Limitations in the Assessment of Prosthesis-Patient Mismatch.

BACKGROUND: Prosthesis-patient mismatch (PPM) after aortic valve replacement (AVR) may affect survival but data are conflicting. It is assessed by relating effective orifice area (EOA) to body surface area (EOAi). EOA is patient-specific as the result of flow-velocity times area at the individual patient's outflow tract levels (LVOTA) divided by trans-prosthetic flow velocity. However, some studies use projected EOAs (i.e., valve size associated EOAs from other patient populations) to assess how PPM affects outcome. METHODS: We analyzed 76 studies addressing hemodynamic outcome and/or mortality after bioprosthetic AVR. RESULTS: In 48 studies, projected or measured EOA for calculation of EOAi and PPM assessment was used (of which 25 demonstrated an effect on survival). We identified 28 additional studies providing measured EOA values and the corresponding Bernoulli's pressure gradients after AVR. Despite EOA being a patient-specific parameter, 77% of studies assessing a PPM impact on survival used projected EOAs. The 28 studies are providing measured EOA values and the corresponding Bernoulli's pressure gradients in patients after AVR showed a highly significant, linear relationship between EOA and Bernoulli's gradient. Considering this relationship, it is surprising that relating EOA to body surface area (BSA) (EOAi) is standard but relating pressure gradients to BSA is not. CONCLUSION: We conclude that the majority of studies assessing PPM have used false assumptions because EOA is a patient-specific parameter and cannot be transferred to other patients. In addition, the use of EOAi to assess PPM may not be appropriate and could explain the inconsistent relation between PPM and survival in previous studies.

Triheptanoin Alleviates Ventricular Hypertrophy and Improves Myocardial Glucose Oxidation in Rats With Pressure Overload.

OBJECTIVE: Cardiac hypertrophy is characterized by changes in substrate utilization and activity of the Krebs cycle. We assessed the effects of triheptanoin, an odd-chain fat that might support the Krebs cycle, on cardiac metabolism and function in a model of cardiac hypertrophy. METHODS AND RESULTS: Rats were subjected to aortic banding (AoB) to induce pressure overload (PO). Starting at 1 week after AoB, rats were blindly fed a control diet or a special diet containing triheptanoin at 7% (T7 group) or 30% (T30 group) of total energy value. Six weeks after AoB, echocardiography revealed attenuated hypertrophy and improved diastolic function of the left ventricle. Isolated working heart perfusion showed similar cardiac power, fatty acid oxidation, substrate preference, and insulin response among groups. However, cardiac glucose oxidation (GO) was increased in the T30 group compared with the T7 and control groups. Blood levels of the odd-chain ketone body beta-hydroxypentanoate confirmed adequate bioavailability of triheptanoin. Importantly, they were directly proportional to cardiac GO. CONCLUSIONS: Treatment with triheptanoin-enriched diet reduces ventricular hypertrophy and improves diastolic function in rats with PO, which is associated with enhanced cardiac GO. The results suggest targeting supplementation of the Krebs cycle to approach ventricular and metabolic remodeling in cardiac hypertrophy.

Novel thoughts on patient-prosthesis mismatch in aortic valve replacement: the rationale for the PAR I trial.

The hemodynamic performance of prosthetic tissue valves is influenced by valve design and valve-specific sizing strategies. Design determines the actual geometric opening area (GOA) of the prosthetic valve and sizing strategy its actual chosen size. Currently, hemodynamic performance is assessed by determining the effective orifice area (EOA; derived from the continuity equation by relating flow velocities with the area of the left ventricular outflow tract [LVOTA]). The question whether a valve is too small (patient-prosthesis mismatch [PPM]) is currently addressed by relating EOA to body surface area (EOA index [EOAi]). However, this relation may not be appropriate because the EOAi relates flow velocity to patient-specific anatomic parameters twice (i.e., LVOTA and body surface area). This potential confounder may explain the controversies regarding PPM. However, intuitively, leaving a gradient behind after aortic valve replacement cannot be irrelevant. PPM becomes even more relevant with transcatheter valve-in-valve implantation, where a second prosthesis is taking up inner space of a valve that may have already been too small initially. Thus, a reliable method to determine the presence of PPM is needed. The Prosthesis-to-Annulus Relation I (PAR I) trial is a German multicenter study assessing the relation between the prosthetic GOA and the LVOTA as a potentially new parameter for the prediction of hemodynamic outcome. The results may possibly guide future valve size selection and may allow prediction of functionally relevant PPM. Here, we will demonstrate the shortcomings of the currently applied EOAi for the assessment of hemodynamic relevance and present the rationale for the PARI trial, which recently started recruiting patients.

Pressure overload differentially affects respiratory capacity in interfibrillar and subsarcolemmal mitochondria.

Years ago a debate arose as to whether two functionally different mitochondrial subpopulations, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), exist in heart muscle. Nowadays potential differences are often ignored. Presumably, SSM are providing ATP for basic cell function, whereas IFM provide energy for the contractile apparatus. We speculated that two distinguishable subpopulations exist that are differentially affected by pressure overload. Male Sprague-Dawley rats were subjected to transverse aortic constriction for 20 wk or sham operation. Contractile function was assessed by echocardiography. Heart tissue was analyzed by electron microscopy. Mitochondria were isolated by differential centrifugation, and respiratory capacity was analyzed using a Clark electrode. Pressure overload induced left ventricular hypertrophy with increased posterior wall diameter and impaired contractile function. Mitochondrial state 3 respiration in control was 50% higher in IFM than in SSM. Pressure overload significantly impaired respiratory rates in both IFM and SSM, but in SSM to a lower extent. As a result, there were no differences between SSM and IFM after 20 wk of pressure overload. Pressure overload reduced total citrate synthase activity, suggesting reduced total mitochondrial content. Electron microscopy revealed normal morphology of mitochondria but reduced total mitochondrial volume density. In conclusion, IFM show greater respiratory capacity in the healthy rat heart and a greater depression of respiratory capacity by pressure overload than SSM. The differences in respiratory capacity of cardiac IFM and SSM in healthy hearts are eliminated with pressure overload-induced heart failure. The strong effect of pressure overload on IFM together with the simultaneous appearance of mitochondrial and contractile dysfunction may support the notion of IFM primarily producing ATP for contractile function.

Not all porcelain is the same: classification of circular aortic calcifications (porcelain aorta) according to the impact on therapeutic approach.

Severe aortic calcification, also known as "porcelain aorta," has a major impact on patient outcome. Its presence also influences the choice of procedure depending on where it is located. However, to date there is no clear definition on how this term should be employed, being often used as an exclusion criteria for conventional surgery where aortic clamping and/or cannulation is required.We here suggest a classification of the "porcelain aorta" regarding its location and how it influences particular therapeutic options. Therefore, making more clear what procedures would represent an increased risk for the patient and which are more suitable when discussed in a "Heart Team."Type I implies localization of a circumferential calcification in the ascending aorta. Type IA represents the calcified aorta with no possibility of clamping and Type IB represents the calcified aorta with possible clamping. Type II addresses the calcification of the descending aorta including or not the aortic arch.

Echocardiography alone allows the determination of heart failure stages in rats with pressure overload.

BACKGROUND: There is currently no standard for the assessment of contractile function in animals. We aimed to determine whether transthoracic echocardiography in rats with chronic pressure overload allows determining the stage of hypertrophy and heart failure (HF). METHODS: Pressure overload was created by placement of a metal clip around the thoracic aorta at a weight of 40 to 50 g. After 1, 2, 6, 10, and 20 weeks, we performed echocardiography according to the American Heart Association guidelines (n = 26, four to six rats for each time point). We also obtained heart, lung, and body weights and regularly evaluated clinical signs of HF. RESULTS: : Pressure overload caused significant hypertrophy within 1 week. Contractile function was normal until 6 weeks when diastolic dysfunction appeared. After 10 weeks of pressure overload, systolic function decreased. At 20 weeks, hearts were dilated and cardiac index was decreased. These findings correlated with increased lung-to-body weight ratio after 6 weeks and clinical signs of HF after 20 weeks. CONCLUSION: Echocardiography alone allows the reproducible determination of HF stages after aortic constriction in rats.

Biphasic response of skeletal muscle mitochondria to chronic cardiac pressure overload - role of respiratory chain complex activity.

Pressure overload induced heart failure affects cardiac mitochondrial function and leads to decreased respiratory capacity during contractile dysfunction. A similar cardiac mitochondrial dysfunction has been demonstrated by studies which induce heart failure through myocardial infarction or pacing. These heart failure models differ in their loading conditions to the heart and show nevertheless the same cardiac mitochondrial changes. Based on these observations we speculated that a workload independent mechanism may be responsible for the impairment in mitochondrial function after pressure overload, which may then also affect the skeletal muscle. We aimed to characterize changes in mitochondrial function of skeletal muscle during the transition from pressure overload (PO) induced cardiac hypertrophy to chronic heart failure. PO by transverse aortic constriction caused compensated hypertrophy at 2 weeks, HF with normal ejection fraction (EF) at 6 and 10 weeks, and hypertrophy with reduced EF at 20 weeks. Cardiac output was normal at all investigated time points. PO did not cause skeletal muscle atrophy. Mitochondrial respiratory capacity in soleus and gastrocnemius muscles showed an early increase (up to 6 weeks) and a later decline (significant at 20 weeks). Respiratory chain complex activities responded to PO in a biphasic manner. At 2 weeks, activity of complexes I and II was increased. These changes pseudo-normalized within the 6-10 week interval. At 20 weeks, all complexes showed reduced activities which coincided with clinical heart failure symptoms. However, both protein expression and supercomplex assembly (Blue-Native gel) remained normal. There were also no relevant changes in mRNA expression of genes involved in mitochondrial biogenesis. This temporal analysis reveals that mitochondrial function of skeletal muscle is changed early in the development of pressure overload induced heart failure without being directly influenced by an increased loading condition. The observed early increase and the later decline in respiratory capacity can be explained by concomitant activity changes of complex I and complex II and is not due to differences in gene expression or supercomplex assembly.

GLP-1 Improves Diastolic Function and Survival in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) has emerged as a public health burden with currently no effective medication. We assessed the treatment effects of the incretin hormone glucagon-like peptide-1 (GLP-1) on cardiac metabolism and function in a model of HFpEF. Following aortic banding, rats developed HFpEF characterized by diastolic dysfunction, pulmonary congestion, and poor survival (38%). A 4-week GLP-1 treatment via osmotic pumps significantly improved survival (70%) and reduced left ventricular stiffness, diastolic dysfunction, and pulmonary congestion. Isolated heart perfusion revealed preserved cardiac glucose oxidation (GO) and a shift in cardiac substrate utilization towards GO. While GLP-1 may boost insulin secretion and responsiveness, the protective effects were not related to cardiac insulin action. GLP-1 improves diastolic function and survival in rats with HFpEF, which was associated with a cardiac substrate switch towards GO. The therapeutic role of GLP-1 in HFpEF is new and warrants further investigation.

Increased Protein Tyrosine Phosphatase 1B (PTP1B) Activity and Cardiac Insulin Resistance Precede Mitochondrial and Contractile Dysfunction in Pressure-Overloaded Hearts.

BACKGROUND: Insulin resistance in diabetes mellitus has been associated with mitochondrial dysfunction. Defects at the level of mitochondria are also characteristic of heart failure. We assessed changes in cardiac insulin response and mitochondrial function in a model of pressure overload-induced heart failure. METHODS AND RESULTS: Rats underwent aortic banding to induce pressure overload. At 10 weeks, rats showed cardiac hypertrophy and pulmonary congestion, but left ventricular dilatation and systolic dysfunction were only evident after 20 weeks. This contractile impairment was accompanied by mitochondrial dysfunction as shown by markedly reduced state 3 respiration of isolated mitochondria. Aortic banding did not affect systemic insulin response. However, insulin-stimulated cardiac glucose uptake and glucose oxidation were significantly diminished at 10 and 20 weeks, which indicates cardiac insulin resistance starting before the onset of mitochondrial and contractile dysfunction. The impaired cardiac insulin action was related to a decrease in insulin-stimulated phosphorylation of insulin receptor ß. Consistently, we found elevated activity of protein tyrosine phosphatase 1B (PTP1B) at 10 and 20 weeks, which may blunt insulin action by dephosphorylating insulin receptor ß. PTP1B activity was also significantly increased in left ventricular samples of patients with systolic dysfunction undergoing aortic valve replacement because of aortic stenosis. CONCLUSIONS: Pressure overload causes cardiac insulin resistance that precedes and accompanies mitochondrial and systolic dysfunction. Activation of PTP1B in the heart is associated with heart failure in both rats and humans and may account for cardiac insulin resistance. PTP1B may be a potential target to modulate insulin sensitivity and contractile function in the failing heart.

Percutaneous cannulation for cardiopulmonary bypass in minimally invasive surgery is associated with reduced groin complications.

OBJECTIVES: Femoral cutdown is standard in most centres if groin cannulation is used for cardiopulmonary bypass in minimally invasive cardiac surgery (MICS). Arterial closure devices (ACDs) allow placement of larger cannulas percutaneously, but its benefit in MICS is unclear. We assessed our results with percutaneous groin cannulation using ACDs in comparison with conventional surgical access in patients undergoing MICS. METHODS: We reviewed 445 consecutive patients having undergone MICS between October 2010 and March 2015. Of those, 92 (21%) were performed with conventional surgical access to the groin vessels and 353 (79%) with the use of ACDs. RESULTS: Operative risk was higher in the ACD group [logistic EuroSCORE 7.9% (SD: 8.1) vs 10.6% (SD: 12.3); P = 0.010]. The use of ACDs significantly reduced operation time [193 min (SD: 43.8) vs 173 min (SD: 47.1); P < 0.001] and hospital stay [Cutdown: median 9 days (8, 14); ACD: median 9 days (7, 12), P = 0.040] without affecting the time to full mobilization. The incidence of any complication was significantly lower in the ACD group (2.3% vs 8.7%; P = 0.007). Complications with conventional cannulation consisted of lymphatic fistulae (n = 4), wound infections (n = 2), stenosis (n = 1) and haematoma (n = 1). In the ACD group, there were local dissections (n = 2) and stenoses (n = 3). There was 1 haematoma in both groups. There were 2 vascular injuries in the ACD group (n = 2), leading to conversion to surgical access. CONCLUSIONS: Percutaneous groin cannulation using ACDs for establishing cardiopulmonary bypass in minimally invasive valve surgery significantly reduces groin complications, operation time and hospital stay. However, the remaining complications are mainly of vascular nature versus wound infection and lymph fistulae with cutdown.

Risk factors for mortality after pericardiectomy for chronic constrictive pericarditis in a large single-centre cohort.

OBJECTIVES: Constrictive pericarditis (CP) is an uncommon disease with multiple causes and unclear clinical outcomes. To date, few publications have clearly defined risk factors of poor outcomes after surgery for CP. We performed a retrospective analysis of almost 100 patients undergoing surgical treatment for CP at a single institution in order to identify risk factors for perioperative and long-term mortality. METHODS: A total of 97 consecutive patients (67.0% male) undergoing surgery for CP at our institution from 1995 to 2012 were included in the study. CP was diagnosed either preoperatively by cardiac catheterization and appropriate imaging or during surgery. Preoperative and intraoperative risk factors for 30-day and late mortality were analysed using stepwise multivariate logistic and Cox regression analyses. Median follow-up was 1.23 ± 3.96 years (mean 3.08 ± 3.96 years). RESULTS: The mean patient age was 60.0 ± 12.5 years and the underlying aetiology was idiopathic (50.5%), prior cardiac surgery (15.5%), prior mediastinal radiation (9.3%), and miscellaneous (24.7%). All patients underwent either radical (55.2%) or partial (44.8%) pericardiectomy. Concomitant procedures were performed in 54 (55.7%) patients. The total procedure time was 197.0 ± 105.0 min. Cardiopulmonary bypass (CPB) was used in 62 patients with a corresponding CPB time of 124.8 ± 68.4 min. In those patients who underwent CPB, cardioplegic arrest was performed in 53.2% of patients with a mean cross-clamp time of 74.9 ± 41.9 min. Overall 30-day, 1-year and 5-year survival rates were 81.4, 66.5 and 51.6%, respectively, without significant differences according to the underlying aetiology. Multivariate analysis revealed patients with reduced left ventricular ejection fraction (LVEF) [P = 0.01, odds ratio (OR) 3.6] and preoperative right ventricular dilatation (P = 0.04, OR 3.5) to be at significant risk of early mortality. Long-term mortality was independently predicted by the presence of coronary artery disease (CAD) [P < 0.001, hazard ratio (HR) 6.44], chronic obstructive pulmonary disease (P = 0.001, HR 4.21) and preoperative renal insufficiency (P = 0.012, HR 1.8). Concomitant tricuspid valve repair (TVR) appeared to provide protective effect on the long-term survival (P = 0.07). CONCLUSIONS: Surgery for CP is associated with a significant risk based on the poor preoperative patient status. Whenever justified, partial over radical pericardiectomy should be preferred and TVR should be indicated liberally. Reduced LVEF and right ventricular dilatation were independent predictors for early mortality, whereas CAD, chronic obstructive pulmonary disease and renal insufficiency were risk factors for late mortality. Thus, an optimal timing for surgery on CP remains crucial to avoid secondary morbidity with an even worse natural prognosis.

Glucagon-like peptide-1 reduces contractile function and fails to boost glucose utilization in normal hearts in the presence of fatty acids.

UNLABELLED: GLP-1 and exendin-4, which are used as insulin sensitizers or weight reducing drugs, were shown to improve glucose uptake in the heart. However, the direct effects of GLP-1 or exendin-4 on normal hearts in the presence of fatty acids, the main cardiac substrates, have never been investigated. We therefore assessed the effects of GLP-1 or exendin-4 on myocardial glucose uptake (GU), glucose oxidation (GO) and cardiac performance (CP) under conditions of fatty acid utilization. METHODS AND RESULTS: Rat hearts were perfused with only glucose (5 mM) or glucose (5 mM) plus oleate (0.4 mM) as substrates for 60 min. After 30 min, GLP-1 or exendin-4 (0.5 nM or 5 nM) was added. In the absence of oleate, GLP-1 increased both GU and GO. Exendin-4 increased GO but showed no effect on GU. Neither GLP-1 nor exendin-4 affected CP. However, when oleate was present, GLP-1 failed to stimulate glucose utilization and exendin-4 even decreased GU. Furthermore, now GLP-1 reduced CP. In contrast to prior reports, this negative inotropic effect could not be blocked by the protein kinase A inhibitor H-89. We then measured myocardial GO and CP in rats receiving a 4-week GLP-1 infusion. Interestingly, this chronic treatment resulted in a significant reduction in both GO and CP. CONCLUSIONS: Under the influence of oleate, GLP-1 reduces contractile function and fails to stimulate glucose utilization in normal hearts. Exendin-4 may acutely reduce cardiac glucose uptake but not contractility. We suggest advanced investigation of heart function and metabolism in patients treating with these peptides.

Where is the common sense in aortic valve replacement? A review of hemodynamics and sizing of stented tissue valves.

Heated debates revolve around the hemodynamic performance of stented aortic tissue valves. Because the opening area strongly influences the generation of a pressure gradient over the prosthesis, and the outer diameter determines which valve actually fits into the aortic root, it would seem logical that the valve with the greatest opening area in relation to its outer diameter should allow the best hemodynamic performance. Interestingly, neither of these 2 parameters is reflected by the manufacturing companies' size labels or suggested sizing strategies. In addition, it is known that valves with the same size label from different companies may differ significantly in their actual dimension (outer diameter). Finally, the manufacturer-suggested sizing strategies differ so much that expected differences from valve design may get lost because of differences in sizing. These size and sizing differences and the lack of information on the geometric opening area complicate true hemodynamic comparisons significantly. Furthermore, some fluid dynamic considerations regarding the determination of opening area by echocardiography (the effective orifice area) introduce additional obscuring factors in the attempt to compare hemodynamic performance data of different stented tissue valves. We analyzed the true dimensions of different tissue prostheses and the manufacturer-suggested sizing strategies in relation to published effective orifice areas. We have demonstrated how sizing and implantation strategy have much greater impact on postoperative valve hemodynamics than valve brand or type. In addition, our findings may explain the different opinions regarding valve hemodynamics of different tissue valves.

Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression.

OBJECTIVE: Myocardial infarction leads to contractile dysfunction. In patients with diabetes, impaired contractility has been associated with the loss of insulin effects and mitochondrial dysfunction. We assessed cardiac insulin sensitivity and mitochondrial and contractile function in rats after ligation of the left coronary artery. METHODS: At 2 weeks after left coronary artery ligation, we performed echocardiography in vivo and assessed the substrate use and insulin response in the isolated working heart and the regulation of insulin (Akt, glucose transporter type 4) and mitochondrial signaling (p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor-γ coactivator 1α, mitochondrial transcription factor A) using polymerase chain reaction and Western blotting. RESULTS: The infarcted hearts were dilated and had a reduced ejection fraction (ejection fraction < 50%). The basal glucose oxidation was preserved, but the fatty acid oxidation was significantly reduced. Insulin's effect on substrate oxidation was significantly impaired for both the decrease in fatty acid oxidation and the increase in glucose oxidation. However, insulin-stimulated glucose uptake was normal in the infarcted hearts, consistent with normal insulin-induced phosphorylation of Akt and unchanged mRNA expression of glucose transporter type 4. The impaired oxidative response to insulin was associated with reduced mRNA expression of the genes regulating fatty acid oxidation (long-chain-acyl-coenzyme A dehydrogenase, carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor-α) and mitochondrial biogenesis (mitochondrial transcription factor A). Although mRNA expression of the mitochondrial master regulator peroxisome proliferator-activated receptor-γ coactivator 1α was normal in the infarcted hearts, the protein expression of its post-transcriptional activator, p38 mitogen-activated protein kinase, was significantly reduced. CONCLUSIONS: Myocardial infarction in rats caused partial insulin resistance at the level of substrate oxidation, which was associated with mitochondrial and cardiac contractile dysfunction. Mitochondrial dysfunction was characterized by a reduced capacity to oxidize fatty acids and might have resulted from impaired mitochondrial biogenesis through the lack of p38 mitogen-activated protein kinase.

Proteomic remodelling of mitochondrial oxidative pathways in pressure overload-induced heart failure.

AIMS: Impairment in mitochondrial energetics is a common observation in animal models of heart failure, the underlying mechanisms of which remain incompletely understood. It was our objective to investigate whether changes in mitochondrial protein levels may explain impairment in mitochondrial oxidative capacity in pressure overload-induced heart failure. METHODS AND RESULTS: Twenty weeks following aortic constriction, Sprague-Dawley rats developed contractile dysfunction with clinical signs of heart failure. Comparative mitochondrial proteomics using label-free proteome expression analysis (LC-MS/MS) revealed decreased mitochondrial abundance of fatty acid oxidation proteins (six of 11 proteins detected), increased levels of pyruvate dehydrogenase subunits, and upregulation of two tricarboxylic acid cycle proteins. Regulation of mitochondrial electron transport chain subunits was variable, with downregulation of 53% of proteins and upregulation of 25% of proteins. Mitochondrial state 3 respiration was markedly decreased independent of the substrate used (palmitoyl-carnitine -65%, pyruvate -75%, glutamate -75%, dinitrophenol -82%; all P < 0.05), associated with impaired mitochondrial cristae morphology in failing hearts. Perfusion of isolated working failing hearts showed markedly reduced oleate (-68%; P < 0.05) and glucose oxidation (-64%; P < 0.05). CONCLUSION: Pressure overload-induced heart failure is characterized by a substantial defect in cardiac oxidative capacity, at least in part due to a mitochondrial defect downstream of substrate-specific pathways. Numerous changes in mitochondrial protein levels have been detected, and the contribution of these to oxidative defects and impaired cardiac energetics in failing hearts is discussed.