Nadjib Hammoudi

Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca(2+)-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism.

Adeno-associated virus-mediated gene therapy in cardiovascular disease

Purpose of review The use of adeno-associated virus (AAV) as an efficient, cardiotropic, and safe vector, coupled with the identification of key molecular targets, has placed gene-based therapies within reach of cardiovascular diseases. The purpose of this review is to provide a focused update on the current advances related to AAV-mediated gene therapy in cardiovascular diseases, and particularly in heart failure (HF), wherein gene therapy has recently made important progress. Recent findings Multiple successful preclinical studies suggest a potential utility of AAV gene therapy for arrhythmias and biological heart pacing, as well as RNA overexpression. Moreover, AAV-mediated overexpression of several molecular targets involved in HF has demonstrated promising results in clinically relevant large animal models. In humans, a safe and successful completion of a phase 2 clinical trial targeting the sarcoplasmic reticulum calcium ATPase pump with AAV has been reported. Serial studies are ongoing to further prove the efficacy of AAV-mediated sarcoplasmic reticulum calcium ATPase pump gene transfer in human HF. Summary Significant progress in clinical translation of AAV-mediated cardiac gene therapy has been achieved in recent years. This will prompt further clinical trials, and positive results could open a new era for cardiac gene therapy.

An experimental model of the Ross operation: Development of resorbable reinforcements for pulmonary autografts

OBJECTIVES To circumvent the issue of pulmonary autograft (PA) dilation after the Ross procedure, surgical reinforcement strategies have been suggested in clinical or anecdotal series. However, no preclinical large-animal model of the Ross procedure is available, which is needed to enable full comprehension of the pathologic mechanisms and the effectiveness of reinforcement techniques during growth. Our aim was to develop a large-animal model of the Ross operation, to reproduce the clinical scenario in which this procedure might be applied, and allow for development and testing of various devices and techniques to improve PA performance. In addition, we aimed to test the effectiveness of a bioresorbable mesh for PA reinforcement. METHODS An experimental model of transposition of the pulmonary trunk as an autograft in the aortic position has been developed and performed under cardiopulmonary bypass in 20 growing lambs, aged 3 months. The experimental design included: a control group that underwent PA transposition; a group in which the PA was reinforced with an external, synthetic, nonresorbable, polypropylene grid; and a group that received various combinations of resorbable meshes. Animals were followed up during growth for 6 months by angiography and echocardiography and eventually killed for pathologic analysis. RESULTS All animals survived the procedure with no complications. The model was easy and reproducible. Resorbable meshes prevented PA dilation and preserved its progressive growth process, aiding histologic remodelling. CONCLUSIONS We developed an easy and reproducible model of the Ross procedure, allowing for a reliable simulation of the clinical scenario. Resorbable PA reinforcement may represent an interesting option in this context.

Outcomes of primary percutaneous coronary interventions in nonagenarians with acute myocardial infarction

BACKGROUND Few data are available on primary percutaneous coronary intervention (pPCI) in nonagenarians. In a large prospective registry on pPCI for STEMI we compared the demographics, procedural and in-hospital outcomes between nonagenarians (age ≥ 90 years) and patients aged < 90 years. METHODS AND RESULTS We included 26,157 consecutive patients with pPCI in the Greater Paris Area region between 2003 and 2011. Of these, 418 (1.6%) were ≥ 90 years old. Nonagenarians (versus patients < 90 years) were more likely to be female (62.3% versus 22.5%, p < 0.0001), nonsmokers (81.6% versus 36.7%, p < 0.0001), in cardiogenic shock (Killip IV) upon admission (10.5% versus 4.8%, p < 0.001), and had significant co-morbidities. Over two-thirds of patients underwent procedures via the radial artery (61% versus 72.1%, p = 0.007). Both groups had high and similar angiographic success rates (98.1% versus 98.7%, p = 0.33). Drug-eluting stents were used less often in nonagenarians (4.4% versus 16.7%, p < 0.0001). Hospital mortality was significantly much higher in patients over 90 years old (24.9% versus 5.1%, p < 0.001) in univariate analysis. After adjustment for sex, cardiogenic shock, diabetes, triple vessel disease, drug-eluting stent use and glycoprotein IIb/IIIa inhibitors use, mortality remains higher in nonagenarian patients (OR: 4.31; 95% CI: 3.26-5.71, p < 0.0001). CONCLUSIONS In a real-world setting, we found important demographic differences in nonagenarian compared to younger patients. Despite achieving a high rate of reperfusion with pPCI using mainly radial access, similar to that achieved in younger patients, hospital mortality was higher in nonagenarians.

Mesalamine-induced myocarditis.

Nowadays mesalamine is a common treatment for Crohns disease and hypersensitive reactions to this product have been reported. Yet there is limited information concerning mesalamine-induced myocarditis and its mechanism is not known. We described a case of mesalamine-induced myocarditis in Crohns disease of the colon.

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.

Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial

Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT‐HF (NCT01966887) trial investigated the impact of adeno‐associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non‐invasive cardiac imaging.

Empagliflozin Improves Left Ventricular Diastolic Dysfunction in a Genetic Model of Type 2 Diabetes

PurposeCardiovascular (CV) diseases in type 2 diabetes (T2DM) represent an enormous burden with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently emerged as a new antidiabetic class that improves glucose control, as well as body weight and blood pressure with no increased risk of hypoglycemia. The first CV outcome study terminated with empagliflozin, a specific SGLT2 inhibitor, has shown a reduction in CV mortality and in heart failure hospitalization, suggesting a beneficial impact on cardiac function which remains to be demonstrated. This study was designed to examine the chronic effect of empagliflozin on left ventricular (LV) systolic and diastolic functions in a genetic model of T2DM, ob/ob mice.Methods and ResultsCardiac phenotype was characterized by echocardiography, in vivo hemodynamics, histology, and molecular profiling. Our results demonstrate that empagliflozin significantly lowered HbA1c and slightly reduced body weight compared to vehicle treatment with no obvious changes in insulin levels. Empagliflozin also improved LV maximum pressure and in vivo indices of diastolic function. While systolic function was grossly not affected in both groups at steady state, response to dobutamine stimulation was significantly improved in the empagliflozin-treated group, suggesting amelioration of contractile reserve. This was paralleled by an increase in phospholamban (PLN) phosphorylation and increased SERCA2a/PLN ratio, indicative of enhanced SERCA2a function, further supporting improved cardiac relaxation and diastolic function. In addition, empagliflozin reconciled diabetes-associated increase in MAPKs and dysregulated phosphorylation of IRS1 and Akt, leading to improvement in myocardial insulin sensitivity and glucose utilization.ConclusionThe data show that chronic treatment with empagliflozin improves diastolic function, preserves calcium handling and growth signaling pathways and attenuates myocardial insulin resistance in ob/ob mice, findings suggestive of a potential clinical utility for empagliflozin in the treatment of diastolic dysfunction.

Increased Stiffness Is the Major Early Abnormality in a Pig Model of Severe Aortic Stenosis and Predisposes to Congestive Heart Failure in the Absence of Systolic Dysfunction

Background It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis. Methods and Results Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure–volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure–volume relationship β: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure–volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca2+) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis. Conclusion Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.

Combination Proximal Pulmonary Artery Coiling and Distal Embolization Induces Chronic Elevations in Pulmonary Artery Pressure in Swine

Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH. This percutaneous model was created in swine (n=6) by combining distal embolization of dextran beads with selective coiling of the lobar pulmonary arteries (2 procedures per lung over 4 weeks). As controls, findings from this model were compared with those from a standard weekly distal embolization model (n=6) and sham animals (n=4). Survival with the combined embolization model was 100%. At 8 weeks after the index procedure, combined embolization procedure animals had increased mean pulmonary artery pressure (mPA) and pulmonary vascular resistance (PVR) compared to the controls with no effect on left heart or systemic pressures. RV remodeling and RV dysfunction were also present with a decrease in the RV ejection fraction, increase in the myocardial performance index, impaired longitudinal function, as well as cardiomyocyte hypertrophy, and interstitial fibrosis, which were not present in the controls. Pulmonary vascular remodeling occurred in both embolization models, although only the combination embolization model had a decrease in pulmonary capacitance. Taken together, these cardiopulmonary hemodynamic and structural findings identify the novel combination embolization swine model as a valuable tool for future studies of chronic PH.