the representative value.LV end diastolic and systolic volumes (LVEDV and LVESV) were calculated using modified Simpson's method. Left ventricular internal diameter in diastole (LVIDd) and systole (LVIDs) and fractional shortening (FS) were measured in parasternal long axis view using the M-mode. The right ventricular internal diameter in diastole (RVIDd) and systole (RVIDs)  were taken in the parasternal long axis view and their mean was taken as the RVID. Left atrial size was measured in systole (LAs) and diastole (LAd) on M-line in parasternal long axis view. Left sided systolic time intervals; LV pre ejection period (LVPEP) and LV ejection time (LVET) were calculated using Doppler aortic flow. Right sided systolic time intervals, RV pre ejection period (RVPEP), and RV ejection time (RVET) were calculated  using Doppler pulmonary flow. The LV diastolic parameters were calculated in apical 5-chamber view keeping the Doppler cursor at a point where both aortic outflow and mitral inflow could be obtained. The LV isovolumic relaxation time (LV-IVRT) was taken as a period from end of aortic flow to beginning of mitral inflow. The acceleration and deceleration time of mitral inflow (MV-AT and MV- DT) were measured from the onset of the mitral inflow to its peak and from peak to return to baseline respectively with the Doppler cursor placed just beyond the mitral annulus in apical four-chamber view. The RV isovolumic relaxation time (RV-IVRT) was calculated using two views. First, the RV electromechanical systole was calculated in parasternal short axis view using Doppler pulmonary flow. This was taken as the period from Q-wave on ECG to the completion of pulmonary flow. An average of three such readings was taken. Then the tricupid valve Doppler inflow tracing was taken in apical four chamber view in the manner similar to mitral inflow. The RV electromechanical systole was marked on this. This point was taken as beginning of the RV diastole and the period from this point to the beginning of tricuspid inflow was taken as RV-IVRT. The tricuspid acceleration and deceleration time (RV-AT and RV-DT) were measured in a manner similar to mitral AT and DT. The systemic and pulmonary cardiac outputs were calculated using velocity time integral (VTI) method across aortic and pulmonary Doppler flow respectively. Colour Doppler was used to conform and quantify AV valvar regurgitation, using area of the regurgitant jet relative to the size of LA ,12.Student 't' test was used for statistical evaluation. The paired 't' test was used to compare the baseline values with the values at day 7, 1 month and 6 months respectively. A 'p' value of <0.05 was considered to be significant. Parameters compared were LVIDd, LVIDs, LVEDV, LVESV, RVID, LVEF, LVFS, LVPEP, LVET, RVPEP, RVET, LAd, LAs, systemic and pulmonic cardiac output, LV-IVRT, LV- AT& DT, RV-IVRT, RV- AT & DT. The effect of confounding parameters as age (< 50 versus > 50 years), sex , indication (complete heart block versus Sick Sinus Syndrome), LV dysfunction (LVEF < 50% versus > 50%) and the requirement of pacing  (intermittent versus regular) were also studied using two way 't' test.Forty-eight patients underwent VVI pacing. Three of the 48 patients had poor echo window and were  excluded from the final analysis. Over the 6 months follow up, 2 patients died. One patient had a haemorrhagic stroke and the other having documented coronary artery disease died suddenly. Two patients were lost to follow up after discharge but postal inquiries showed that they had no fresh symptoms. Data could therefore be obtained for all 45 patients at baseline and day 7, in 44 patients at 1 month and 41 patients at 6 months.Baseline characteristics of the patients are given in Syncope did not recur in any patients over the 6 month period. Eight patients who had presented on admission with dyspnoea experienced initial relief with drug therapy but dyspnoea worsened in 4 of these patients. Over the 6 months follow up period new onset dyspnoea occurred in 7 patients. In 4 patients, it was considered as a part of pacemaker syndrome while in 3 it was attributed to progressive LV dysfunction. New onset persistent atrial fibrillation developed in 9 patients, it was noted at the end of 1 month in 2 patients and at 6 months in remaining 7 patients. Nine patients were adjudged to be having intermittent pacing showing <90% paced complexes on 24 hours ambulatory ECG monitoring at 6 months.Cardiac dimensions, volumes, systolic functions and systolic time intervals are shown in . The LVEAmong the diastolic parameters , LV-IVRTThe changes observed were largely uniform and independent of age, sex, indication for pacing and pre-existing LV dysfunction. Only persistent pacing, as identified by >90% paced beats  in a 24 hour holter, was associated with a significantly higher decrease in LVEF (p<0.02) in persistently paced group. This group also showed a higher LVESV (p<0.005), greater RV dysfunction as suggested by higher RVPEP/RVET ratio (p=0.024), and a tendency to have a larger LAd (p=0.063).In the present study, the first significant change to appear in myocardial functions following VVI pacing was in diastolic properties of RV. This was manifest by an increase in RV-IVRT at one week, followed by an increase in RV dimensions and the appearance of RV systolic abnormality i.e. increased RV-PEP and RV-PEP/RV-ET ratio at one month. The LV diastolic parameters were significantly altered at one month, which were manifest by an increase in IVRT and DT, followed by LV systolic dysfunction which appeared at 6 months with an increase in LV-PEP and LV-PEP/LV-ET ratio. The reduction in LVEF also manifest at 6 months without change in the resting cardiac output.Our findings suggest two inter-related sequence of events. Firstly, it appears that changes in cardiac haemodynamics start appearing as early as one-week after VVI pacing, which are subtle and are limited to right ventricle only. Left ventricular dysfunction occurs later and this follows RV dysfunction, as reported in previous studies ,6-8. SecThere is often a debate whether LV dysfunction after long term ventricular pacing is real or is dependent on pre-existing disease. Mohan et al4 in their study found no significant difference in resting LVEF in long term follow up of AAI and VVI paced patients of sinus node dysfunction without structural heart disease. Similarly, Anderson et al , in theiThe true mechanism of cardiac dysfunction is still unclear. It has been shown that pacing from RV apex induces an electrical sequence of depolarisation, which results in reduced stroke output of both the ventricles ,18. RV aBeside this, animal experimental studies have shown myofibrillar disarray , redistrHowever, these mechanisms are not enough to explain significant reduction in systolic performance of the left ventricle as adjudged by gross reductions of the LVEF on long term pacing. It is hypothesized that left ventricular diastolic and systolic functions are deranged in many conditions secondary to involvement of right ventricle. Isolated right ventricular infarction, atrial septal defect with right sided chronic volume over load, cor pulmonale and chronic obstructive lung disease result in altered LV diastolic as well as systolic functions secondary to RV dysfunction -32. LV dEchocardiographic evaluation of RV size may not be a reliable and reproducible method with inherent problems of inter and intra observer variability. However, since every patient was serving as their own control, and a change in the parameters could be attributed to permanent pacing. The study was designed to include consecutive patients undergoing single chamber VVI pacing and those having a baseline ejection fraction of less than 50% were also included, however in the final analysis on comparison with patients having ejection fraction greater than 50% there was no difference in the observed parameters. A critically timed atrial contraction can change the filling characteristics of ventricle and alter the measured diastolic and systolic parameters. Though, we chose to evaluate only paced complexes, it may not have completely removed the impact of atrial contribution to ventricular filling during the intervening sinus rhythm.In conclusion, the present study shows that right ventricular apical pacing has a major effect on systolic and diastolic ventricular functions. On serial evaluation, right ventricle dysfunction is the first abnormality that occurs in right ventricular apical paced patients, followed by LV dysfunction which appears later and on both sides, diastolic dysfunction precede the systolic dysfunction.