Ablate and pace: Comparison of outcomes between conduction system pacing and biventricular pacing.

BACKGROUND: Conduction system pacing (CSP), including His-bundle pacing (HBP) and left bundle branch area pacing (LBBAP), have been proposed as alternatives to biventricular pacing (BVP) in patients scheduled for ablate and pace (A&P) strategy. The aim of this study was to compare the clinical outcomes, including the rate and nature of device-related complications, between BVP and CSP in a cohort of patients undergoing A&P. METHODS: Prospective, multicenter, observational study, enrolling consecutive patients undergoing A&P. The risk of device-related complications and of heart failure (HF) hospitalization was prospectively assessed. RESULTS: A total of 373 patients (75.3 ± 8.7 years, 53.9% male, 68.9% with NYHA class ≥III) were enrolled: 263 with BVP, 68 with HBP, and 42 with LBBAP. Baseline characteristics of the three groups were similar. Compared to BVP and HBP, LBBAP was associated with the shortest mean procedural and fluoroscopy times and with the lowest acute capture thresholds (all p < .05). At 12-month follow-up LBBAP maintained the lowest capture thresholds and showed the longest estimated residual battery longevity (all p < .05). At 12-months follow-up the three study groups showed a similar risk of device-related complications (5.7%, 4.4%, and 2.4% for BVP, HBP, and LBBAP, respectively; p = .650), and of HF hospitalization (2.7%, 1.5%, and 2.4% for BVP, HBP, and LBBAP, respectively; p = .850). CONCLUSIONS: In the setting of A&P, CSP is a feasible pacing modality, with a midterm safety profile comparable to BVP. LBBAP offers the advantage of reducing procedural times and obtaining lower and stable capture thresholds, with a positive impact on the device longevity.

Impact of atrioventricular junction ablation and CRT-D on long-term mortality in patients with left ventricular dysfunction, permanent, refractory atrial fibrillation, and narrow QRS: Results of a propensity-matched analysis.

INTRODUCTION: In patients with symptomatic permanent atrial fibrillation (PEAF) and narrow QRS, atrio-ventricular junction ablation (AVJA) plus cardiac resynchronization therapy (CRT) is superior to medical therapy in reducing heart failure (HF) hospitalization and all-cause mortality. To compare the mortality of a population of patients with HF, reduced EF (rEF), and PEAF treated with AVJA plus CRT with that of a contemporary cohort of patients in sinus rhythm (SR) with similar baseline characteristics. METHODS AND RESULTS: In this prospective, multicentre, observational study, all-cause mortality in a group of consecutive patients undergoing AVJA and implantable cardioverter-defibrillator (ICD) combined with CRT implantation for HFrEF, narrow QRS, and PEAF with uncontrolled ventricular rate was compared with that of a contemporary cohort of patients in SR undergoing ICD implantation (not combined with CRT) for HFrEF and narrow QRS. Individual 1:1 propensity matching of baseline characteristics was performed. A total of 824 patients were enrolled. Propensity matching yielded 107 matched pairs. After a median follow-up of 52 months, all-cause mortality was similar in patients treated with AVJA plus CRT and in the control group (p = .434). In AVJA plus CRT patients, mortality was significantly lower than in control group patients with a history of paroxysmal/persistent AF (n = 45, p = .020), and similar to that of patients without a history of AF (n = 62, p = .459). CONCLUSIONS: After adjustment for patient characteristics, the long-term prognosis of patients with HFrEF, narrow QRS, and PEAF who underwent AVJA plus CRT was similar to that of a population of patients in SR with similar characteristics.

Optimized radiofrequency lesions through local impedance guidance for effective CTI ablation in right atrial flutter.

BACKGROUND: Although radiofrequency (RF) catheter ablation of cavo-tricuspid isthmus (CTI) is an established treatment for typical right atrial flutter (RAFL), it remains to be established whether local tissue impedance (LI) is able to predict effective CTI ablation and what LI drop values during ablation should be used to judge a lesion as effective. We aimed to investigate the ability of LI to predict ablation efficacy in patients with RAFL. METHODS: RF delivery was guided by the DirectSense™ algorithm. Successful single RF application was defined according to a defragmentation of atrial potentials (DAP), reduction of voltage (RedV) by at least 80% or changes on unipolar electrogram (UPC). The ablation endpoint was the creation of bidirectional conduction block (BDB) across the isthmus. RESULTS: 392 point-by-point RF applications were analyzed in 48 consecutive RAFL patients. The mean baseline LI was 105.4 ± 12Ω prior to ablation and 92.0 ± 11Ω after ablation (p < 0.0001). According to validation criteria, absolute drops in impedance were larger at successful ablation sites than at ineffective ablation sites (DAP: 17.8 ± 6Ω vs. 8.7 ± 4Ω; RedV: 17.2 ± 6Ω vs. 7.8 ± 5Ω; UPC: 19.6 ± 6Ω vs. 10.1 ± 5Ω, all p < 0.0001). LI drop values significantly increased according to the number of criteria satisfied (ranging from 7.5Ω to 19.9). BDB was obtained in all cases. No procedure-related adverse events were reported. CONCLUSIONS: A LI-guided approach to CTI ablation was safe and effective in treating RAFL. The magnitude of LI drop was associated with effective lesion formation and BDB and could be used as a marker of ablation efficacy. CLINICAL TRIAL REGISTRATION: Catheter Ablation of Arrhythmias with a High-Density Mapping System in Real-World Practice (CHARISMA). URL: http://clinicaltrials.gov/ Identifier: NCT03793998.

Effect of SAcubitril/Valsartan on left vEntricular ejection fraction and on the potential indication for Implantable Cardioverter Defibrillator in primary prevention: the SAVE-ICD study.

PURPOSE: Sacubitril/valsartan has been associated with a positive reverse left ventricular remodelling in patients with heart failure with reduced ejection fraction (HFrEF). These patients may also benefit from an ICD implant. We aimed to assess EF improvement after 6 months of treatment with sacubitril/valsartan, evaluating when ICD as primary prevention was no longer indicated. METHODS: Multicentre, observational, prospective study enrolling all consecutive patients with HFrEF and EF ≤ 35% with an ICD as primary prevention and starting treatment with sacubitril/valsartan (NCT03935087). Resynchronization therapy and patients experiencing appropriate ICD therapies before sacubitril/valsartan were excluded. RESULTS: Two-hundred-and-thirty patients were enrolled (73.9% males, mean age 64.3 ± 12.1 years) After 6 months of treatment, a reduction in left ventricular end-diastolic and end-systolic volumes was noted and LVEF increased from 28.3 ± 5.6% to 32.2 ± 6.5% (p < 0.001). At 6 months, a non-ischemic aetiology of cardiomyopathy and a final dose of sacubitril/valsartan > 24/26 mg twice daily were associated with a higher probability of an absolute increase of > 5% in LVEF. A total of 5.3% of primary prevention patients still had an arrhythmic event in the first 6 months after treatment with sacubitril/valsartan started. CONCLUSIONS: Sacubitril/valsartan improves systolic function in HFrEF, mainly due to reverse left ventricular remodelling. Improvement in EF after 6 months of treatment could help prevent ICD implantation in nearly one out of four patients, with important clinical and economic implications. However, the risk of sudden cardiac death in this recovered HFrEF population has not been thoroughly studied, and the present data should be interpreted only as hypothesis-generating.

Cardiac implantable electronic devices replacements in patients followed by remote monitoring during COVID-19 lockdown.

Aims: Following coronavirus disease (COVID-19) outbreak, the Italian government adopted strict rules of lockdown and social distancing. The aim of our study was to assess the admission rate for cardiac implantable electronic devices (CIEDs) replacement procedures in Campania, the 3rd-most-populous region of Italy, during COVID-19 lockdown. Methods and results: Data were sourced from 16 referral hospitals in Campania from 10 March to 4 May 2020 (lockdown period) and during the same period in 2019. We retrospectively evaluated consecutive patients hospitalized for CIEDs replacement procedures during the two observational periods. The number and type of CIEDs replacement procedures among patients followed by remote monitoring (RM), the admission rate, and the type of hospital admission between the two observational periods were compared. In total, 270 consecutive patients were hospitalized for CIEDs replacement procedures over the two observation periods. Overall CIEDs replacement procedures showed a reduction rate of 41.2% during COVID-19 lockdown. Patients were equally distributed for sex (P = 0.581), and both age [median 76 years (IQR: 68-83) vs. 79 years (IQR: 68-83); P = 0.497]. Cardiac implantable electronic devices replacement procedures in patients followed by RM significantly increased (IR: +211%; P < 0.001), mainly driven by the remarkable increase rate trend of both PM (IR: +475%; P < 0.001) and implantable cardiac defibrillator replacement procedures (IR: +67%, P = 0.01), during COVID-19 lockdown compared with 2019 timeframe. Conclusions: We showed a significant increase trend rate of replacement procedures among CIEDs patients followed by RM, suggesting the hypothesis of its increased use to closely monitoring and to optimize the hospital admission time during COVID-19 lockdown.

High-density mapping of Koch's triangle during sinus rhythm and typical AV nodal reentrant tachycardia: new insight.

BACKGROUND: Atrial activation during typical atrioventricular nodal reentrant tachycardia (AVNRT) exhibits anatomic variability and spatially heterogeneous propagation inside the Koch's triangle (KT). The mechanism of the reentrant circuit has not been elucidated yet. Aim of this study is to describe the distribution of Jackman and Haïssaguerre potentials within the KT and to explore the activation mode of the KT, in sinus rhythm and during the slow-fast AVNRT. METHODS: Forty-five consecutive cases of successful slow pathway (SP) ablation of typical slow-fast AVNRT from the CHARISMA registry were included. RESULTS: The KT geometry was obtained on the basis of the electroanatomic information using the Rhythmia mapping system (Boston Scientific) (mean number of points acquired inside the KT = 277 ± 47, mean mapping time = 11.9 ± 4 min). The postero-septal regions bounded anteriorly by the tricuspid annulus and posteriorly by the lateral wall toward the crista terminalis showed a higher prevalence of Jackman potentials than mid-postero-septal regions along the tendon of Todaro and coronary sinus (CS) (98% vs. 16%, p < 0.0001). Haïssaguerre potentials seemed to have a converse distribution across the KT (0% vs. 84%, p < 0.0001). Fast pathway insertion, as located during AVNRT, was mostly recorded in an antero-septal position (n = 36, 80%), rather than in a mid-septal (n = 6, 13.3%) or even postero-septal (n = 3, 7%) location. During typical slow-fast AVNRT, two types of propagation around the CS were discernible: anterior and posterior, n = 31 (69%), or only anterior, n = 14 (31%). During the first procedure, the SP was eliminated, and acute procedural success was achieved (median of 4 [3-5] RF ablations). CONCLUSION: High-density mapping of KT in AVNRT patients both during sinus rhythm and during tachycardia provides new electrophysiological insights. A better understanding and a more precise definition of the arrhythmogenic substrate in AVNRT patients may have prognostic value, especially in high-risk cases. TRIAL REGISTRATION: Catheter Ablation of Arrhythmias With High Density Mapping System in the Real World Practice (CHARISMA) URL: http://clinicaltrials.gov/ Identifier: NCT03793998.

Is signal resolution of linear cryocatheters appropriate to map superoparaseptal accessory pathways? A comparison with Orion high-resolution mapping.

Larger tip cryoablation catheters can dampen the signal at the distal tip reducing the resolution of mapping of supero paraseptal APs. The aid of high resolution mapping should be considered to improve safety and efficacy.

Electroanatomical Remodeling of the Atria in Obesity: Impact of Adjacent Epicardial Fat.

OBJECTIVES: The aims of the study were to characterize: 1) electrical and electroanatomical remodeling in patients with atrial fibrillation (AF) with obesity; and 2) the impact of epicardial fat depots on adjacent atrial tissue. BACKGROUND: Obesity is associated with an increased risk of AF. METHODS: A total of 115 patients with AF who underwent AF ablation were screened. After exclusion, 26 patients were divided into 2 groups (obese: body mass index [BMI] ≥27 kg/m2 and reference: BMI <27 kg/m2). They underwent cardiac magnetic resonance (CMR) imaging and electroanatomic mapping of the left atrium (LA) in sinus rhythm before AF ablation. Atrial and ventricular epicardial adipose tissue (EAT) were assessed by CMR. The following electrophysiological parameters were assessed: global and regional voltage, conduction velocity (CV), electrogram fractionation, and CV heterogeneity. In addition, the regional relationship between LA EAT depots and the electrophysiological substrate was evaluated. RESULTS: The BMIs of the obese and reference groups were 30.2 ± 2.6 and 25.2 ± 1.3 kg/m2, respectively (p < 0.001). There was no difference in the left ventricular ejection fraction and a nonsignificant increase in LA size with obesity. Obesity was associated with increase in all measures of EAT (p < 0.05), with a predominant distribution adjacent to the posterior LA and the atrioventricular groove. Obesity was associated with reduced global CV (0.86 ± 0.31 m/s vs. 1.26 ± 0.29 m/s; p < 0.001), with a nonsignificant increase in conduction heterogeneity (p = 0.10), increased fractionation (54 ± 17% vs. 25 ± 10%; p < 0.001), and regional alteration in voltage (p < 0.001). Although the global LA voltage was preserved, there was greater voltage heterogeneity (p = 0.001) and increased low-voltage areas (13.9% vs. 3.4%; p < 0.001) in the obese group compared with the reference group. The low voltage areas were predominantly seen in the posterior and/or inferior LA, which was similar to location of EAT on CMR imaging. Among various measures of obesity, LA EAT volume correlated best with posterior LA fractionation (r2 = 0.55 for LA EAT volume vs. r2 = 0.36 for BMI) and CV (r2 = 0.31 for LA EAT volume vs. r2 = 0.22 for BMI). CONCLUSIONS: Obesity is associated with electroanatomical remodeling of the atria, with areas of low voltage, conduction slowing, and greater fractionation of electrograms. These changes were more pronounced in regions adjacent to epicardial fat depots, which suggested a role for fat depots in the development of the AF substrate.

Atopic dermatitis treatment: what's new on the horizon?

Atopic dermatitis (AD) is an inflammatory disorder of the skin characterized by an impaired immune response and skin barrier function. It is very frequent in adult population being present in up to 10% of population. Quality of life is often reduced in AD patients due to disease burden and symptoms like itch. AD is also frequently associated with psychological diseases such as anxiety or depression. Due to its chronic nature and severity of presentation AD often may not respond to topical treatment and requires systemic treatments which can be associated with significant side effects. A Medline search of the last five years with the keywords "Atopic dermatitis" and "treatment" was performed. Moreover a search throughout the clinicaltrial.gov webpage was performed with the keyword AD. Several topical and systemic treatments are being studied in randomized controlled trials or in case series or in pivotal studies. The progression of the insight on AD pathogenesis have made possible to target single molecules responsible for key aspect of the development of this disease. We discuss the various molecules (small anti-inflammatory molecules, monoclonal antibodies against cytokines) that will be hopefully soon available for the treatment of this disease which still carries an important burden of unmet needs for its treatment.

Characterisation of Myocardial Injury via T1 Mapping in Early Reperfused Myocardial Infarction and its Relationship with Global and Regional Diastolic Dysfunction.

BACKGROUND: Cardiovascular magnetic resonance (CMR) advances in imaging techniques, permits the ability to accurately characterise tissue injury post myocardial infarction. Pre-contrast T1 mapping enables this through measurement of pre-contrast T1 relaxation times. We investigate the relationship between T1 characterisation of myocardial injury with global and regional diastolic function. METHODS: Revascularised acute myocardial infarction patients with normal left ventricular (LV) systolic function on TTE were assessed by 1.5T CMR. Acute regional diastolic wall motion abnormalities, global diastolic function measurements, acute segmental damage fraction with LGE and mean segmental pre-contrast T1 values were assessed on matching short axis slices. RESULTS: Forty-four patients were analysed. Mean LVEF was 62.1±9.4%. No difference between NSTEMI (22/44) and STEMI in mean pre-contrast T1 values of infarcted (1025.0±109.2 vs 1011.0±81.6ms, p=0.70), adjacent (948.3±45.3 vs 941.1±46.6ms, p=0.70) and remote (888.8±52.8 vs 881.2±54.5ms, p=0.66) segments was detected. There was no correlation between pre-contrast T1 of infarcted segments with global diastolic dysfunction (E/A, r2=0.216, p=0.06; S/D, r2=0.243, p=0.053; E/E', r2=0.240, p=0.072), but there was significantly positive, moderate correlation with circumferential diastolic strain rate, (r2=0.579, p<0.01) with excellent agreement and reproducibility. CONCLUSION: Cardiac magnetic resonance evaluation of pre-contrast T1 values revealed no difference between NSTEMI and STEMI patients in terms of tissue characterisation post-myocardial infarction. However, pre-contrast T1 of infarcted tissue is significantly correlated with regional diastolic circumferential strain rate.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL): a possible pathogenic role in chronic plaque psoriasis.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine member of the tumour necrosis factor (TNF) family. Its role has been investigated in skin cancers and some inflammatory and/or immune-mediated skin diseases. An involvement of TRAIL in psoriasis pathogenesis has recently been hypothesized. We investigated the expression and localization of TRAIL and its receptors in psoriatic skin and measured serum TRAIL. The intracellular pathways activated by TRAIL were assessed to investigate its potential role in the pathogenesis of psoriasis. METHODS: Twenty-four consecutive patients with plaque psoriasis and age- and sex-matched healthy subjects were recruited. Serum TRAIL was measured by means of an enzyme-linked immunosorbent assay (ELISA). TRAIL and TRAIL receptors were evaluated by reverse transcription - polymerase chain reaction (RT-PCR) (RNA of lesional and non-lesional psoriatic skin) and by immunohistochemistry (lesional skin). Caspase 8 and NF-kB immunoexpression were also evaluated by immunohistochemistry. RESULTS: RT-PCR demonstrated increased synthesis of TRAIL and its receptors in lesional vs. non-lesional skin. Immunohistochemistry showed a strong staining of TRAIL and TRAIL receptors both in the epidermis and in the dermal infiltrate. Finally, a correlation emerged between caspase 8 and TRAIL immunoexpression in the dermis. CONCLUSIONS: Our findings suggest an involvement of TRAIL in psoriasis pathogenesis, probably through an action at the site of the inflammatory infiltrate, likely via caspase 8.

The first skin cancer screening day at the Italian parliament: a Euromelanoma initiative.

BACKGROUND: The effort to decrease incidence/mortality of skin cancer should target not only the general public but also politicians and decision makers, to create a proper health policy. We report the results of the first Skin Cancer Screening Day at the Italian Parliament, organized to draw politicians' attention on skin cancer. METHODS: A questionnaire was used to collect data on participants' characteristics and suspected skin cancers. RESULTS: We screened 70 members of parliament (61.4% males, median age 54 years). Overall skin cancer suspicion rate was 14.5%. Suspicion rate, detection rate, and positive predictive values for melanoma were respectively 1.6, 1.6, and 100%, and for basal cell carcinoma 6.5, 1.6, and 25%. Highly educated, <54-year-old females reported sun-seeking behaviors. CONCLUSIONS: The considerable suspicion rate produced by this screening is justified by the particular demographics of the study population. Italian members of parliament display sun-seeking behaviors similar to those previously described in the general public. Increasing politicians' attention on skin cancer is vital for sufficient resources to be allocated to prevention strategies. Expert medical groups and politicians should cooperate to create a proper, integrated policy on skin cancer.

Coronary atheroma composition and its association with segmental endothelial dysfunction in non-ST segment elevation myocardial infarction: novel insights with radiofrequency (iMAP) intravascular ultrasonography.

Little is known of the relationship between coronary atheroma composition and corresponding endothelial dysfunction. We tested the hypothesis that segmental epicardial vasoreactivity relates to atheroma composition in patients with non-ST segment elevation myocardial infarction (NSTEMI) in vivo. In 23 NSTEMI patients referred for coronary angiography, a non-culprit vessel underwent intracoronary salbutamol (0.30 µg/min) provocation during automated IVUS pullback. A 40 MHz rotational IVUS catheter delivered radiofrequency signals at constant 67 µm intervals via a custom-built IVUS console (iMAP, iLAB, Boston Scientific). Macrovascular response [change in segmental lumen volume (SLV) at baseline and following salbutamol], percent atheroma volume (PAV) and tissue composition was evaluated in 187 contiguous non-overlapping 5 mm coronary segments. Compared with segments that dilated, constrictive segments showed similar SLV, but greater vessel volumes and PAV at baseline. The extent of necrotic and lipidic plaque was significantly greater in constrictive segments, whereas fibrotic plaque content was significantly greater in segments that dilated. Calcific plaque content did not relate to endothelium-dependent vasoreactivity. The change in SLV correlated inversely with the amount of lipidic and necrotic plaque (both r = -0.23, p = 0.002), and directly with fibrotic plaque content (r = 0.23, p = 0.002). In a multivariable model, the extent of both lipidic and necrotic plaque independently associated with segmental vasoconstriction (ß = 1.2, p = 0.023; ß = 0.66, p = 0.027). Following NSTEMI, both lipidic and necrotic plaque content each associate with segmental endothelial dysfunction. The link between plaque composition and vessel reactivity provides a mechanistic basis of the pathogenesis associated with vulnerable plaque in humans in vivo.

Coronary artery wall shear stress is associated with endothelial dysfunction and expansive arterial remodelling in patients with coronary artery disease.

AIMS: To investigate in vivo relationships between segmental wall shear stress (WSS), endothelium-dependent vasoreactivity and arterial remodelling. METHODS AND RESULTS: Twenty-four patients with minor angiographic coronary arterial disease (≤30% stenosis severity) underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound (IVUS)-upon-Doppler guidewire imaging. Macrovascular response (change in segmental lumen volume [SLV] at baseline and following IC salbutamol), plaque burden (percent atheroma volume [PAV]), remodelling indices (RI), eccentricity indices (EI) and WSS were evaluated in 179 consecutive 5 mm coronary segments. Baseline WSS was directly related to endothelium-dependent epicardial coronary vasomotion (% change SLV, coefficient 17.2, p=0.004), and inversely related to RI (coefficient -0.23, p=0.02) and EI (coefficient -10.0, p=0.001). Baseline WSS was lower in segments displaying endothelial dysfunction (defined as any change in SLV ≤0) compared with preserved function (0.66±0.33 vs. 0.71±0.22 N/m2, p=0.046). Independent of plaque burden, segments with the lowest tertile of WSS displayed less vasodilatation, or vasoconstriction, than segments with the highest tertile of WSS. Higher plaque burden segments harbouring the lowest tertiles of WSS displayed vasoconstriction, expansive arterial remodelling and greater plaque eccentricity. CONCLUSIONS: In patients with stable coronary syndromes and minor angiographic coronary disease, coronary segments with lower in vivo WSS values display functional and morphological features of plaque vulnerability.

Left main coronary arterial endothelial function and heterogenous segmental epicardial vasomotor reactivity in vivo: novel insights with intravascular ultrasonography.

AIMS: While the relationship between epicardial coronary vasomotor reactivity and cardiovascular events is well established, this observation has yet to be evaluated within the left main coronary artery (LMCA) in humans in vivo. Our aims were to test the endothelium-dependent vasomotor properties of the LMCA, and to compare these responses to downstream epicardial segments. METHODS AND RESULTS: Thirty patients referred for coronary angiography underwent intracoronary (IC) salbutamol provocation during intravascular ultrasound imaging within a non-critically diseased, left-sided conduit vessel. Macrovascular vasomotor response [change in average lumen area (LA) at baseline and following 5 min of 0.30 µg/min IC salbutamol] and percent atheroma volume (PAV) were evaluated in 30 LMCA, 42 proximal, 109 mid, and 132 distal epicardial coronary segments. In comparison with all other segments, the LMCA had the greatest lumen and vessel areas (P < 0.001), yet the proximal epicardial segments contained the greatest PAV (P < 0.02). The mid and distal epicardial segments displayed significant endothelium-dependent vasodilatation from baseline (P = 0.017 and <0.001, respectively); however, the proximal epicardial and LMCA segments did not (P = 0.45 and 0.16, respectively). Significant segmental vasomotor heterogeneity was noted in all 30 patients, with opposing vasomotor responses between adjacent LMCA and epicardial segments. Across all segments, baseline LA inversely correlated with the % change in LA (r = -0.16, P = 0.0005). CONCLUSION: Endothelium-dependent vasomotor reactivity is heterogenous within the conduit coronary system. Vascular dynamic responses were less prominent in the larger calibre LMCA and proximal epicardial segments. This may, in part, relate to higher shear stress in smaller, distal segments and yet also may explain the propensity for culprit plaques to cluster proximally.

Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction.

BACKGROUND AIMS: Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). METHODS: Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 10(6) cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. RESULTS: Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. CONCLUSIONS: Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.

Coronary endothelium-dependent vasoreactivity and atheroma volume in subjects with stable, minimal angiographic disease versus non-ST-segment-elevation myocardial infarction: an intravascular ultrasound study.

BACKGROUND: Epicardial plaque burden and endothelial function are recognized predictors of coronary events. We aimed to investigate mechanistic relationships between atheroma volume and endothelial function in patients with non-ST-segment-elevation myocardial infarction (NSTEMI) using intravascular ultrasound. METHODS AND RESULTS: In coronary vessels of patients with near-normal or minimal angiographic disease (n=23) and NSTEMI (n=24), intravascular ultrasound-derived measures (percent atheroma volume), arterial remodeling index, and segmental lumen volumes were performed in contiguous 5-mm epicardial segments. Repeat intravascular ultrasound imaging was performed after consecutive 5-minute intracoronary infusions (vehicle solution, 0.30 µg/min and 0.60 µg/min intracoronary salbutamol) to measure changes in segmental lumen volume (endothelium-dependent function). Male sex, diabetes mellitus, smoking, higher triglycerides, and lower high-density lipoprotein cholesterol were more prevalent in the NSTEMI group. Patients with NSTEMI demonstrated greater segmental percent atheroma volume (40.4 ± 12 versus 27.5 ± 14%, P<0.001), remodeling index (1.2 [1.0-1.5] versus 1.0 [0.9-1.0], P<0.001), and displayed less endothelium-dependent vasomotion (% change segmental lumen volume: 2.1 ± 0.89 versus 5.1 ± 0.89%, P=0.02) compared to patients with minimal angiographic disease. No significant difference in endothelial function between both groups was observed when controlling for plaque burden. Multivariate analysis for change in segmental lumen volume identified percent atheroma volume (ß=-0.18, P=0.0004), high-sensitivity C-reactive protein >2 mg/L (ß=-3.1, P=0.03), diabetes mellitus (ß=-6.9, P<0.0001), low-density lipoprotein cholesterol levels (ß=-0.04, P=0.01), and smoking (ß=-3.2, P=0.01) as independent associates. CONCLUSIONS: Although coronary endothelial vasoreactivity is blunted in the setting of NSTEMI, this is a reflection of the greater volume of atherosclerosis and cardiovascular risk factors. Thus, the relationship between coronary endothelium-dependent vasomotor reactivity and atheroma volume remains constant irrespective of the nature of the clinical presentation.