Pulmonary hypertension is an important prognostic factor in cardiac surgery associated with increased morbidity and mortality. With the aging population and the associated increase severity of illness, the prevalence of pulmonary hypertension in cardiac surgical patients will increase. In this review, the definition of pulmonary hypertension, the mechanisms and its relationship to right ventricular dysfunction will be presented. Finally, pharmacological and non-pharmacological therapeutic and preventive approaches will be presented. Sevig. (1),  the simp2). Therefore, this ratio  seems to be a very robust estimator of the severity of PHT. To demonstrate the utility of the MAP/MPAP ratio, we compared it to the other hemodynamic parameters listed in Table 1 in 1439 patients undergoing cardiac surgery after the induction of general anesthesia but before cardiopulmonary bypass (CPB). We observed that the MAP/MPAP ratio behaved similarly to the other hemodynamic parameters , and had the highest receiver operating curve value to predict hemodynamic complications after cardiac surgery. The hemodynamic complications were defined as postoperative death or requirement for an intra-aortic balloon pump, cardiac arrest and vasoactive support for more than 24 hours. Finally, using transesophageal echocardiography (TEE), we can confirm that the presence of an abnormal MAP/MPAP ratio is almost invariably associated with abnormal systolic or diastolic cardiac function  [Following the induction of general anesthesia, a reduction of both the systemic and the pulmonary artery pressures will be observed. Consequently, absolute values of SPAP used in defining PHT will tend to underestimate its severity. In 2006, we addressed this issue and published a study involving 1557 patients who underwent cardiac surgery . We firsFinally, PHT is typically classified as capillary, precapillary or post-capillary, depending on the site where the cause of PHT is present. The 2003 World Symposium on PHT proposed a classification based on 5 groups: 1-Pulmonary arterial hypertension, 2-PHT secondary to left heart disease, 3-PHT secondary to lung disease and/or hypoxia, 4-PHT secondary to thrombotic and/or embolic disease and 5-A miscellaneous category . In cardIn summary, PHT in cardiac surgery should be carefully defined. It is generally a post-capillary PHT. In awake patients, the absolute values have been used and correlated with outcome. However, in patients under general anesthesia, the relative value seems to be more appropriate.2.5) focuses on the role of PHT in cardiac surgery [The mechanism of PHT in cardiac surgery is complex and can result from several mechanisms acting alone or in combination. These mechanisms can be present before the operation, secondary for instance from valvular heart disease. The cause of PHT can appear after CPB from mechanical failure or from the pulmonary reperfusion syndrome. Finally, PHT can be present or persist postoperatively secondary for instance from/to a mitral or aortic patient-prosthesis-mismatch (PPM). Fig. ( surgery  based on2.1.5).The 6 most important causes of PHT in cardiac surgery factors are illustrated in Fig.  [During cardiac surgery, the extent of the systemic inflammatory response, the pulmonary reperfusion syndrome and the need for blood transfusions may exacerbate PHT  , 10. The6)  through 6) , 13. Thi6) .The administration of protamine can induce catastrophic pulmonary vasoconstriction in up to 1.8% of patients . Protamiet al.[Mitral PPM is another recently described cause of residual postoperative PHT. Magne et al. studied 2 will increase PHT through vasoconstriction. Finally, although pulmonary embolism is rare in the immediate postoperative period, they can occur particularly in patients with predisposing factors .Hypoxia, hypercarbia and pulmonary embolism are other causes of PHT. They can appear before, during or after CPB. For instance, PHT can cause RV dysfunction, which will lead to an increase in right atrial pressure. This can lead to the opening of a patent foramen ovale (PFO), which is present in 20-30% of the general population . The con8). Clinically, this may be observed when hyperinflation of the lungs greatly increases PVR [Lung volumes have a differential effect on intra- and extra-alveolar vessels, which accounts for the unique U-shaped relationship between lung volume and pulmonary vascular resistance (PVR). PVR is minimal at functional residual capacity and increased at large and small lung volumes  [The importance of RV function in cardiac surgery has been demonstrated in a variety of clinical settings such as high risk coronary or valvular heart disease, congenital heart disease, heart transplantation, in patients requiring mechanical assist devices and in the unstable postoperative patient (Table 2) . However2) -30. A re2) .2.2.1.et al. have demonstrated that preoperative RV dysfunction was associated with a greater requirement of postoperative inotropic support [et al. demonstrated that preoperative RV failure was associated with perioperative mortality. In this same study, postoperative RV failure was the most important independent predictor of late survival [et al. found that preoperative RVEF≤ 20% predicted late postoperative deaths [et al. [n=41), patients with RV dysfunction had a higher prevalence of diabetes mellitus and renal disease as well as a higher incidence of postoperative inotropic or mechanical support, longer intensive care unit and hospital stay and a decreased short term and long term survival.In patients presenting with severe aortic stenosis, Boldt  support . In a resurvival . In a sme deaths . In pati [et al.  showed tn=20), the number of patients with DSB (difficult separation from bypass) (16/20 (80%) vs. 6/30 (20%), p<0.0001) and the end-point of mortality of postoperative heart failure (14/20 (74%) vs. 3/30 (10%), p<0.0001) were significantly higher. On a multivariate analysis, among all other demographic, hemodynamic and echocardiographic variables, the RVMPI was the only independent predictor of heart failure and mortality .To further assess the value of RV function relative/-compared to other validated risk factors in open valvular heart surgery, we recently published our experience related to 50 patients undergoing valvular surgery . We conf2.2.2.The presence of RV failure after CPB is associated with a mortality rate ranging from 44% to 86% . The inc3.PHT present before any cardiac procedure is associated with increased morbidity and mortality ,37-40. Hn=80, 40±14 mmHg), followed by combined CABG and valve , multiple valves  and heart transplantation . A total of 605 patients (42%) presented with elevated SPAP defined as above 30 mmHg. If we select patients with more severe PHT using a MAP/MPAP ratio < 2, there were only 16 patients, all experienced difficult separation from CPB, 3 died  and half required vasoactive support for more than 24 hours after the procedure.Using our database in 1999, the mean preoperative systolic pulmonary artery pressure (SPAP) was 31±10 mmHg. Elevated SPAP above 30 mmHg were present mostly in mitral valve replacement , ‘humans’, ‘adults’, ‘English’ and ‘PHT’. Articles related to cardiac surgery were then selected and classified according to the levels of evidence proposed by Sackett  for evid4.1.4.1.1.2), nitric oxide (NO) and intravenous vasodilators such as prostacyclin E1 (PGE1), nitroglycerin (NTG), nitroprusside (NTP), milrinone, enoximone and dobutamine. One large RCT compared heparinise to protamine and explored as a secondary end-point the prevention of PHT from protamine administration [The agents studied were: inhaled prostacyclin  undergoing MVR for mitral stenosis. Inhaled PGI2 (iPGI2) and iNO were compared to conventional intravenous vasodilators. The inhaled drugs were given just before the end of CPB. Significant reductions in PHT indices as well as increase in cardiac output (CO) and in RV ejection fraction were observed in both inhaled groups compared to conventional treatment. In addition, in both inhaled groups, separation from CPB was easier, the amount of vasoactive drugs administered was smaller and the duration of stay in the ICU and hospital was shorter. The same group also compared the same three strategies in the treatment of PHT after MVR upon arrival in the intensive care unit (ICU) [2 was associated with a reduction in PVR and an increase in stroke volume. Inhaled NO reduced PVR but did not increase stroke volume, and NTP was associated with a reduction in systemic arterial pressure and systemic vascular resistance.In the most recent trial, Fattouch et al.  studied it (ICU) . Inhalatn=3800), Ocal et al. [2 and the other intravenous NTG in addition to standard vasoactive agents. The iPGI2 group showed improved hemodynamics and only 14 patients (39%) had to return on CPB compared to all 30 patients (100%) in the NTG group. A tendency for shorter length of stay in the ICU and reduced mortality was observed in the iPGI2 group, but the numbers were too small to be statistically significant.The administration of protamine can be associated with severe PHT followed by RV failure. This condition requires immediate treatment. In a study of CABG patients  in a crossover study; these were used to treat PHT after cardiac surgery in 14 patients. Only stable patients were included in the study, which limits the application of the results. Inhaled NO decreased PVR without reducing SVR, did not change coronary perfusion pressure of the right coronary pressure and increased oxygen transport.Schmid et al.  comparedet al. [Finally, Hachenberger et al.  explored2 [In our practice at the Montreal Heart Institute, we regularly use iPGI2 , 53 and 2 , 55 in t4.1.2.5). In the presence of PHT secondary to LV failure, intra-aortic balloon counterpulsation will facilitate recovery of LV dysfunction. If prosthetic valve dysfunction is present after CPB, then return on CPB and correction of the problem will be the treatment of choice. The correction of hypoxia, hypercapnia and surgical thrombo-embolectomy  can help control PHT. In patients with elevated intrathoracic pressure from accumulated air or blood, chest drainage will be the solution. However, in some patients undergoing long procedures and long CPB duration, chest closure can be associated with hemodynamic instability. This is a sort of “thoracic compartment” syndrome. In these situations, the chest temporarily can be left open to reduce the surrounding pressures. Finally, pulmonary artery balloon pump, RV assist device (RVAD) or cavopulmonary diversion have been described as potential treatments for severe RV dysfunction [The non-pharmacological approach to the treatment of PHT will be directed to the cause or the consequence of PHT, as illustrated in Fig. (function .4.2.9). Right ventricular function is evaluated visually, using the RV pressure waveform and TEE. Once RVOTO is ruled out, the etiology of RV systolic dysfunction is divided in two categories. If ischemia is suspected to contribute to RV failure, then both the medical and the surgical treatment will be oriented toward the promotion of RV perfusion. In a non-ischemic etiology is suspected, the medical and surgical treatment will be oriented toward an increase in contractility (inotropes) and a reduction in RV afterload .We summarize our approach to the treatment of RV failure in Fig. . No changes in SPAP were observed in the control group and no differences in systemic arterial pressure between the groups were observed. We also published our preliminary experience in the use of inhaled milrinone involving 70 high risk patients (Parsonnet Score of 27±14) [n=30) was associated with a lesser rate of re-initiation of CPB  in this very high risk group. We also observed postoperatively lower pulmonary artery pressures in the pre-CPB group. Further studies will be required to determine the efficacy of this approach.We have completed a randomized controlled trial on the use of inhaled milrinone administered before CPB in 21 patients. There were 8 males and 13 females of a mean age of 70±6.3 years and a mean Parsonnet Score of 32±9. All procedures were valvular surgeries, 14 of which were complex surgeries and 5 reoperations. Mean systolic pulmonary artery pressures (SPAP) were reduced in the inhaled milrinone group from 66±20 mmHg (pre-CPB) to 46±20 mmHg (after CPB) (f 27±14) . Compare5.2.The selection of the type and size of an aortic prosthetic valve could be a very important strategy, because it has been shown that, if the effective orifice area (EOA) of the aortic valve is too small in relation to body size, the so-called PPM, the intraoperative and long-term mortality, is increased -64. HencIn summary, PHT in cardiac surgery is an important variable in cardiac surgery. It should be diagnosed before cardiac surgery and the impact of PHT on RV function determined. Future trials should address the role of preemptive reduction in the severity of PHT before cardiac surgery and their impact on post-operative outcome.


Mitral regurgitation (MR) is the second most common valvular disease in western countries after aortic stenosis. Optimal management of patients with MR depends on the etiology of the regurgitation and is based predominantly on left ventricular function and functional status. Recent outcome studies report high risk subsets of asymptomatic patients with MR, and practice guidelines underscore the importance of a well-established estimation of exercise tolerance and recommend exercise testing to objectively assess functional status and hemodynamic factors. Mitral regurgitation (MR) is the second most common valve disease in western countries, after aortic stenosis, representing 32% of single native left-sided valve disease in a recent European survey . MR resuExercise echocardiography plays an important role in the evaluation and management of chronic mitral regurgitation. It can assist in the evaluation of symptoms, more fully assess the mechanism and severity of regurgitation, determine functional capacity, and assess contractile reserve to help optimize the timing of surgical intervention. In addition, exercise echocardiography has been beneficial in assessing the response of MR to cardiac resynchronization therapy.This review will summarize the clinical utility of exercise echocardiography in chronic MR, examining both primary and secondary MR.The regurgitant orifice in MR serves as an “escape valve”, decreasing the impedance to and enhancing left ventricular emptying. The volume of MR flow depends on both the size of the regurgitant orifice and the (reverse) pressure gradient between the left ventricle (LV) and the left atrium (LA) . Both thIn chronic MR, volume overload of the left ventricle results in an increase in LV end-diastolic volume (LVEDV). The increase in LVEDV allows augmentation of total stroke volume, while maintaining forward stroke volume near normal. Ejection indices such as ejection fraction and fractional shortening are initially supra-normal due to the low impedance of the outflow circuit; these indices can appear “normal” even after contractile function has been impaired .Although the compensatory mechanisms are effective, the prolonged volume overload ultimately leads to myocardial dysfunction. Consequently, end-systolic volume rises, and ejection fraction and stroke volume decline. Therefore, surgical intervention is usually recommended prior to the onset of LV dysfunction and is important in preventing further deterioration of systolic function and improve survival .The hemodynamic response to exercise in MR depends on the change in the severity of the regurgitant lesion and the ability of the left ventricle to meet increases in demands on workload. These two factors interact in complex ways. The effective regurgitant orifice (ERO) can be relatively fixed throughout systole such as in rheumatic mitral valve disease. On the other hand, in ischemic MR, and occasionally in cases with flail mitral leaflets , the ERORisk stratification using exercise echocardiography, especially in asymptomatic patients, becomes important not only in accurate quantification and characterization of the etiology of MR, but also in guiding therapy.1). This latter series included many patients who had left ventricular dysfunction or atrial fibrillation and thus might have been considered to be at a higher risk.The most recent ACC/AHA guidelines for the management of valvular disease  include,With the current guidelines, reasonable surgical candidates who develop symptoms related to MR should undergo surgical correction. However, symptom status can be subjective and variable and it is sometimes difficult to relate those symptoms to severe mitral regurgitation. Patients also often have other co-morbidities that may be contributing to their symptoms. Due to the morbidity and mortality associated with severe MR and the potential benefit of surgical intervention, it is important to differentiate symptoms caused by mitral regurgitation from those of other causes. Differentiating the symptoms of chronic obstructive pulmonary disease (COPD), for example, from those of MR can be extremely challenging. Approaches involving combined cardio-pulmonary function testing during exercise may help distinguish between pulmonary and cardiovascular etiologies of dyspnea . ExercisIn symptomatic patients with a clinical picture suspicious for severe MR, but not evident on the resting echocardiogram, exercise echocardiography demonstrating worsening MR helps correlate the pathology with the patient’s symptoms . Similar2 had an excess risk of death and cardiac events . In addition, cardiac surgery markedly reduced the risk of heart failure and death. Conversely, watchful waiting of asymptomatic patients with severe MR until development of symptoms, LV dysfunction or dilatation, or pulmonary hypertension has recently been advocated [Among asymptomatic patients with initially normal left and right ventricular ejection fractions, severe MR is associated with a high rate of symptoms or left ventricular dysfunction requiring surgery. Mitral valve surgery (repair or replacement) during a 5-year follow-up was independently associated with a reduced risk of death . In 102 dvocated . 132 conde novo or even increase in duration and severity. Stoddard et al. [et al. showed that more than 30% of these “low risk” patients have exercise-induced MR and are at a higher risk for morbid events than usually expected [With exercise, mitral regurgitation that is non-holosystolic can appear d et al.  studied expected . Exerciset al. [Stress echocardiography has been evaluated in the setting of mitral regurgitation secondary to rheumatic heart disease. Symptoms can often appear to be out of proportion to the degree of valvular pathology. Tischler et al.  performeLeft ventricular contractile function can be impaired even in the presence of a normal ejection fraction in patients with chronic MR because of altered loading conditions , 19,  20et al. evaluated functional and prognostic implications of LV contractile reserve in patients with isolated severe MR pre- and post-mitral valve replacement as well as in those being treated medically [Lee edically . Contrac2, an exercise ejection fraction < 68% and an increase in ejection fraction with exercise of < 4% (Table 1) [A similar study used exercise echocardiography prior to mitral valve surgery to identify those patients with asymptomatic, chronic severe MR who were at risk of developing postoperative LV dysfunction . A postoTable 1) .et al. studied asymptomatic and symptomatic patients with significant mitral regurgitation due to diverse etiologies (most with LV ejection fraction < 50%). Right ventricular ejection fraction both at rest and during exercise was slightly more predictive of long term mortality than were left ventricular ejection fraction during rest and exercise, symptoms and treadmill exercise time during follow-up [Evaluation of right ventricular function and pulmonary artery pressure, especially with exercise, can aid in deciding to intervene on patients with severe MR (ACC/AHA Class IIa indication). In patients with mitral valve prolapse, the change in right ventricular ejection fraction with exercise was the only predictor of the need for surgical intervention over 4.7 years of follow-up . Hochreiollow-up . AlthougThe onset of resting pulmonary hypertension (> 50mm Hg) secondary to severe mitral regurgitation is considered an indication for surgery, for, if left untreated, it is associated with a greater severity of mitral regurgitation and higher operative morbidity and mortality . Furtheret al. studied 32 patients with severe MR and normal LV ejection fraction. They observed that the early diastolic mitral annulus velocity (E’) and pulmonary vein A-wave peak velocity (PVa), both accepted surrogate estimates of LV diastolic function, showed a significant correlation with maximal exercise time [Although exercise capacity is an important parameter of quality of life and provides prognostic information, cardiac determinants affecting it have not been clearly defined in patients with chronic MR. It is well known that LV diastolic function is an important determinant of exercise capacity in normal individuals and in patients with various cardiac disease , 30. To ise time . This stise time . From thIn chronic, severe mitral regurgitation, once patients develop symptoms or LV dysfunction, the decision to intervene becomes straightforward. However, decision-making is more challenging in patients with vague, atypical symptoms. It is important to accurately, and in a timely fashion, identify symptoms related to chronic MR as well as occult LV dysfunction. The combination of stress testing with echocardiography can detect and quantify occult symptoms as well as worsening mitral regurgitation. Stress echocardiography, therefore, provides a comprehensive and cost-effective evaluation of patients with primary mitral regurgitation that combines functional, diagnostic, and prognostic information.3). Further studies have corroborated that the degree of ischemic MR at rest in patients with systolic dysfunction is determined by local  and not global LV remodeling [Ischemic mitral regurgitation (IMR) results from restricted leaflet closure secondary to tethering of the mitral leaflets as a consequence of an infarcted, thinned ventricle. IMR is characteristically dynamic and sensitive to changes in ventricular size, shape, and loading that restrict closure of the mitral leaflet , 35. In modeling , 38. IMR is a dynamic phenomenon, its severity varying depending on loading conditions , 39. OftPierard and Lancellotti showed that patients with known ischemic LV dysfunction who present with acute pulmonary edema not due to myocardial ischemia demonstrate large exercise-induced increases in mitral regurgitation and related pulmonary pressures . Exercis2). IMR has also been shown to worsen with worsening LV function during exercise . AnnularDuring exercise, the magnitude of changes in IMR is widely different from one patient to another and does not correlate with the degree of MR at rest. Most patients exhibit small increases in the amount of IMR, whereas others have either a large rise or a significant decrease in ERO . The dem2 during exercise, an ERO > 20mm2 at rest [Ischemic mitral regurgitation may exhibit a broad range of severity and conveys a dismal prognosis -50. The  at rest , greater at rest .The use of exercise echocardiography is becoming a more valuable tool in the evaluation of ischemic MR. It can be used to quantify, and determine the reason for limitations in, exercise capacity. As well, it’s utility in testing the dynamic component of IMR in patients with chronic ischemic LV dysfunction presenting with unexplained dyspnea or acute pulmonary edema cannot be ignored. Exercise echocardiography has been shown to be useful in the evaluation and risk stratification of patients with IMR.Mitral regurgitation is seen in over half of all patients with symptomatic heart failure and is an independent predictor of mortality . Non-isc4). The cardiac structural changes associated with CRT include not only volumetric improvement but also true reverse LV structural remodeling, evidenced by progressive reduction in LV mass and restoration of regional wall symmetry [Cardiac resynchronization therapy (CRT) improves exercise tolerance in addition to providing symptomatic and mortality benefits in patients with severe heart failure refractory to  medical  therapy -58. The symmetry , improvesymmetry  and imprsymmetry -67. et al. showed that CRT attenuated the increase in mitral ERO and regurgitant volume during exercise among 21 patients undergoing symptom-limited exercise stress testing; a phenomenon attributed to an increase in LV contractility  [et al. did not show an improvement in exercise-induced MR within the 1st week of implantation. However, the attenuation of exercise-induced MR did occur in parallel with LV remodeling at 3 months post-implantation [There are varying results describing the effect of CRT on exercise-induced MR prior to the occurrence of LV remodeling. Ennezat  . Conversantation . The varantation , 68. 6) [et al. studied 25 patients who showed an immediate improvement in MR after CRT was accompanied by an improvement in mitral deformation indices  and synchrony between the two LV papillary muscles. Acute loss of resynchronization after interruption of CRT lead to acute recurrence of MR and worsening in mitral deformation indices [LV asynchronism, as measured by Doppler tissue imaging at rest, substantially contributes to worsening of MR during dynamic exercise in patients with CHF due to LV systolic dysfunction   Ypenburg indices . et al. described a series of 60 patients with idiopathic dilated cardiomyopathy and QRS interval < 120 ms who were submitted to supine bicycle exercise Doppler echocardiography and cardiopulmonary exercise testing [D’Andrea  testing . DynamicThere is a close correlation between exercise-induced changes in LV dyssynchrony and functional MR. Acute changes in MR have been observed with the induction and interruption of CRT. Initiation of CRT acutely reduces MR severity at rest and its dynamic component during exercise well before the occurrence of significant LV inverse remodeling , 71. In In summary, exercise echocardiography provides useful data in patients with mitral regurgitation. Information that can be acquired with this modality include:An assessment of functional capacity;A quantification of change in MR severity during exercise;An assessment of contractile reserve of the left ventricle;An evaluation of the response of the right ventricle, especially with worsening MR during exercise;Obtaining prognostic information.


Superior diagnostic performance is observed among those with higher baseline risk (such as hypertensives or diabetics). As well, unlike for acute HF, the cut off value for outpatient testing for BNP is 20-40 pg/mL and for NTproBNP it is 100-150 ng/L. In symptomatic primary care patients, both BNP and NT-proBNP serve as excellent tools for excluding HF based on their excellent negative predictive values and their use may be cost effective. Among those with established HF, it is logical to assume that titration of treatment to achieve lower NPs levels may be advantageous. There are several ongoing trials looking at that prospect.The incidence, as well as the morbidity and mortality associated with heart failure (HF) continue to rise despite advances in diagnostics and therapeutics. A recent advance in the diagnostic and therapeutic approach to HF is the use of natriuretic peptide (NP) testing, including both B-type natriuretic peptide (BNP) and its amino terminal cleavage equivalent (NT-proBNP). NPs may be elevated at an early stage among those with symptoms as well among those without. The optimal approach for applying NP testing in  Heart failure (HF) is a major and growing public health problem in the United States. The prevalence of HF in US is estimated around 5 million, and over 550 000 new cases are diagnosed with HF each year . HF is tIn addition to the diagnostic challenges, the timing and sequence of initiating treatments, gauging adequacy of therapy and monitoring of therapy for adverse events are significant challenges. Due to these factors the current care of patients with HF remains suboptimal  and manyA recent advance in the diagnostic and therapeutic approach to HF is the use of natriuretic peptide testing. Including both B-type natriuretic peptide (BNP) and its amino terminal cleavage equivalent (NT-proBNP), this class of biomarker has proven to be more useful than original expectations. This review will discuss recent advances in the use of natriuretic peptide testing to assist in the primary care recognition and management of patients with suspected or proven HF.HF is a progressive disorder accompanied with changes in left ventricular (LV) structure and geometry such that the chamber dilates and/or hypertrophies and becomes more spherical—a process referred to as cardiac remodeling. This change further deteriorates myocardial function which in turn perpetuates the remodeling process. Cardiac remodeling generally precedes the development of symptoms  and may continue despite treatment. Several factors can accelerate the process of LV remodeling, of these the activation of endogenous neurohormonal systems plays a vital role in cardiac remodeling and thereby in the progression of HF. Because natriuretic peptides (NPs) are produced in the heart, they may serve as a biological marker of LV remodeling and changes in circulating NPs may parallel the changes in LV structure -8.Human BNP is synthesized as a pre-pro-peptide which is cleaved by endoprotease yielding a 108-amino-acid pro-peptide (proBNP1-108) . The proMultiple mechanisms induce the BNP gene, however, mechanical stretch is probably the most potent inducer of the BNP gene expression in cardiac myocytes . In addiWhile BNP may have several endocrine functions including vasodilation, natriuresis, inhibition of the sympathetic nervous as well as the renin-angiotensin aldosterone system , it may Plasma concentrations of both NPs (BNP and NT-proBNP) in healthy persons are much lower than in diseased states, are quite comparable to each other (unlike in disease states), and are more modified by physiologic factors including age, gender and drugs than in the disease state.NPs increase with age , probablThe effects of drugs on circulating NP concentrations are complex. Cardiovascular drugs with favorable effects on the neurohormonal system such as diuretics, angiotensin-converting enzyme inhibitors, β-adrenergic blockers, and spironolactone may lower NP values, in parallel with the improved prognosis seen with treatment with these drugs -52.The biological variation of NPs secretion must be considered when interpreting serial natriuretic peptide results. Biological variability refers to the expected day-to-day or week-to-week changes in NPs levels measured in apparently stable patients in response to physiologic changes such as changes vascular tone and filling pressures, without overt destabilization -55, as wRecent studies suggest that in stable chronic heart failure patients, long-term intra-individual variation in natriuretic peptide levels is in the order of 30%, with a change of more than 23% likely to indicate a clinically significant change beyond background variation , 60. NT-In summary, considering biological variation, changes in BNP or NT-proBNP in the range of 25-30% likely reflects a “true” change, and may be interpretable in the context of therapeutic monitoring. While NT-proBNP appears less subject to the effects of biological variability than BNP, the significance of this finding relative to the value for management of HF patients remains unclear.1).Despite biological variability and conditions that modify NP levels, NPs remain potentially useful to discern a wide range of clinical conditions in HF patients. The applicability of natriuretic peptides is well accepted in inpatient care both in an emergency department setting as well as in a hospitalized patient with respect to diagnosis and prognosis, moreover, it has been found useful for screening, diagnosis and prognosis in outpatient care as well  may be advantageous.It has been shown in population studies examining such patients that NP levels are generally higher in diabetics, hypertensives as well as those with increased LV mass . These h2). Areas under the receiver operating characteristic (ROC) curve have ranged from 0.59 [Thus, depending upon the population investigated, there have been varying reports on the value of BNP for detecting LVSD in general populations , rather than their positive predictive value (PPV). That is, these assays are best used to exclude risk than to identify it. As an example, Epshteyn et al.  showed tet al. . Similaret al. . Utility of BNP testing for identifying any structural heart disease in addition to LV systolic dysfunction was assessed in another study  involvinet al. [p<0.001); patients with restrictive-like filling patterns on echocardiography had the highest BNP levels (408±66 pg/mL) and AUC =0.97 . Importantly, however, while NP levels are unable to differentiate systolic vs. diastolic dysfunction [In patients with isolated diastolic dysfunction, NPs may be elevated and may reflect the severity of dysfunction -89. Moreet al. , the areet al., showed that BNP was an independent predictor of 4-year all-cause mortality [Importantly, even in the absence of overt HF, modest elevations in plasma NPs levels are prognostically meaningful in population-based testing. In a population-based prospective study of 1991 subjects without apparent heart failure both BNP and NT-proBNP were predictive of mortality after a median follow up of 5.6 years even after adjustment for clinical and echocardiographic abnormalities including left ventricular hypertrophy and diastolic dysfunction ; in thisortality . Overall, studies would thus suggest that the optimal approach for applying NP testing to detect HF or prognosticate in general populations is to select the target population carefully, with superior performance observed among patients with a higher baseline risk (such as hypertensives or diabetics). As well, unlike for acute HF, where higher decision limits are used, the cut off value for outpatient testing for BNP is 20-40 ng/mL and for NT-proBNP it is 100-150 ng/L. Values below these cut-points exclude the presence of cardiac abnormalities with a high NPV; values above these cut-points suggest further evaluation is necessary but do not absolutely guarantee the presence of cardiac structural abnormalities. et al. [2), NT-proBNP levels identified those with symptoms of heart failure and LVEF ≤40% among general population with a sensitivity of 92%, a specificity of 86%, negative predictive values of 100% and area under the curve of 0.94. Similarly in another study [In symptomatic primary care patients, both BNP and NT-proBNP serve as excellent tools for excluding HF based on their excellent negative predictive values -100. In et al.  investiget al. . In anotet al.  er study  both BNPIn a meta analysis involving 19 studies, 22 populations, authors suggested that in a low risk population appropriate use of NPs can help reduce the demands of echocardiogrpay and cardiac referrals . In a re3). Importantly, age exerts a significant effect on NP concentrations, thus, lower cut-points might be useful for younger patients, while higher cut-points (e.g. an NT-proBNP of 300-450 ng/L) might provide superior NPV for elders. The optimal cut-points for BNP in elders remain unclear.Thus, in the presence of symptoms, a general recommendation would be to apply NP testing with the goal to exclude HF. Using cut-points of 20-40 pg/mL for BNP and 125-150 ng/L for NT-proBNP provides excellent NPV in this regard. Results above these levels do not necessarily confirm HF, but suggest that further evaluation is necessary  in HF is difficult because of the lack of strong predictors of mortality or morbidity. Plasma natriuretic peptide levels increase in patients with symptomatic HF in proportion to the severity of disease and correlate with several indices of heart failure such as the New York Heart Association (NYHA) functional class, hemodynamics, left ventricular ejection fraction and filling pressure -104. In et al. [While elevated baseline values of NPs are predictive of poorer outcomes, the prognostic value of the changing levels of BNP and NT-proBNP levels measured during treatment could be even more meaningful -115. Furet al.  analyzedBecause lower levels of BNP or NT-proBNP are associated with better clinical outcome, and patterns of NP concentrations appear to be more prognostic than single measurements, it is logical to assume that titration of treatment to achieve lower NPs levels may be advantageous. The logic behind this concept is that concentrations of NPs decrease following institution or intensification of several established therapies of HF; among these agents are diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), β blockers, spironolactone, and nesiritide -52. While levels of BNP and NT-proBNP fall parallel to the fall in filling pressures with institution of diuretics and vasodilators -36, it iet al. [The clinical benefit of titrating therapy according to NP levels was tested in a landmark study by Troughton et al.  patientset al. . In thiset al. . While tThe effect of guiding treatment to achieve targeted levels of NPs is currently being tested in several larger randomised trials. Methods papers have been published for the BATTLESCARRED  and TIME


It is well known that cardiopulmonary complications are often associated to subarachnoid haemorrhage. For appropriate therapeutic managing it is very important to distinguish acute coronary syndrome from neurogenic myocardial injury, which is a reversible condition. Furthermore, because the hearts of brain dead patients may be utilized for therapeutic purpose, it has became of importance to rule out erroneous diagnosis of cardiac ischemia in order to avoid rejection of hearts potential suitable for transplantation.We present a report of two female patients affected by cardiac complications caused by aneurismal subarachnoid haemorrhage admitted to our neurosurgical intensive care department. A 54-year-old Caucasian nun, with history of hypertension, treated with beta-blockers and ACE-inhibitors, was admitted to the neurosurgery department of our hospital for severe nuchal pain, vomit and reduced level of consciousness (Hunt -Hess grade IV). Brain CT scan revealed aneurysm of internal right carotid, in addition subarachnoid haemorrhage (SAH) was evidenced with extension into the III and IV ventricles.ECG on admission showed normal sinus rhythm, without anomalies of ST-T tract, the corrected QT interval was 455 ms. Laboratory results demonstrated Troponin T level of 3.75 ng/ml , creatinine kinase (CK) was 386 UI/l , NT pro BNP (brain natriuretic peptide) peak level was 259.5 pg/ml . The patient was sedated and intubated.Transthoracic echocardiography documented wall motion abnormalities, namely akinesis of apex and distal interventricular septum, moreover ejection fraction was about 45%. Inotropic agents, oxygen and Furosemide were administered. Clinical condition suddenly deteriorated after second haemorrhage, occurred soon before surgical correction of aneurysm. Since left ventricular wall motion anomalies persisted after declaration of cerebral death, the heart was considered not suitable for transplantation and only liver and kidneys could be successfully transplanted.The second patient was a 71-year-old, Caucasian housewife, with no significant medical history, a part of arterial hypertension, she was not smoker nor diabetic. The patient presented with SAH (Hunt-Hess grade III-IV). First ECG demonstrated normal sinus rhythm, with a heart rate of 96/m, and inverted T waves in V1 → V5, the corrected QT interval was 518 ms. After few hours it was observed the onset of paroxysmal atrial flutter that was successfully treated with Amiodarone (900 mg iv). Troponin T peak level was 0.469 ng/ml, at admission K + was 3.4 mEq/L, which after two days increased to 4.2 mEql/L, Na+ was136 mEq/L, NTpro-BNP reached the peak level of 8166 pg/ml. The echocardiogram demonstrated hypokinesis of distal septum and of apical region, moreover ejection fraction was 48%. Clipping of the anterior left carotid was successfully performed. On the third postoperative day, wall motion abnormalities disappeared; the post-operative course was uneventful and the patient was discharged home after some weeks.In 1947 Byer et al firstly reported ECG changes in patients with cerebrovascular accidents ,3.ECG changes seen in these patients may be divided in two categories: arrhythmias and repolarisation abnormalities.Alteration of rhythm and conduction have been detected in about 4% of patients with SAH, the most common arrhythmias are sinus bradycardia and atrial fibrillation/flutter  [Moreover, approximately 40% of patients with SAH show a modest elevation of Troponin, CPK and CK-MB, although they do not rise to levels observed during acute myocardial infarction. Troponin elevation is correlated more to the degree of brain injury than to severity of cardiac dysfunction evidenced by echocardiography ,9.Transient abnormalities of regional wall motion are detected by echocardiography in less than 5% of patients with minimal neurological deficit but in approximately half of patients with poor neurological grade ,12. WallAmong the proposed pathophysiologic mechanisms underlying ECG changes, ischemic heart disease was excluded by both autopsies and coronary angiographies.The most plausible pathologic theory remains an autonomic dysregulation caused by a lesion of cortical, hypothalamic and mesencephalic centers controlling the autonomic nervous system -15.As a matter of fact, an elevated concentration of catecholamines was observed in the hearts of animal models of intracranial haemorrhage ,15. FurtPost mortem examinations of patients who died of SAH demonstrated diffuse small and patchy subendocardial lesions, histologically appearing as myocardial contraction band necrosis . Such myThe clinical manifestations of SAH-induced cardiac dysfunction are similar to those observed in other conditions determined by massive release of catecholamine, such as tako-tsubo cardiomyopathy or transient left ventricular ballooning. As a matter of fact this syndrome, which predominates in post-menopausal women, is characterized by reversible wall motion abnormalities, slight elevation in myocardial markers, and transitory ST-T changes, in the absence of obstructive coronary artery disease. Although diagnostic criteria for tako-tsubo cardiomyopathy have initially excluded patients with intracranial bleeding, transient left ventricular apical ballooning could be a complication of SAH .Cardiac involvement induced by SAH has several important clinical implications.Firstly association of ECG changes, elevations of serum markers of myocardial necrosis and left ventricular dysfunction, may mislead to an erroneous diagnosis of myocardial ischemia with delay in the diagnosis of SAH . Since aLast but not least, patients affected by SAH are generally relatively young and healthy patients, that represent potential numerous organ donors ,20.There may be the risk of considering the hearts of irreversibly comatose patients not to be fit for a transplant because they often reveal mild-to-severe left ventricular wall motion abnormalities that, as demonstrated by several studies , are genCT: computed tomography; ECG: electrocardiogram; SAH: subarachnoid haemorrhage.Written informed consents were obtained from the second patient and from the first patient's relatives for publication of this case report, a copy of the written consents is available for review by the Editor-in-chief of this journal.The authors declare that they have no competing interests.MM, FL, NS analyzed and interpreted patient's ECG and echocardiograms. MM was a major contributor in writing the manuscript. BR, AP, PS, GG contributed to acquisition of data, analyzed the patient data regarding the neurological disease and the intensive care. All Authors read and approved the final manuscript.


Left ventricular (LV) dysfunction frequently occurs after cardiac surgery, requiring inotropic treatment and/or mechanical circulatory support. In this study, we aimed to identify clinical, surgical and echocardiographic factors that are associated with LV dysfunction during weaning from cardiopulmonary bypass (CPB) in high-risk patients undergoing valve replacement for aortic stenosis.Perioperative data were prospectively collected in 108 surgical candidates with an expected operative mortality ≥9%. All anesthetic and surgical techniques were standardized. Reduced LV systolic function was defined by an ejection fraction <40%. Diastolic function of the LV was assessed using standard Doppler-derived parameters, tissue Doppler Imaging (TDI) and transmitral flow propagation velocity (Vp).P = 0.044) and an increased incidence of serious cardiac events .Doppler-derived pulmonary flow indices and TDI could not be obtained in 14 patients. In the remaining 94 patients, poor systolic LV was documented in 14% (n = 12) and diastolic dysfunction in 84% of patients (n = 89), all of whom had Vp <50 cm/s. During weaning from CPB, 38 patients (40%) required inotropic and/or mechanical circulatory support. By multivariate regression analysis, we identified three independent predictors of LV systolic dysfunction: age , 1.01 to 1.22), aortic clamping time  and Vp . Among echocardiographic measurements, Vp was found to be superior in terms of prognostic value and reliability. The best cut-off value for Vp to predict LV dysfunction was 40 cm/s (sensitivity of 72% and specificity 94%). Patients who experienced LV dysfunction presented higher in-hospital mortality (18.4% vs. 3.6% in patients without LV dysfunction, This study provides the first evidence that, besides advanced age and prolonged myocardial ischemic time, LV diastolic dysfunction characterized by Vp ≤ 40 cm/sec identifies patients who will require cardiovascular support following valve replacement for aortic stenosis. Over the last two decades, the operative mortality rate has steadily declined from 10% to 4% along with improvements in surgical and anesthetic techniques . Howeverve death ,6.In large cohorts of patients undergoing cardiac surgery, post-CPB LV dysfunction has been linked to age, female gender, history of heart failure, recent myocardial infarct, low LV ejection fraction, prolonged aortic cross-clamping and complexity of surgery -11. MoreAlthough clinical signs  and markers of systolic LV function  have been studied extensively and incorporated in scoring algorithms for predicting perioperative risk, the prognostic value of diastolic dysfunction assessed by transoesophageal echocardiography (TEE) has not been examined in patients undergoing aortic valve replacement ,5,14,15.The main purpose of this study was to identify predictors of LV dysfunction in high-risk patients with aortic stenosis undergoing valvular replacement. Secondarily, we analyzed different Doppler parameters of diastolic function regarding their ability to predict post-CPB LV dysfunction.This prospective cohort study was conducted in a tertiary reference center, from January 2006 to December 2008. The study was approved by the Institutional Research Board of the University Hospital of Geneva and informed consent was obtained from each patient with severe aortic valvular stenosis who met the eligibility criteria. The Bernstein-Parsonnet algorithm was used to assess the operative risk of mortality . During The usual medications were continued on the morning of the procedure, except diuretics and angiotensin-converting enzyme inhibitors or angiotensin II antagonists that were interrupted one day before. In the operating theatre, all patients were equipped with a noninvasive oscillometric monitor , a radial arterial catheter, a central venous line and a bispectral monitor of the electroencephalogram . Anesthesia management consisted of intra-thecal morphine, low doses of intravenous sufentanyl and an infusion of propofol to target BIS values between 40 and 60. Cardiac preconditioning was also provided with inhaled isoflurane (1% to 1.5%) before CPB.A TEE probe  was introduced after anesthesia induction and images were digitally acquired before CPB and stored on a Philips Sonos 5500 Ultrasound Imaging system .2) and alpha-stat control for acid-base management. The circuit and the membrane oxygenator were primed with 2 L of normal saline solution and mean arterial pressure (MAP) was maintained between 50 and 70 mmHg with vasoactive medications as necessary. During aortic cross-clamping, myocardial protection was achieved by intermittent antegrade infusion of cold blood. The aortic valve prosthesis  was implanted in the supra-annular position with interrupted mattress sutures. All patients received tranexamic acid (20 mg/kg) and the transfusion threshold was a hematocrit less than 18 to 20% during CPB and less than 25% before/after CPB.After full heparinization, normothermic CPB was instituted with a nonpulsatile flow (2.2 to 2.5 L/minute/m2), MAP between 65 and 100 mmHg and heart rate between 70 and 100 beats/minute  were eventually introduced to target the specific hemodynamic endoints: LV end-diastolic diameter .2, need for inotropic and/or IABP support to maintain MAP >65 mmHg).The diagnostic criteria for post-CPB LV dysfunction was based on the need of inotropic support for at least two hours  in the presence of low MAP (<60 mmHg ascertained by both invasive and noninvasive pressure monitors) and with persistent, new or worsening LV functional impairment  <40%). Secondary outcome variables were any postoperative cardiac adverse event occurring in the ICU such as myocardial infarct , supra-ventricular or ventricular arrhythmias  and low cardiac output syndrome , LV end-diastolic and end-systolic areas  were measured. FAC of the LV was computed as (LVEDA -LVESA)/LVEDA. From a mid-esophageal four-chamber view, peak early (E) and late (A) mitral inflow velocities, deceleration time (DT) and isovolumic relaxation time (IVRT) were derived from recordings obtained with the pulsed Doppler sample volume positioned at the tip of the mitral leaflets. Peak systolic (S), diastolic (D) and atrial reversal velocities (Ar) were measured with the pulsed Doppler sample volume positioned within 1 to 2 cm of the left upper pulmonary vein. Thereafter, the TDI function was activated for recording early and late diastolic velocities of the mitral annulus  by positioning the 5-mm sample volume within the septal and lateral insertion sites of the mitral leaflets to cover the longitudinal excursion of the mitral annulus. Finally, a color M-mode map was displayed from a mid-oesophageal four-chamber view, to obtain the longest column of flow from the mitral annulus to the apex. The M-mode cursor was aligned through the center, parallel to the transmitral inflow and a clear propagation wave front was obtained by adjusting the Nyquist limit and baseline shift. Vp was defined as the slope of the first aliasing velocity during early filling, measured from the mitral valve opening to 4 cm into the LV cavity.Cardiac stroke volume was calculated as the flow surface area multiplied by the velocity time integral through the LV outflow tract obtained by pulsed wave Doppler. Cardiac index (CI) was calculated as the product of SV and HR divided by body surface area. All recorded values were averaged from three consecutive beats.Poor systolic LV function was considered if the LV ejection was <40% on the preoperative transthoracic echocardiographic examination. According to the working group of the European Association of Echocardiography and the American Society of Echocardiography, LV diastolic function was graded into four classes: normal , impaired relaxation , pseudo-normalization , and restrictive pattern  .To test the intra- and interobserver variabilities, E and A, E' and A' as well as Vp were measured twice by two independent operators, in 10 randomly selected cases.2 test for categorical variables (expressed in percentage) and the Student t test  or Wilcoxon rank test (non-Gaussian distribution) for continuous variables .Perioperative clinical, surgical and echocardiographic characteristics of patients with and without post-CPB LV dysfunction were compared with the χP < 0.2) to predict post-CPB LV dysfunction. All analyses were performed using SPSS software  and statistical significance was specified as a two-tailed type I error  set below the 0.05 level.Variables that had a univariate probability value <0.20 or those judged to be clinically important were selected for inclusion in a logistic regression model by stepwise selection. To avoid multi-colinearity, only one variable was retained in a set of variables with a correlation coefficient greater than 0.5. Independent predictors of LV dysfunction and factor-adjusted odds ratios (ORs) with 95% confidence interval (CI) were calculated. Model discrimination was evaluated by the area under the receiver-operator-characteristic (ROC) curve, and calibration was assessed with the Hosmer-Lemeshow goodness-of-fit statistic. Receiver operating characteristics (ROC) curves were constructed to determine the best cut-off of echocardiographic parameters . In the remaining 94 patients, all presented LV hypertrophy (PWT >11 mm), poor systolic LV function was found in 14% of patients (n = 12) whereas diastolic dysfunction was diagnosed in 84% of patients (n = 89), all of whom had Vp < 50 cm/s. Regarding echocardiographic measurements, intra-and interobserver variabilities were lowest for Vp and highest for E' and A' measurements . Inotropic support consisted in the administration of dobutamine , epinephrine (0.52 ± 0.41 mcg/kg/h over 6 ± 3 hours), norepinephrine (0.08 ± 0.04 mcg/kg/h over 12 ± 7 hours) and/or milrinone (0.27 ± 0.14 mcg/kg/h over 6 ± 2 hours). Five patients were also treated with an IABP in combination with inotropes. As shown in Table P = 0.21 by the Wald link specification test).Stepwise logistic regression analyses identified three independent predictors of LV dysfunction: age , aortic clamping time  and Vp . This multivariate model for predicting LV dysfunction was robust, with an area under the ROC curve of 0.96  and a Hosmer-Lemeshow goodness-of-fit probability value of 0.49 indicating good model calibration and discrimination. Substitution of aortic clamping time for CPB time and diastolic classes (1 to 4) for Vp, did not improve the area under the ROC curve. There was no evidence that additional covariates would improve the model  and an increased incidence of serious cardiac events . These patients also required prolonged mechanical ventilation and longer stay in the ICU and in the hospital.The expected mortality of the whole cohort was 22% whereas the observed mortality was only 10.6%. As shown in Table The incidence of LV dysfunction and cardiac complications increased significantly with the severity of diastolic dysfunction, particularly in patients with a restrictive filling pattern and those with Vp less than 40 cm/s Figure . NoteworIn this prospective study, 40% of high-risk patients undergoing aortic valve replacement required inotropic support and/or an intraortic balloon pump for weaning from CPB. Advanced age, preoperative LV diastolic dysfunction and prolonged aortic clamping time were identified as independent risk factors of post-CPB LV dysfunction. Among the echocardiographic markers of LV diastolic dysfunction, the transmitral flow propagation wave (Vp) was found superior in terms of prognostic value and reliability. Below a cut-off value of 40 cm/s, 90% of patients required inotropic support after weaning from CPB as opposed to only 11% among those with preoperative Vp >40 cm/s.The anesthetic and surgical techniques were all standardized and protocol-driven hemodynamic treatments were based on information gathered from pressure monitors and TEE examination. In contrast to previous large cohort studies, we focused on aortic valvular patients with an expected operative mortality ≥9% based on the Bernstein-Parsonnet algorithm . The higet al. reported a higher 30-day mortality rate among patients receiving inotropic drugs following cardiac surgery [Predictors of LV dysfunction after aortic valvular replacement have been investigated in four other studies which largely differ in their case-mix, hemodynamic treatments and criteria to define the main study endpoint -8,22. InOur study is the first investigation assessing the prognostic implication of echocardiographic markers in addition to clinical and surgical variables in patients undergoing aortic valve replacement. Based on standard Doppler-derived measurements, more than 80% of patients presented LV diastolic dysfunction and, all of them had Vp <50 cm/s. This was consistent with previous reports identifying abnormal LV relaxation and filling patterns in more than 50% of elderly, in patients with aortic stenosis and those undergoing coronary artery bypass surgery ,24. As rcongestive heart failure and the functional states of elevated LV end-diastolic pressure or low LV ejection fraction which are all considered strong predictors of LV dysfunction, cardiac complications and mortality after cardiac surgery [Preoperative LV diastolic dysfunction associated with myocardial hypertrophic and fibrotic changes could predispose patients to LV dysfunction during weaning from CPB for several reasons. First, patients with enlarged cardiac muscular mass and reduced capillary density are prone to develop ischemic lesions due to suboptimal delivery of the cardioplegic solution particularly after prolonged aortic cross-clamping time ,29. Seco surgery ,5-8,32.pseudo-normalization patterns. In our experience, these measurements were less reproducible  and could not be obtained in 13% of patients. In addition, extensive calcifications of the aortic valve likely restrain the downward excursion of the mitral annulus resulting in low peak annular velocities (E') which underestimates LV longitudinal relaxation. Likewise, the success rate of Doppler-derived pulmonary flow measurements has been reported within a wide range (37% to 99%) and with considerable inter-reader variability (3% to 21%) [Although Doppler-derived mitral inflow and pulmonary venous flow measurements as well as TDI currently provide the cornerstones of the assessment of LV diastolic function, their practical application in the operating room may be hampered by difficulties in recording and measuring each of these parameters within a short time in anesthetized cardiac patients. In addition, most of these echo-Doppler parameters are highly influenced by age, heart rate and loading conditions . Therefo to 21%) ,35.et al. [In agreement with other studies, we could easily determine Vp in all patients without post-acquisition manipulation and with minimal inter-and intraoperator variability (<5%) ,36. Basiet al.  confirmeWe are mindful of several limitations. First, being conducted in a single centre with a relatively small population sample focusing mainly on LV function, this observational study requires further validation in a larger group of patients with a combined assessment of left and right ventricular function. Patients with arrhythmias and pulmonary hypertension were excluded from the study and the low prevalence of systolic LV failure, anemia and renal failure precluded any conclusion regarding these potential risk factors . Second, Vp might underestimate the severity of diastolic dysfunction in cases presenting LV chamber dilation due to swirlings of the inflow along the LV wall ,34. SincThis study provides the first evidence that diastolic dysfunction as defined by Vp <40 cm/s, in addition to advanced age and prolonged ischemic time, identifies patients at risk of LV dysfunction after valvular aortic surgery. Clinicians should anticipate a greater impact of perioperative TEE to identify high-risk cardiac patients while improving fluid and inotropic/lusitropic drug treatments. The association of preoperative diastolic dysfunction with adverse cardiac outcome begs the question as to whether trials of specific perioperative strategies to improve LV relaxation and filling patterns should be considered in patients undergoing aortic valve surgery.• Advanced age, preoperative LV diastolic dysfunction and prolonged aortic clamping time are significant predictors of LV dysfunction following CPB requiring inotropic support in patients undergoing valve replacement for aortic stenosis.• Among several echocardiographic parameters, transmitral flow propagation velocity (Vp) less than 40 cm/sec best identified patients at higher risk of LV dysfunction after CPB and was associated with more frequent cardiac complications in the ICU.BNP: brain natriuretic peptides; CI: confidence interval; CPB: cardiopulmonary bypass; DT: deceleration time; E' and A': early and late diastolic velocities of the mitral annulus; EDA: end-diastolic area; ESA: end-systolic area; FAC: fractional area change; IABP: intra-aortic balloon pump; IVRT: isovolumic relaxation time; LV: left ventricular; MAP: mean arterial pressure; ORs: odds ratios; PWT: posterior wall thickness; ROC: receiver-operator-characteristic; S: D and Ar: peak systolic, diastolic and atrial reversal velocities of pulmonary venous flow; TDI: tissue Doppler imaging; TEE: transoesophageal echocardiography; Vp: transmitral flow propagation velocity.The authors declare that they have no competing interests.ML and JD participated in the study design, data analysis, interpretation of the data as well as the writing of the manuscript. JD, VC and CI participated in data collection, literature search and data interpretation. AK, TC, TT and MC participated in revising the bibliography, and correcting and editing the manuscript. All the authors have read and approved the final manuscript.


Tetralogy of Fallot (TOF) is an important lesion for all pediatric and congenital heart surgeons. In designing the most appropriate operation for children with TOF, the postoperative physiology should be taken into account, both in the short and long term. The balance between pulmonary stenosis (PS) and pulmonary insufficiency (PI) may be critical for preservation of ventricular function. A unified repair strategy that limits both residual PS and PI is presented, along with supporting experimental evidence, a strategy for dealing with coronary anomalies, and comments regarding best timing of operation. TOF is an important lesion for pediatric and congenital cardiac surgeons. It was the first cyanotic lesion to be described, and generated some of the initial palliative and definitive cardiac operations. TOF is therefore an excellent model for natural history studies of treated congenital heart disease. Moreover, TOF has had a central role in our understanding of molecular biology, myocardial protection, and inflammation as they relate to congenital heart disease (CHD). Most importantly, although TOF is often lethal if untreated, it now has a good prognosis with timely surgical intervention, even if a uniformly excellent result remains elusive.The ideal TOF repair should be suitable for children of all ages, and should provide good relief of right ventricular outflow tract obstruction (RVOTO) to prevent progression of right ventricular hypertrophy. There should be complete atrial and ventricular septation, with avoidance of ventriculotomy and circulatory arrest. Preservation of pulmonary valve (PV) and tricuspid valve (TV) function and biventricular contractility would also be considered fundamental, along with minimal early mortality and morbidity. In the current era, in which the immediate outcome of TOF repair is good employing diverse surgical strategies, the goal of treatment should include the avoidance of long-term complications and a low probability of early and late reoperations. A good neurodevelopmental and functional status and quality of life could complete the expectations.Lillehei's original TOF repairs (whether with cross circulation or cardiopulmonary bypass(CPB)) generally employed a large right ventricular incision for access to both the RVOTO and ventricular septal defect (VSD). The relatively favorable long term results have been noted in numerous studies.–3 HoweveThe traditional thinking regarding post repair TOF physiology has emphasized two points. The first is that postoperative RVOTO is undesirable, to the point that many teams would consider revision of a repair in the setting of a right ventricle (RV) / left ventricle (LV) pressure ratio > .75. The second traditional belief is that postoperative PI is well tolerated and that only very significant RV dilation is problematic. Both concepts have been challenged in recent years. PI is exacerbated by loss of distal compliance and lessened or prevented by proximal resistance. Free PI causes right ventricular dilation that in turn compresses the LV. The degree of PI depends in part on pulmonary arterial compliance, and the location of resistance relative to valveless RV-PA junction.The functional reserve and myocardial contractility of the right (and possibly left) ventricle decrease with chronic PI, detectable in experimental models as early as 3 months after the onset of PI. Such phy66Following TOF repair, there is almost always residual RVOTO, seen immediately or over time. Furthermore, the degree of RVOTO may be inversely proportional to the grade of PI. With an isolated pressure load, increases in cellular hypertrophy, microtuble density, and interstitial collagen formation will lead to decreased contractility over time. In balancing PS and PI, it would be useful to know which is worse for the RV and LV over the long term: isolated PI or combined PSPI? Should we try to limit PI by accepting more PS at the initial repair? Can we eliminate both problems using appropriate techniques?The UCSF interventional cardiology team have created a non surgical porcine model to assess the effects of chronic combined PSPI on RV and LV function over time, looking at both anatomic and functional changes Figure . GrowingAfter 3 months of PSPI, indices of RV systolic pump function were decreased at rest and failed to increase appropriately during dobutamine stress. Impaired systolic pump function was associated with decreased RV diastolic compliance but enhanced RV myocardial contractility. These findings contrasted markedly with the effects of isolated PI observed in a similar model. In additStenosis, in addition to insufficiency, seemed to have been beneficial by promoting hypertrophy, limiting RV dilatation, and enhancing myocardial contractility. These beneficial effects of short- to intermediate-term stenosis on RV myocardial contractility raise many questions in light of the known adverse effects of long-term severe PS on RV function. Our physiological findings need to be confirmed in long-term studies and for different degrees of PSPI. However, this also brings into question the long-held belief that stenosis, even mild, is detrimental to ventricular function while insufficiency is well tolerated.The acute change from a pressure-loaded to a volume-loaded RV, in addition to the right ventriculotomy, can adversely affect the performance of the RV in the immediate postoperative period.26 Our un29Our current operative technique is outlined in Figures  and 4. Aet al.[In the majority of cases the pulmonary valve will be bicuspid with location of the commissures at the 3 and 9 o'clock positions. An incision is made in the middle of the anterior cusp and then extended to the right ventricular free wall for approximately 10 to 15 mm. When the commissures are located at the 6 and 12 o'clock positions or the commissures are anterior and posterior but located off the midline, we divide the pulmonary valve at or near the anterior commissure to preserve as much valve tissue as possible, as described by Sung et al. The diviFor transannular reconstructions (i.e. cases in which the PV cannot be spared) a triangular glutaraldehyde-treated autologous pericardial patch is sutured to the endocardium from the most inferior aspect of the right ventriculotomy all the way up to the hinge point of the anterior cusp and then along the divided edge of the valve on either side. When the anterior cusp is small or the anterior commissure is located at the 12 o'clock position, the patch is anchored to the main PA. In patients in whom the commissure is eccentric, the patch is sutured to the main PA on one side and to the free edge of the leaflet on the other side. Then a second patch is used to close the RVOT and the pulmonary arteriotomy, thus recreating a sinus over the augmented valve leaflet .In our initial study of this technique, beginning in November 2001, 43 patients with TOF and 2 patients with isolated pulmonary valve stenosis had relief of RVOTO with either a transannular patch plus pulmonary valve cusp augmentation (n = 18) or a transannular patch alone (n = 25). The mediet al, employing this technique.[Of the 18 patients who underwent pulmonary valve cusp augmentation, 1 was lost to follow-up. Two patients required reintervention. One patient presented to the hospital 3 months postoperatively with a delayed pericardial effusion and required a pericardial window. The second patient was symptomatic with persistent subvalvar pulmonary stenosis. She underwent operative RVOT muscle bundle resection 2 years after her original repair. This patient had moderate PI at discharge, and the degree of PI did not change during follow-up. At a median follow-up of 7.5 months (range 0-29 months), 6 of the 17 patients (35.3%) had moderate or severe PI at follow-up. Three patients (17%) who underwent pulmonary valve cusp augmentation had progression of PI when compared with the degree of PI at discharge. Similar improved outcomes have been demonstrated in a larger cohort by Sung echnique.Several groups have described strategies to limit the size of the right ventriculotomy and reduce the incidence of PI. Valved homografts and xenografts were proposed as the most anatomic and physiologic way to resolve RVOT obstruction, but all will eventually need replacement because of patient growth and conduit deterioration. The use 33The current technique may be different, in that it preserves the native hinge mechanism of the valve cusps, especially when the pulmonary valve is bicuspid and the commissures are located in the 3 and 9 o'clock positions. The use of native valve tissue also offers the theoretic potential of growth. The pulmonary kneecaps technique can be used in the majority of patients with TOF and pulmonary stenosis who require division of the pulmonary valve annulus for relief of RVOT obstruction. In our experience it cannot be applied only in a certain subgroup of patients who have a small pulmonary annulus with hypoplastic inadequate native pulmonary valve tissue. In this group of patients the TA-TP repair with a minimal right ventriculotomy and closure of the RVOT with a simple transannular patch is preferred.Despite the limitations of our study, the augmentation of the pulmonary valve cusp with autologous pericardium is simple, does not significantly prolong the operation, reduces the degree of PI in the immediate postoperative period, and improves the early outcome after TA-TP TOF repair requiring a transannular patch. When technically feasible, it has become our preferred technique for RVOT reconstruction in patients with TOF and in patients with pulmonary stenosis who require surgical intervention.Coronary anomalies occur in between 5% and 12% of patients with TOF.–15 The met al at the Royal Children's Hospital, Melbourne.[352 nor cardiac output can be guaranteed. Although survival statistics are generally favorable, most published neonatal TOF series have not had a long enough followup time to fully assess the effects of free PI.[The best age for TOF repair remains controversial, and the strategy employed may influence the technique of operation. TOF can be repaired at any age with a low operative risk in units equipped to deal safely with complex heart surgery in infants. The TA-TP strategy particularly is easier and more reliable in infants 2 - 6 months of age than in neonates, but is certainly possible at any age. In our unit since November of 2001, we have used the TA-TP approach for TOF repair, following the policy set forth by Mee elbourne. Neonateselbourne.3536 Prop free PI.–39The argument is often put forth as primary neonatal repair versus palliative systemic to pulmonary arterial shunt with later repair. However, virtually every published report of infant or neonatal tetralogy repairs excludes or mentions patients who had a palliative shunt rather than a primary repair. Therefore even the strongest proponents of neonatal primary repair still consider the modified Blalock Taussig shunt (MBTS) a requirement for selected cases, such as anomalous coronaries, multiple VSDs, generalized critical illness, rehabilitation of small or distorted PAs, prematurity and low birth weight, need to establish a volume load to prevent diastolic dysfunction after repair (older children), and even religious objection to blood transfusion. In fact, most tetralogy patients (probably 75%) do not require any surgical treatment in the neonatal period. The important argument therefore is not “primary repair vs shunt” but “neonatal vs non-neonatal” elective primary repair”.Newborns with CHD are known to be susceptible to abnormal brain development and widespread CNS abnormalities, which may be exacerbated following neonatal operations utilizing CPB, especially with deep hypothermia-circulatory arrest (DHCA). Arguments for neonatal repair in the current era should include a detailed assessment of neurodevelopmental status, which rarely appears in outcome data for “early” tetralogy repair, even if “prevention of cerebral injury” is widely cited as a justification for early repairs. Newborns are known to be more susceptible to brain injury such as periventricular leukomalacia in the perioperative period, especially with the use of DHCA.41 NonethConsiderable progress has been made in the repair strategy for TOF, based on our improved understanding of post repair physiology. There are important implications for timing as well as technique of surgery, and continued evolution is expected.


By comparing rest and stress values, their respective reserve values  are generated. We evaluated myocardial ischaemia by RTP-ASE Qontrast® quantification, compared to visual perfusion evaluation with 99mTc-tetrofosmin single-photon emission computed tomography (SPECT).Real-time perfusion (RTP) adenosine stress echocardiography (ASE) can be used to visually evaluate myocardial ischaemia. The RTP power modulation technique angio-mode (AM), provides images for off-line perfusion quantification using Qontrast® infusion, before and throughout adenosine stress, also used for SPECT. Visual myocardial perfusion and wall motion analysis, and Qontrast® quantification, were blindly compared to one another and to SPECT, at different time points off-line.Patients admitted to SPECT underwent RTP-ASE (SONOS 5500) using AM during SonovueWe analyzed 201 coronary territories  in 67 patients. SPECT showed ischaemia in 18 patients and 19 territories. Receiver operator characteristics and kappa values showed significant agreement with SPECT only for β-r and Axβ-r in all segments: area under the curve 0.678 and 0.665; P < 0.001 and < 0.01, respectively. The closest agreements were seen in the LAD territory: kappa 0.442 for both β-r and Axβ-r; P < 0.01. Visual evaluation of ischaemia showed good agreement with SPECT: accuracy 93%; kappa 0.67; P < 0.001; without non-interpretable territories.® quantification of myocardial ischaemia was less accurate and less feasible than visual evaluation and needs further development to be clinically useful.In this agreement study with SPECT, RTP-ASE Qontrast In low risk patients with suspected myocardial ischaemia, evaluation of ischaemia is generally recommended for optimal care and treatment ,2. Exerc®  is a recently developed and commercially available software, with algorithms that automatically follow the left myocardium contours throughout the cardiac cycle and throughout the replenishment period of the RTP image loop. Qontrast® may provide a practical way to quantify myocardial perfusion by contrast echocardiography, and has shown promising initial results in both animals and patients with acute myocardial infarction [Qontrastfarction ,26. Howe® quantification can be used to correctly evaluate myocardial ischaemia in patients with known or suspected stable coronary artery disease, as compared with visual evaluation of ischaemia by RTP-ASE, as well as with SPECT.The aim of the present study was to examine if RTP-ASE QontrastWe prospectively asked 69 randomly selected patients, without prior knowledge of acoustic windows, admitted to adenosine SPECT evaluation of known or suspected stable coronary artery disease, to participate in the study. Part of the study population has been presented previously . Two of ® was infused in the left decubital vein using an infusion pump dedicated for this purpose , which automatically rotates the syringe to prevent sedimentation. The infusion rate of Sonovue was set between 1.0 and 1.3 ml/min [The echocardiographic equipment used was a Sonos 5500  with S3 probe and RTP using the power modulation angio-mode. Patients were examined in a left lateral recumbent position. The second-generation contrast agent Sonovue3 ml/min . AdenosiAll 67 patients underwent RTP imaging  during infusion of echo contrast, at rest and after a minimum of one minute of hyperaemia during adenosine stress (at 140 μg/kg/min). Image acquisition was started after at least one minute of Sonovue infusion. RTP image loops containing 8–10 heartbeats were collected from the parasternal long-axis and apical four- and two-chamber views, respectively. At the beginning of each loop a destruction impulse of 10 high mechanical index frames  were given to destroy all contrast micro bubbles in the myocardium .During RTP the angio-mode gain was set between 60 and 70%, depending on what was suitable for the individual patient as judged by a visual on-line assessment, and 2D greyscale gain was set at zero. Focus was set close to the base of the left ventricle. All images were stored digitally for later off-line analysis.® was used to produce parametric images of contrast replenishment values for the RTP loops collected from both rest and stress. Two points were manually placed in the left ventricular cavity of the perfusion images. The first point was placed in the centre of the cavity where the apex "half-circle" ends, i.e. approximately two thirds from the base of ventricle, where it was always inside the cavity (never in the myocardium) during the complete loop. The point was placed in a cavity area that was fully opacified directly after the destruction impulse in the beginning of the loop, as well as throughout the entire RTP-loop, since this formed the basis of the maximum image contrast intensity reference-point. Any isolated frames not fulfilling these criteria were excluded from analysis. The second point was placed at the base of the ventricle, enabling the software to automatically outline the complete left ventricle, including both cavity and myocardium, with dotted "M-mode" lines crossing perpendicular through the myocardial wall  [Three parametric images were then automatically generated from the perfusion analysis, displaying either the peak signal intensity (A), myocardial blood flow velocity (β) or myocardial blood flow (Axβ). These were generated for each pixel, from the replenishment curve of each pixel, according to the replenishment curve A = A(1-e-βt) . These pTo acquire quantitative values of A, β and Axβ, region of interests were manually traced both at rest and stress, corresponding to the distribution territories of the three main coronary arteries; left anterior descending (LAD), left circumflex (LCx) and right coronary artery (RCA) Figure . Since eComparing A, β and Axβ values at rest and stress (hyperaemia), the corresponding reserve values  were derived by dividing the stress value with the matching rest value, thus resembling invasive measurement of coronary flow reserve. Accordingly, this generated three A-r, β-r, and Axβ-r values from the LAD territory, originating from the three different echocardiographic views , two reserve values each from the LCx territory (four-chamber and long-axis views) and two from the RCA territory (four- and two-chamber views). The lowest A-r, β-r and Axβ-r value from any of the views corresponding to a coronary territory was selected for the ischaemia comparison with SPECT, since the lowest reserve value should originate from the most ischaemic or the least perfused territory.Two separate visual image interpretation were performed with off-line analysis of myocardial perfusion and wall motion at RTP-ASE, using the EnConcert Image Diagnosis Application . The first visual analysis was a combined analysis of perfusion and wall motion. The second visual analysis, performed separately, was an analysis excluding wall motion to estimate the value of sole perfusion analysis. Visual and quantitative perfusion analyses were done on separate occasions, blinded to one another and blinded to the result of SPECT. Each segment of the left ventricular myocardium was attributed to the same coronary vessel territory at all analyses. Myocardial ischaemia was visually evaluated comparing rest and stress images, using both perfusion and wall motion analysis in a complementary manner. A visually detected perfusion defect during stress was used as the principal marker of ischaemia. Thus, a myocardial segment was considered ischaemic if perfusion was impaired in the stress images, compared to the rest images . Perfusi99mTc-tetrofosmin at stress. Stress was simultaneous with the RTP-ASE. Normal findings at stress were not followed by a rest study [99mTc-tetrofosmin. Patients who had cardiac medications, which could interfere with the stress test, were informed to have their medication interrupted prior to the stress test. The decision whether to interrupt the drug administration was at the discretion of the referring physician. A five-minute adenosine infusion protocol was used. Starting the infusion with 100 μg/ml/min of adenosine for 1 minute, the dose was then increased to 140 μg/ml/min for two minutes before injecting 99mTc-tetrofosmin. Infusion of adenosine was continued for 2 min after the injection of 99mTc-tetrofosmin. The scintigraphic data were acquired one hour after the end of the stress test, using continuous SPECT over 180 degree elliptical rotation from the 45 degree right anterior oblique position, with a dual-head gamma camera . Low energy high-resolution collimator and a zoom factor of 1.0 were used. We obtained 64 projections in a 128 × 128 matrix, with an acquisition time of 20 s per projection. Tomographic reconstruction and calculation of short axis slice images were performed using Siemens software. A two-dimensional Butterworth pre-reconstruction filter was used with critical frequency of 0.35, order 5. For each patient, the same sets of short axis slices were then processed with an automatic software package (4D-MSPECT) on a Siemens e.soft workstation. The software package defined apex and base and generated, coronal, longitudinal, sagital tomographic slices as well as polar maps with schematic map of the territories of the main coronary arteries used for scoring. Radiotracer uptake of the vascular segments were scored visually and stress images were compared with rest images regarding ischaemia and infarct. The specialist in nuclear medicine who performed the scoring was blinded to the results of the RTP analysis.The rest and stress studies were performed using a 2-day protocol, starting with injection of 600 MBq st study ,32. PathMethod of reference for the ischaemia evaluation in the study was the presence or absence of reversible ischaemia at the SPECT examination. Continuous variables are expressed as mean ± 1SD and as percent. P < 0.05 denoted significance. Receiver operating characteristic (ROC) curves were used to examine and compare predictive ability of different parametric variables, by calculating sensitivity, specificity, accuracy, positive and negative predictive values  and area under the curve (AUC). Unpaired t-test was used to test for difference between patients. For intra-assay variability of quantitative measurements of A and β, coefficient of variation was used.Clinical data were retrieved form patients records. Patient characteristics are presented in Table ® software due to low parametric image quality, which made it too difficult to differentiate the left ventricular myocardium from the cavity. A summary of non-interpretable territories is presented in Table Of the 201 coronary distribution territories, 28 (14%) could not be analyzed due to perfusion artefacts according to the visual perfusion analysis. These territories were still evaluated in the visual perfusion analysis with combined wall motion evaluation, since wall motion still could be analyzed in these territories. In the quantitative analysis two more territories were considered non-interpretable using the QontrastFrom the ROC curves Figure  AUC is vIntra-observer variability for A and β was assessed by a second blinded reading of 10 randomly selected patients from the study. Variability was 6.0% and 18% for A and β, respectively. Visual inter- and intra-observer variability is presented in Table ® could possibly be used for quantitative measurements of myocardial ischaemia from RTP-ASE acquired images, but only in the LAD territory. All three quantitative parameters, A-r, β-r and Axβ-r showed significant agreement with SPECT in the LAD territory. Only β-r and Axβ-r showed significant agreement with SPECT in the all-territory analysis, but in the analyses by the specific coronary territories they only showed significant agreement with SPECT in the LAD territory. Qontrast® provides consistently high negative predictive values and reasonably high specificity at present cut off values, which is of importance for ruling out ischaemia. Sensitivity and positive predictive value could perhaps have been higher if the segments analyzed had been more detailed, i.e. following a 17 segment model. However, then there probably would have been a greater anatomical mismatch between echocardiography and SPECT. Visual evaluation of myocardial ischaemia showed better results than automated quantification using Qontrast®. The visual analysis using a combination of perfusion and wall motion to increase the number of interpretable segments, as well as the sole perfusion analysis, both showed excellent agreement with SPECT, which has been suggested previously [This agreement study indicates that Qontrasteviously ,11,33,34®. Visual interpretation with complementary wall motion analysis could be performed in all of the included patients. The study findings only apply to patient groups with suspected myocardial ischaemia and, for example, not to patient populations with acute coronary syndrome.There are of course differences between RTP-ASE and SPECT. The spatial resolution of echocardiography is higher than with SPECT, which might suggest missed minor ischaemic territories at SPECT. However, it is known that a SPECT image without signs of ischaemia is associated with few cardiac events . Also, rThe results indicate that the quantification of myocardial ischaemia is still in need of improvement to be clinically useful, which is in line with previous studies ,30. The The U.S. Food and Drug Administration issued on October the 10th 2007 a "black box" warning for perflutren-containing contrast agents, which caused considerable controversies within the echocardiography community . This wa® quantification of myocardial ischaemia is less accurate than visual evaluation, as compared with SPECT. At present this method cannot be recommended for clinical use, but future development of echocardiographic image quality and software properties may improve the method.The results of the present agreement study indicate that RTP-ASE QontrastThe authors declare that they have no competing interests.PG, RW, MD and RBW initiated the study. RW, MD and OT supervised the study and participated in the interpretation of the results and manuscript preparation. PG performed measurements, made all data conversions, plots and calculations from ultrasound data, and participated in the preparation of the manuscript. PG, KS, RW and MD participated in data collection, performed statistical analysis and participated in the interpretation of the results. LL and RBW participated in the interpretation of the results, in the creation of plots and in the preparation of the manuscript. MK participated in the interpretation of the results and preparation of the manuscript. All authors read and approved the final manuscript.