Target Balloon-Assisted Antegrade and Retrograde Use of Re-Entry Catheters in Complex Chronic Total Occlusions.

Purpose, Retrograde recanalizations have gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well described adjunct for antegrade recanalizations. We present our experience with target balloon-assisted antegrade and retrograde recanalizations using re-entry devices in challenging chronic total occlusions. MATERIALS AND METHODS: We report data from a retrospective multicenter registry. Eligibility criteria included either antegrade or retrograde use of the OutbackTM or GoBackTM re-entry catheter in combination with a balloon as a target to accomplish wire passage, when conventional antegrade and retrograde recanalization attempts had been unsuccessful. Procedural outcomes included technical success (defined as wire passage though the occlusion and delivery of adjunctive therapy with <30% residual stenosis at final angiogram), safety (periprocedural complications, e.g., bleeding, vessel injury, or occlusion of the artery at the re-entry site, and distal embolizations), and clinical outcome (amputation-free survival and freedom from target lesion revascularization after 12-months follow-up). RESULTS: Thirty-six consecutive patients underwent target balloon-assisted recanalization attempts. Fourteen (39 %) patients had a history of open vascular surgery in the index limb. Fifteen patients were claudications (Rutherford Class 2 or 3, 21 presented with chronic limb threatening limb ischemia (Rutherford Class 4 to 6). The locations of the occlusive lesions were as follows: iliac arteries in 3 cases, femoropopliteal artery in 39 cases, and in below-the-knee arteries in 12 cases. In 15 cases, recanalization was attempted in multilevel occlusions. Retrograde access was attempted in 1 case in the common femoral artery, in the femoropopliteal segment in 10 cases, in below-the-knee arteries in 23 cases, and finally in 2 patients via the brachial artery. In 10 cases, the re-entry devices were inserted via the retrograde access site. Technical success was achieved in 34 (94 %) patients. There were 3 periprocedural complications, none directly related to the target balloon-assisted re-entry maneuver. Amputation-free survival was 87.8 % and freedom from clinically driven target lesion revascularization was 86.6 % after 12-months follow-up. CONCLUSION: Target balloon-assisted use of re-entry devices in chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed.

Retrograde use of the Outback re-entry catheter in complex infrainguinal arterial recanalizations.

OBJECTIVE/BACKGROUND: Retrograde recanalizations gained increasing recognition in complex arterial occlusive disease. Re-entry devices are a well-described adjunct for antegrade recanalizations. We present our experience with retrograde, infrainguinal recanalizations using the Outback re-entry catheter in challenging chronic total occlusions. METHODS: We report data from a retrospective multicenter registry in complex retrograde recanalizations. Eligibility criteria included retrograde infrainguinal use of the Outback re-entry catheter where both conventional antegrade and retrograde recanalizations had been unsuccessful. Procedural outcomes included technical success (defined as successful wire passage and delivery of adjunctive therapy with <30% residual stenosis), safety (periprocedural complications, eg, bleeding, vessel injury, or occlusion of the artery at the re-entry site, and distal embolizations), and clinical outcome (amputation-free survival and freedom from clinically driven target lesion revascularization [cd-TLR]). RESULTS: Forty-five consecutive patients underwent retrograde, infrainguinal recanalization attempts with the Outback re-entry catheter between February 2015 and August 2020. Thirty (67%) patients had a history of open vascular surgery in the index limb. In four patients, recanalizations were even more challenging due to previous surgical removal and/or ligation of the proximal segment of the superficial femoral artery. The retrograde access site of the Outback catheter was the femoropopliteal segment in 31 (69%) patients and crural vessels in 14 (31%) patients. The re-entry target sites were as follows: common femoral artery in 31 (69%) patients, superficial femoral artery in 9 (20%) patients, popliteal artery in 1 patient, and below-the-knee arteries in 2 patients. In four patients, the needle of the re-entry device was targeted to an inflated balloon, inserted via the antegrade route. The Outback re-entry catheter was placed via a 6-French sheath in 19 (42%) cases and sheathless in 26 (58%) cases. Technical success was achieved in 41 (91%) patients There were two instances of distal embolizations and three bleeding episodes. Amputation-free survival was 100% at 30 days, and after 12 months, freedom from cd-TLR was 95% at 30 days and 75% at 12 months of follow-up. Female sex was an independent predictor for cd-TLR at 12 months of follow-up. CONCLUSIONS: Retrograde use of the Outback re-entry catheter in infrainguinal chronic total occlusions provides an effective and safe endovascular adjunct, when conventional antegrade and retrograde recanalization attempts have failed.

Implantation of vascular mimetic implants in challenging chronic total occlusions - SuperaTM Extreme.

Standard nitinol stents (SNS), with or without drug eluting technology, are an essential tool within the interventional armamentarium in the treatment of patients with peripheral arterial disease. However, they are plagued by a number of limitations: a.) stent fractures, although observed predominately in first-generation stents, do still occur in state-of-the art stent platforms, b.) lack of radial strength, resulting in inadequate stent expansion, c.) kinking up to a complete collapse of the stent, therefore compromising its use in areas of high mechanical stress such as bending zones. In contrast, the interwoven design of the SuperaTM stent, also referred to as "vascular mimetic implant", overcomes all of the above limitations of SNS. Several registries and studies not only confirmed its mechanical superiority (lack of stent fractures etc.) but also demonstrated remarkable clinical performance (patency and freedom from target lesion revascularization), despite its use in challenging lesions (calcification etc.) and territories (popliteal arteries etc.). Increasing confidence in the mechanical properties of the SuperaTM stent platform prompted interventionalists to further "push the limits" of this unique implant. The present article summarizes the clinical data and shows examples of "extreme" applications of this dedicated stent platform.

Dried-Blood-Spot Technique to Monitor Direct Oral Anticoagulants: Clinical Validation of a UPLC-MS/MS-Based Assay.

Plasma concentrations of direct oral anticoagulants (DOACs) vary largely between individuals, and they correlate well with desired and adverse outcomes. Although regular concentration monitoring of DOACs is not recommended, information on DOAC exposure could be useful in situations when multiple DOAC-clearance pathways are impaired or nonadherence is suspected. Self-sampling techniques, like the use of dried-blood spots (DBSs), would be particularly useful because they enable the collection of information in ambulatory patients at relevant points in time of the dosing interval (e.g., trough). We developed and validated a DBS-based assay to quantify all currently marketed DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in a single ultraperformance-liquid-chromatography-tandem-mass-spectrometry assay. It fulfilled all validation standards within a hematocrit range of 0.33-0.65 and was linear over the calibration ranges of 2.5-750 ng/mL (apixaban and rivaroxaban), 4.4-750 ng/mL (dabigatran), and 9.3-750 ng/mL (edoxaban). Only minor ion suppression (matrix effect ≤13%) was present, inter- and intra-assay precision was ≤13%, and inter- and intra-assay accuracies ranged between 88 and 110%. All DOACs were stable in DBSs up to 52 days at room temperature, if the DBSs were protected from light and humidity. The correlation between (whole blood) DBS and plasma concentrations was assessed in 33 patients under regular DOAC therapy. Deming-regression coefficients between simultaneously collected capillary DBSs and plasma samples were used to predict plasma concentrations from DBSs. Bland-Altman plots revealed a strong agreement between predicted and observed plasma concentrations, thus confirming the suitability of DBSs for DOAC monitoring as an important step toward the important aim of self-sampling at home.

Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome.

BACKGROUND: This article about the emerging field of cardio-oncology highlights typical side effects of oncological therapies in the cardiovascular system, cardiovascular complications of malignancies itself, and potential preventive or therapeutic modalities. METHODS: We performed a selective literature search in PubMed until September 2016. RESULTS: Cardiovascular events in cancer patients can be frequently attributed to oncological therapies or to the underlying malignancy itself. Furthermore, many patients with cancer have pre-existing cardiovascular diseases that can be aggravated by the malignancy or its therapy. Cardiovascular abnormalities in oncological patients comprise a broad spectrum from alterations in electrophysiological, laboratory or imaging tests to the occurrence of thromboembolic, ischemic or rhythmological events and the impairment of left ventricular function or manifest heart failure. DISCUSSION: A close interdisciplinary collaboration between oncologists and cardiologists/angiologists as well as an increased awareness of potential cardiovascular complications could improve clinical care of cancer patients and provides a basis for an improved understanding of underlying mechanisms of cardiovascular morbidity.

Simultaneous quantification of direct oral anticoagulants currently used in anticoagulation therapy.

Direct oral anticoagulants (DOACs) are among the most effective options to prevent serious thromboembolic events in patients with atrial fibrillation. Coagulation assays are used to assess DOAC activity, but lack the possibility to quantify drugs with concurrent pharmacodynamic effect. We developed a selective multi-drug assay to analyze apixaban, betrixaban, dabigatran, edoxaban, edoxaban M4, and rivaroxaban with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC/MS/MS) in plasma fulfilling all requirements of the FDA und EMA guidelines for bioanalytical method validation. Plasma samples were extracted using solid phase extraction in a 96-well micro volume format. Chromatographic separation was performed on a Waters BEH Phenyl 1.7µm column coupled to tandem mass spectrometry. Extraction recoveries exceeded 80 %. Concentrations of 1-1000 ng/ml can be precisely quantified (correlation coefficient of >0.99) using 100 µL plasma volume. Intra-day and inter-day accuracies ranged between 91.0 % and 116 %. Precisions at low and high concentrations were below 13.3 %. The method was applied within a clinical drug trial and eight short pharmacokinetic profiles of patients under DOAC therapy were analyzed. The assay allows for highly sensitive and selective simultaneous quantification of DOACs in patient plasma samples.

Platelet function monitoring for stent thrombosis in critically III patients with an acute Coronary syndrome.

BACKGROUND: Patients after cardiac arrest or in cardiogenic shock due to acute coronary syndrome (ACS) are at high risk for stent thrombosis (ST) and recurrent cardiovascular events after primary percutaneous coronary intervention (PCI). High post-interventional platelet reactivity (HPR) might be an additional risk factor for ST in these critically ill patients. METHODS: Between 2006 and 2016, 401 critically ill patients from a cardiologic intensive care unit underwent platelet function testing after primary PCI using whole blood impedance aggregometry. After exclusion of patients with an abnormal platelet count, 357 patients have been included into the final analysis of this retrospective observational study. RESULTS: The incidence of definite early ST was 19.2% in patients with HPR to P2Y12 antagonists and 1.2% in patients without HPR. Likewise, the incidence of early ST in patients with HPR to acetylsalicylic acid (ASA) was 21.4% versus 1.8% in patients without HPR. In contrast, the incidence of late ST or recurrent myocardial infarction in untreated lesions was not associated with HPR to ASA or P2Y12 antagonists. CONCLUSIONS: Platelet function testing in critically ill ACS patients identified patients at high risk for early ST and might be beneficial for risk stratification.

Efficacy of enteral ticagrelor in hypothermic patients after out-of-hospital cardiac arrest.

INTRODUCTION: Delivery of crushed ticagrelor via a nasogastric tube is a widely spread off-label use in unconscious patients following out-of-hospital cardiac arrest (OHCA). Notwithstanding the importance of a potent dual antiplatelet therapy in these patients, the efficacy of crushed ticagrelor after OHCA has not been established yet. METHODS: In a prospective, single-center, observational trial, 38 consecutive MI patients after OHCA were included. 27 patients (71.1 %) underwent mild induced hypothermia. The primary outcome was platelet inhibition at 24h measured by impedance aggregometry. RESULTS: There was sufficient platelet inhibition in most patients after OHCA. In all hypothermic patients, there was an adequate platelet inhibition by ticagrelor at 24 h (p < 0.001). 15 patients (39.5 %) had significant gastroesophageal reflux and one patient with significant reflux had inadequate platelet inhibition at 24 h. There were no stent thrombosis or recurrent atherothrombotic events in these patients. CONCLUSION: Administration of crushed ticagrelor via a nasogastric tube reliably inhibited platelet function in vitro and in vivo regardless of the presence of hypothermia in MI patients. Thus, platelet inhibition can be reliably achieved in MI patients during neuroprotective hypothermia following OHCA.

Stem cell factor gene transfer improves cardiac function after myocardial infarction in swine.

BACKGROUND: Stem cell factor (SCF), a ligand of the c-kit receptor, is a critical cytokine, which contributes to cell migration, proliferation, and survival. It has been shown that SCF expression increases after myocardial infarction (MI) and may be involved in cardiac repair. The aim of this study was to determine whether gene transfer of membrane-bound human SCF improves cardiac function in a large animal model of MI. METHODS AND RESULTS: A transmural MI was created by implanting an embolic coil in the left anterior descending artery in Yorkshire pigs. One week after the MI, the pigs received direct intramyocardial injections of either a recombinant adenovirus encoding for SCF (Ad.SCF, n=9) or ß-gal (Ad.ß-gal, n=6) into the infarct border area. At 3 months post-MI, ejection fraction increased by 12% relative to baseline after Ad.SCF therapy, whereas it decreased by 4.2% (P=0.004) in pigs treated with Ad.ß-gal. Preload-recruitable stroke work was significantly higher in pigs after SCF treatment (Ad.SCF, 55.5±11.6 mm Hg versus Ad.ß-gal, 31.6±12.6 mm Hg, P=0.005), indicating enhanced cardiac function. Histological analyses confirmed the recruitment of c-kit(+) cells as well as a reduced degree of apoptosis 1 week after Ad.SCF injection. In addition, increased capillary density compared with pigs treated with Ad.ß-gal was found at 3 months and suggests an angiogenic role of SCF. CONCLUSIONS: Local overexpression of SCF post-MI induces the recruitment of c-kit(+) cells at the infarct border area acutely. In the chronic stages, SCF gene transfer was associated with improved cardiac function in a preclinical model of ischemic cardiomyopathy.

Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions.

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 ± 25 ml/m(2) vs. 51 ± 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies.

Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure.

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 10(13) vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 10(12) vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.

SUMO-1 gene transfer improves cardiac function in a large-animal model of heart failure.

Recently, the impact of small ubiquitin-related modifier 1 (SUMO-1) on the regulation and preservation of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2a) function was discovered. The amount of myocardial SUMO-1 is decreased in failing hearts, and its knockdown results in severe heart failure (HF) in mice. In a previous study, we showed that SUMO-1 gene transfer substantially improved cardiac function in a murine model of pressure overload-induced HF. Toward clinical translation, we evaluated in this study the effects of SUMO-1 gene transfer in a swine model of ischemic HF. One month after balloon occlusion of the proximal left anterior descending artery followed by reperfusion, the animals were randomized to receive either SUMO-1 at two doses, SERCA2a, or both by adeno-associated vector type 1 (AAV1) gene transfer via antegrade coronary infusion. Control animals received saline infusions. After gene delivery, there was a significant increase in the maximum rate of pressure rise [dP/dt(max)] that was most pronounced in the group that received both SUMO-1 and SERCA2a. The left ventricular ejection fraction (LVEF) improved after high-dose SUMO-1 with or without SERCA2a gene delivery, whereas there was a decline in LVEF in the animals receiving saline. Furthermore, the dilatation of LV volumes was prevented in the treatment groups. SUMO-1 gene transfer therefore improved cardiac function and stabilized LV volumes in a large-animal model of HF. These results support the critical role of SUMO-1 in SERCA2a function and underline the therapeutic potential of SUMO-1 for HF patients.

Stimulating myocardial regeneration with periostin Peptide in large mammals improves function post-myocardial infarction but increases myocardial fibrosis.

AIMS: Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI). METHODS AND RESULTS: We developed a controlled release system to deliver recombinant periostin peptide into the pericardial space. A single application of this method was performed two days after experimental MI in swine. Animals were randomly assigned to receive either saline or periostin peptide. Experimental groups were compared at baseline, day 2, 1 month and 3 months. Treatment with periostin peptide increased the EF from 31% to 41% and decreased by 22% the infarct size within 12 weeks. Periostin peptide-treated animals had newly formed myocardium strips within the infarct scar, leading to locally improved myocardial function. In addition the capillary density was increased in animals receiving periostin. However, periostin peptide treatment increased myocardial fibrosis in the remote region at one week and 12 weeks post-treatment. CONCLUSION: Our study shows that myocardial regeneration through targeted peptides is possible. However, in the case of periostin the effects on cardiac fibrosis may limit its clinical application as a viable therapeutic strategy.

AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling.

BACKGROUND: Heart failure is characterized by impaired function and disturbed Ca2+ homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca2 cycling and preserve cardiac performance in the failing heart. The aim of this study was to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction. METHODS AND RESULTS: Myocardial infarction was created by a percutaneous, permanent left anterior descending artery occlusion in Yorkshire Landrace swine (n=16). One month after myocardial infarction, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 9 carrying I-1c (n=8) or saline (n=6) as control. One month after myocardial infarction was created, animals exhibited severe heart failure demonstrated by decreased ejection fraction (46.4±7.0% versus sham 69.7±8.5%) and impaired (dP/dt)max and (dP/dt)min. Intracoronary injection of AAV9.I-1c prevented further deterioration of cardiac function and led to a decrease in scar size. CONCLUSIONS: In this preclinical model of heart failure, overexpression of I-1c by intracoronary in vivo gene transfer preserved cardiac function and reduced the scar size.

Comparison of left ventricular stroke volume assessment by two- and three-dimensional echocardiography in a swine model of acute myocardial infarction validated by thermodilution method.

BACKGROUND: Accurate left ventricular stroke volume (LVSV) measurement is clinically important in patients presenting with acute myocardial infarction. Three-dimensional echocardiography (3DE) is expected to overcome limitations of two-dimensional echocardiography (2DE). However, inaccuracy in volumetry by 3DE has often been reported hindering further clinical application. This study aimed at comparing agreement and correlation with the thermodilution method (TDM) between 2DE and 3DE measurement of LVSV. METHODS: Swine model of myocardial infarction was created and LVSV was measured by 3DE by subtracting end-systolic from end-diastolic volume (3DE-method). Pulsed Doppler ultrasound and left ventricular outlet tract area were used to measure LVSV by 2DE (2DE-method). TDM was performed by the Swan-Ganz catheter. Bland-Altman analysis followed by assessment of intraclass correlation coefficient (ICC) were performed between 2DE-method and TDM as well as 3DE-method and TDM. RESULTS: A total of 25 comparisons revealed a significant overestimation of LVSV by the 2DE-method (bias = 6.5 mL; 95% confidence interval [CI], 3.9-9.0 mL; P < 0.0001), whereas there was no significant bias by the 3DE-method (bias =-1.6; 95% CI, -4.3 to 1.1 mL; P = 0.22). The ICC between 2DE and TDM was 0.49 (95% CI, 0.14-0.74) whereas ICC between 3DE and TDM was 0.75 (95% CI, 0.51-0.88). CONCLUSIONS: This study elucidated that LVSV is better estimated by 3DE-method compared to the conventional 2DE-method. This investigation will provide a more accurate, quick and noninvasive way of LVSV and cardiac output assessment at bedside by further application of 3DE.

Gene therapy for heart failure.

Congestive heart failure accounts for half a million deaths per year in the United States. Despite its place among the leading causes of morbidity, pharmacological and mechanic remedies have only been able to slow the progression of the disease. Today's science has yet to provide a cure, and there are few therapeutic modalities available for patients with advanced heart failure. There is a critical need to explore new therapeutic approaches in heart failure, and gene therapy has emerged as a viable alternative. Recent advances in understanding of the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), along with the start of more recent phase 1 trials, opens a new era for gene therapy for the treatment of heart failure.

Assessing left ventricular systolic dysfunction after myocardial infarction: are ejection fraction and dP/dt(max) complementary or redundant?

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In naïve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in naïve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.

Temporal changes of strain parameters in the progress of chronic ischemia: with comparison to transmural infarction.

The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar.

Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts.

SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.