Behfar, Atta

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

Abstract Background Clinical trials utilizing mesenchymal stem cells (MCSs) for the treatment of perianal Crohn disease are expanding. Most enrolled Crohn patients are being actively treated with corticosteroids, immunomodulators, and biologic therapy for their luminal and perianal disease at the time of enrollment and treatment. Aim We sought to broaden the understanding of the effect of corticosteroids, immunomodulators, and biologic therapy on the viability and function of MCSs. This information is important for tailoring inclusion and exclusion criteria of clinical trials. Methods Human adipose–derived mesenchymal stem cells (hAMCSs) were harvested and isolated from healthy patient donors. At Passage 3, hAMCSs were treated with 7 commonly used immunosuppressive therapies used to treat Crohn disease at increasing concentrations: dexamethasone, methotrexate, azathioprine, 6-mercaptopurine, infliximab, vedolizumab, and ustekinumab. Cell proliferation, migration, and cytokine secretion were analyzed at Day 4. Results Dexamethasone and azathioprine and 6-mercaptopurien affected cell proliferation and migration. Dexamethasone even resulted in cell death at high physiologic concentrations. The same drugs also had the most profound impacts on IL-6, IL-8, and monocyte chemoattractant protein-1 secretion profiles. Biologic therapies, including anti-tumor necrosis factor, anti-interleukin, and anti-integrins, had the smallest impact on hAMSC proliferation, migration, and cytokine secretion profile. Conclusions In clinical trials with MCSs, a washout period may be recommended for corticosteroids and immunomodulators to minimize any effect of systemic immunosuppression on MSC function and efficacy.

Background Diastolic pulmonary gradient ( DPG ) was proposed as a better marker of pulmonary vascular remodeling compared with pulmonary vascular resistance ( PVR ) and transpulmonary gradient ( TPG ). The prognostic significance of DPG in patients requiring a left ventricular assist device ( LVAD ) remains unclear. We sought to investigate whether pre‐ LVAD DPG is a predictor of survival or right ventricular ( RV ) failure post‐ LVAD . Methods and Results We retrospectively reviewed 268 patients who underwent right heart catheterization before LVAD implantation from 2007 to 2017 and had pulmonary hypertension because of left heart disease. Patients were dichotomized using DPG ≥7 mm Hg, PVR ≥3 mm Hg, or TPG ≥12 mm Hg. The associations between these parameters and all‐cause mortality or RV failure post LVAD were assessed with Cox proportional hazards regression and Kaplan–Meier analyses. After a mean follow‐up time of 35 months, elevated DPG was associated with increased risk of RV failure (hazard ratio [ HR ]: 3.30; P =0.004, for DPG ≥7 versus DPG <7), whereas elevated PVR ( HR 1.85, P =0.13 for PVR ≥3 versus PVR <3) or TPG ( HR 1.47, P =0.35, for TPG ≥12 versus TPG <12) were not associated with the development of RV failure. Elevated DPG was not associated with mortality risk ( HR 1.16, P =0.54, for DPG ≥7 versus DPG <7), whereas elevated PVR , but not TPG , was associated with higher mortality risk ( HR 1.55; P =0.026, for PVR ≥3 versus PVR <3). Conclusions Among patients with pulmonary hypertension because of left heart disease requiring LVAD support, elevated DPG was associated with RV failure but not survival, while elevated PVR predicted mortality post LVAD implantation.

Abstract Response to stem cell therapy in heart failure is heterogeneous, warranting a better understanding of outcome predictors. This study assessed left ventricular volume, a surrogate of disease severity, on cell therapy benefit. Small to large infarctions were induced in murine hearts to model moderate, advanced, and end-stage ischemic cardiomyopathy. At 1 month postinfarction, cardiomyopathic cohorts with comparable left ventricular enlargement and dysfunction were randomized 1:1 to those that either received sham treatment or epicardial delivery of cardiopoietic stem cells (CP). Progressive dilation and pump failure consistently developed in sham. In comparison, CP treatment produced significant benefit at 1 month post-therapy, albeit with an efficacy impacted by cardiomyopathic stage. Advanced ischemic cardiomyopathy was the most responsive to CP-mediated salvage, exhibiting both structural and functional restitution, with proteome deconvolution substantiating that cell therapy reversed infarction-induced remodeling of functional pathways. Moderate cardiomyopathy was less responsive to CP therapy, improving contractility but without reversing preexistent heart enlargement. In end-stage disease, CP therapy showed the least benefit. This proof-of-concept study thus demonstrates an optimal window, or “Goldilocks principle,” of left ventricular enlargement for maximized stem cell-based cardiac repair. Disease severity grading, prior to cell therapy, should be considered to inform regenerative medicine interventions. Significance statement This article documents that cardiac chamber enlargement postinfarction is a predictor of cardiopoietic stem cell therapy response. Left ventricular size pretherapy could thus serve to guide the selection of ischemic heart failure candidates most suitable to receive a regenerative intervention.

Background: We aim to study the incidence of major complications related to procedure defined as in-hospital death, myocardial infarction, stroke, pericardial effusion or tamponade, percutaneous coronary intervention due to iatrogenic coronary dissection, or unplanned bypass surgery within 72 hours after diagnostic left heart catheterization (LHC; primary end point). Furthermore, all causes of in-hospital death after LHC were adjudicated and reported (secondary end point). Methods and Results: Diagnostic LHC procedures (aortic angiography; coronary, including graft, angiography; and left ventricular angiography) from January 1, 2002, through December 31, 2013, were identified using the clinical scheduling system at Mayo Clinic, Rochester, and complications were identified through electronic records. International Classification of Diseases, Ninth Revision billing codes were used. Registration was queried to identify all-cause mortality. All events were reviewed and adjudicated. There were 43 786 diagnostic LHC procedures; 97.3% were coronary angiograms. The mean age of patients was 64.5 years (13.6), and the majority were male (61.5%). Primary end point was seen in 36 (0.082%) procedures or 8.2 of 10 000 LHCs. Combined right sided procedures with LHC did not increase the risk of major complications. Cardiogenic and septic shock, cardiac arrhythmia, and postsurgical complication were the most common causes of in-hospital death after LHC. Conclusions: The overall rates of major complications related to diagnostic cardiac catheterization procedures are extremely rare. The majority of the deaths occurring post-diagnostic LHC procedures were secondary to acute illness rather than directly related to diagnostic procedure.

Background Left ventricular (LV) hemodynamic assessment has been sparsely performed in patients supported on continuous‐flow LV assist devices (cf LVADs ). Insight into dynamic changes of left heart parameters during ramp studies may improve LV assist device optimization and evaluate pathology. Methods and Results To complement right heart catheterization, a novel technique for left heart catheterization in patients with a cf LVAD was developed. Patients implanted with cf LVAD s underwent hemodynamic ramp left heart catheterization and right heart catheterization with transthoracic echocardiography. Continuous aortic and LV pressures were measured along with right atrial, pulmonary artery, and pulmonary capillary wedge pressures. A novel index, the transaortic gradient ( TAG ) was established. Thirty eight patients with cf LVADs were evaluated at a median of 446 days (interquartile range, 183–742) after device implant. During left heart catheterization performed for hemodynamic optimization, drop‐in LV end‐diastolic pressure and pulmonary capillary wedge pressure were associated with a rise in TAG . A range was identified for TAG (20–40 mm Hg) as providing the most optimal level of hemodynamic offloading. Pathologic states deviated from normal responses to ramp. LV assist device thrombosis was associated with an inability to increase in TAG during speed ramp. Significant aortic insufficiency was associated with a marked increase in LV end‐diastolic pressure despite a concomitant decrease in pulmonary capillary wedge pressure with increasing LV assist device speeds. Conclusions Inclusion of left heart catheterization to a typical right heart catheterization LV assist device ramp protocol imparted unique insights to optimize cf LVAD speeds in different clinical scenarios. A novel index, the TAG was defined and provided additional resolution to optimized offloading.

Background The Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation ( IRE ) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE . Methods and Results In an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90‐μs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T‐wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250–833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV ( P =0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J ( P =0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J. Conclusions Our study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.