Pulmonary arterial remodelling by deficiency of peroxisome proliferator-activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension.

BACKGROUND: Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. METHODS: Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ-/-) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. RESULTS: HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ-/- mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ-/- mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. CONCLUSIONS: Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.

Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial.

AIMS: Sympathetic stimulation induces left ventricular hypertrophy and is associated with increased cardiovascular risk. Catheter-based renal denervation (RDN) has been shown to reduce sympathetic outflow and blood pressure (BP). The present multi-centre study aimed to investigate the effect of RDN on anatomic and functional myocardial parameters, assessed by cardiac magnetic resonance (CMR), in patients with resistant hypertension. METHODS AND RESULTS: Cardiac magnetic resonance was performed in 72 patients (mean age 66 ± 10 years) with resistant hypertension (55 patients underwent RDN, 17 served as controls) at baseline and after 6 months. Clinical data and CMR results were analysed blindly. Renal denervation significantly reduced systolic and diastolic BP by 22/8 mm Hg and left ventricular mass index (LVMI) by 7.1% (46.3 ± 13.6 g/m(1.7) vs. 43.0 ± 12.6 g/m(1.7), P < 0.001) without changes in the control group (41.9 ± 10.8 g/m(1.7) vs. 42.0 ± 9.7 g/m(1.7), P = 0.653). Ejection fraction (LVEF) in patients with impaired LVEF at baseline (<50%) significantly increased after RDN (43% vs. 50%, P < 0.001). Left ventricular circumferential strain as a surrogate of diastolic function in the subgroup of patients with reduced strain at baseline increased by 21% only in the RDN group (-14.8 vs. -17.9; P = 0.001) and not in control patients (-15.5 vs. -16.4, P = 0.508). CONCLUSIONS: Catheter-based RDN significantly reduced BP and LVMI and improved EF and circumferential strain in patients with resistant hypertension, occurring partly BP independently.

Estimation of central blood pressure waveform from femoral blood pressure waveform by blind sources separation.

Background: Central blood pressure (cBP) is a better indicator of cardiovascular morbidity and mortality than peripheral BP (pBP). However, direct cBP measurement requires invasive techniques and indirect cBP measurement is based on rigid and empirical transfer functions applied to pBP. Thus, development of a personalized and well-validated method for non-invasive derivation of cBP from pBP is necessary to facilitate the clinical routine. The purpose of the present study was to develop a novel blind source separation tool to separate a single recording of pBP into their pressure waveforms composing its dynamics, to identify the compounds that lead to pressure waveform distortion at the periphery, and to estimate the cBP. The approach is patient-specific and extracts the underlying blind pressure waveforms in pBP without additional brachial cuff calibration or any a priori assumption on the arterial model. Methods: The intra-arterial femoral BPfe and intra-aortic pressure BPao were anonymized digital recordings from previous routine cardiac catheterizations of eight patients at the German Heart Centre Berlin. The underlying pressure waveforms in BPfe were extracted by the single-channel independent component analysis (SCICA). The accuracy of the SCICA model to estimate the whole cBP waveform was evaluated by the mean absolute error (MAE), the root mean square error (RMSE), the relative RMSE (RRMSE), and the intraclass correlation coefficient (ICC). The agreement between the intra-aortic and estimated parameters including systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressure (PP) was evaluated by the regression and Bland-Altman analyses. Results: The SCICA tool estimated the cBP waveform non-invasively from the intra-arterial BPfe with an MAE of 0.159 ± 1.629, an RMSE of 5.153 ± 0.957 mmHg, an RRMSE of 5.424 ± 1.304%, and an ICC of 0.94, as well as two waveforms contributing to morphological distortion at the femoral artery. The regression analysis showed a strong linear trend between the estimated and intra-aortic SBP, DBP, MAP, and PP with high coefficient of determination R2 of 0.98, 0.99, 0.99, and 0.97 respectively. The Bland-Altman plots demonstrated good agreement between estimated and intra-aortic parameters with a mean error and a standard deviation of difference of -0.54 ± 2.42 mmHg [95% confidence interval (CI): -5.28 to 4.20] for SBP, -1.97 ± 1.62 mmHg (95% CI: -5.14 to 1.20) for DBP, -1.49 ± 1.40 mmHg (95% CI: -4.25 to 1.26) for MAP, and 1.43 ± 2.79 mmHg (95% CI: -4.03 to 6.90) for PP. Conclusions: The SCICA approach is a powerful tool that identifies sources contributing to morphological distortion at peripheral arteries and estimates cBP.

Real-World and Regulatory Perspectives of Artificial Intelligence in Cardiovascular Imaging.

Recent progress in digital health data recording, advances in computing power, and methodological approaches that extract information from data as artificial intelligence are expected to have a disruptive impact on technology in medicine. One of the potential benefits is the ability to extract new and essential insights from the vast amount of data generated during health care delivery every day. Cardiovascular imaging is boosted by new intelligent automatic methods to manage, process, segment, and analyze petabytes of image data exceeding historical manual capacities. Algorithms that learn from data raise new challenges for regulatory bodies. Partially autonomous behavior and adaptive modifications and a lack of transparency in deriving evidence from complex data pose considerable problems. Controlling new technologies requires new controlling techniques and ongoing regulatory research. All stakeholders must participate in the quest to find a fair balance between innovation and regulation. The regulatory approach to artificial intelligence must be risk-based and resilient. A focus on unknown emerging risks demands continuous surveillance and clinical evaluation during the total product life cycle. Since learning algorithms are data-driven, high-quality data is fundamental for good machine learning practice. Mining, processing, validation, governance, and data control must account for bias, error, inappropriate use, drifts, and shifts, particularly in real-world data. Regulators worldwide are tackling twenty-first century challenges raised by "learning" medical devices. Ethical concerns and regulatory approaches are presented. The paper concludes with a discussion on the future of responsible artificial intelligence.

Angiographic assessment of cardiac allograft vasculopathy: results of a Consensus Conference of the Task Force for Thoracic Organ Transplantation of the German Cardiac Society.

Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa=0.371, P<0.001). The kappa value for peripheral obliteration was 0.331 (P=0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.

Serelaxin Improves Regional Myocardial Function in Experimental Heart Failure: An In Vivo Cardiac Magnetic Resonance Study.

Background Animal studies demonstrated that serelaxin lessens fibrosis in heart failure. This study assessed its effect on myocardial deformation using cardiac magnetic resonance and elucidated its relationship to gene regulation and histology in a mouse heart failure model. Methods and Results C57BL/6J mice were subjected to SHAM (n=4) or transverse aortic constriction (TAC). At week 10, TAC mice were randomized to receive either serelaxin (0.5 mg/kg per day; n=11) or vehicle (n=13) for 4 weeks. Cardiac magnetic resonance imaging was performed at baseline and repeated at the end of the study (week 14). Cine images were used to calculate left ventricular (LV) global longitudinal, circumferential, and radial strain. Hearts were examined for histology and gene expression. Compared with SHAM, mice 10 weeks after TAC showed increased LV mass with significant decreases in LV deformation parameters, indicating subclinical deterioration of myocardial function. At week 14, TAC mice given serelaxin demonstrated significant improvements in all LV strain parameters and no decrease in LV stroke volume and ejection fraction compared with TAC mice given vehicle. A significant positive correlation between global circumferential strain and the extent of myocardial fibrosis was found, and global circumferential strain correlated significantly with the expression of heart failure genes in serelaxin-treated mice. Conclusions Serelaxin improved cardiac magnetic resonance-derived myocardial deformation parameters as well as histomorphometric and gene expression findings in mice with heart failure. Cardiac magnetic resonance-derived myocardial mechanics correlate with histology and gene expression, stressing its utilization in myocardial remodeling.

Prognostic impact of microvasculopathy on survival after heart transplantation: evidence from 9713 endomyocardial biopsies.

BACKGROUND: Epicardial vasculopathy has been shown to be associated with poor outcome after heart transplantation. We demonstrate that histologically proven stenotic microvasculopathy is a novel prognostic factor for long-term survival. METHODS AND RESULTS: In 9713 biopsies harvested within the first posttransplantation year from 873 patients (83% male; mean age, 49.1+/-0.6 years), light microscopic evaluations (x200) were performed for microvasculopathy, defined as stenotic endothelial and/or medial disease. Prevalence of severe epicardial vasculopathy was defined by presence of > or = 75% luminal stenosis in coronary angiography (available in 611 of 873 patients), which was present in 118 of 611 patients (19%). For Kaplan-Meier analysis, we defined fatal cardiac events as lethal acute myocardial infarction, sudden cardiac death, and graft failure. Stenotic microvasculopathy was present in 379 of 873 patients (43%) and was due to medial (345/379; 91%) rather than endothelial disease (2/379; 1%) or a combination of both (31/379; 8%; P<0.001). Endothelial disease (median [95% CI], 12.07 [10.69 to 13.44] versus 12.73 years [10.16 to 15.30]; P=0.3329) and nonstenotic medial disease (12.44 [11.14 to 13.74] versus 12.43 years [10.51 to 14.35]; P=0.4047) did not decrease overall survival or time to fatal cardiac event. Stenotic microvasculopathy was associated with poor overall survival (10.90 [9.16 to 12.60] versus 13.40 years [11.79 to 15.07]; P=0.0374) and decreased freedom from fatal cardiac events (1, 5, 10 years, 95.6+/-1.4%, 86.9+/-2.3%, 75.5+/-3.1% versus 99.1+/-0.5%, 96.8+/-1.0%, 89.8+/-1.9%; P<0.0001). This finding was independent of epicardial transplant vasculopathy (P=0.0031). CONCLUSIONS: Stenotic microvasculopathy is frequent in routinely processed biopsies and a new prognostic factor for long-term survival after heart transplantation.

Beneficial effect of female gender on long-term survival after heart transplantation.

BACKGROUND: We aimed to test whether stenotic microvasculopathy affects the more beneficial course in female cardiac transplant recipients. METHODS: We studied 873 patients (35/151 premenopausal women aged < or =40 years) who underwent primary heart transplantation. In 7750 biopsies harvested within the first posttransplant year endothelial disease and stenotic microvasculopathy were evaluated by light microscopy (Hematoxylin and Eosin). Kaplan-Meier and Cox regression analyses were performed for major cardiac events (MACE; lethal myocardial infarction, sudden cardiac death, graft failure, and cardiac retransplantation). RESULTS: Stenotic microvasculopathy was found equally in men (38%) and women (39%). Allografts from premenopausal female-to-male transplants more frequently developed endothelial disease (78% vs. 65%; P=0.021) and stenotic microvasculopathy (46% vs. 28%, P=0.024). Beyond the first 5 posttransplant years women presented MACE less often than men, independently of donor gender and stenotic microvasculopathy (P=0.0001). Multivariate regression analysis found women to be at lower risk for MACE (Relative Risk [RR] 0.38; 95% Confidence Interval [CI] 0.17-0.81), whereas stenotic microvasculopathy (RR 2.15; 95% CI 1.42-3.26) and treated diabetes (RR 1.65; 95% CI 1.08-2.52) indicated a higher risk for MACE. CONCLUSIONS: Stenotic microvasculopathy has prognostic impact on survival of male and female cardiac recipients; however, it does not affect the more beneficial course of women in the long-term follow-up.

Quilty in biopsy is associated with poor prognosis after heart transplantation.

We tested if Quilty (endocardial infiltration of lymphocytes) in routinely processed endomyocardial biopsy is associated with poor outcome after heart transplantation (HTx). Biopsies (n=9829) harvested within the first post-transplant year from 938 patients (778 men, mean age 49 years) were evaluated for Quilty and acute cellular rejection (according to the International Society for Heart and Lung Transplantation, ISHLT, classification). Transplant vasculopathy was evaluated by coronary angiography, and severe stenosis was found in 19% of patients. Survival was tested by Kaplan-Meier and Cox regression analyses for all-cause mortality and major cardiac events (lethal acute cellular rejection, graft loss or myocardial infarction). We found 1840 (19%) Quilty-positive biopsies in 487 Quilty-positive patients (52%). Quilty was more prevalent in women (p=0.038) and younger men (p=0.001), and was correlated with ISHLT grade 1R (OR 1.45, 95% CI 1.36-1.55; p<0.001) and ISHLT grade 2R (OR 2.48, 95% CI 2.21-3.41; p<0.001). Quilty in any biopsy was associated with a higher all-cause mortality (log rank p=0.045) due to a higher risk for major cardiac event (p=0.0001). Multivariate regression analysis showed Quilty (RR 1.69, 95%CI 1.05-2.73) and transplant vasculopathy (RR 2.78, 95%CI 1.68-4.61) as risk factors for major cardiac events and treated hyperlipidemia as lowering the risk for major cardiac events (RR 0.47, 95%CI 0.28-0.77). Quilty is associated with graft loss and poor outcome post HTx. Index biopsy during the first post-transplant year is a useful tool to identify patients at risk and is recommended during routine post-transplant management.

Enhanced inotropic state of the failing left ventricle by cardiac contractility modulation electrical signals is not associated with increased myocardial oxygen consumption.

BACKGROUND: Previous studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO(2)) in both patients and dogs with chronic HF. METHODS AND RESULTS: Six dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO(2) was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 +/- 1 versus 31 +/- 2 %, P = .001) without increasing MVO(2) (257 +/- 41 versus 180 +/- 34 micromol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 +/- 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO(2) (13.6 +/- 9.7 versus 12.5 +/- 7.2 mL O(2)/min). CONCLUSIONS: The study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO(2).

Time course of left ventricular volumes in severe congestive heart failure patients treated by optimized AV sequential left ventricular pacing alone--a 3-dimensional echocardiographic study.

BACKGROUND: This study evaluates the acute and chronic resynchronizing effects of AV sequential left ventricular (LV) pacing on LV function in patients with impaired cardiac function and conduction disorders by 3-dimensional transesophageal echocardiography. METHODS AND RESULTS: Twenty-nine patients with congestive heart failure, with LV ejection fraction (LVEF) < or = 30%, QRS duration > or = 120 milliseconds, and New York Heart Association Class II to IV, were implanted with a cardiac resynchronization device using an LV lead only, according to the invasively determined hemodynamic optimal pacing site and AV delay. Patients underwent 3-dimensional transesophageal echocardiography before randomization to treatment (baseline) and at 12-month follow-up (resynchronization--12 months). Three-dimensional volumes were acquired on resynchronization and during intermittent switch-off at intrinsic depolarization. The values of stroke volume were 43.2 +/- 13.3 (intrinsic-baseline), 51.7 +/- 17.4 (intrinsic--12 months), 57.2 +/- 15.6 (resynchronization-baseline), and 64.6 +/- 18.9 (resynchronization--12 months). Analysis of variance demonstrated a significant effect of resynchronization at different periods (P < .001) and a significant time effect (P < .05) for stroke volume. Similar results were observed with ejection fraction (LVEF). No effect was observed with LV end-diastolic volume, whereas a therapy effect with no time effect was observed with LV end-systolic volume. CONCLUSIONS: A significant acute increase of LV stroke volume and LVEF was found by resynchronization by LV pacing alone. A continuous improvement of LV stroke volume and LVEF occurred with time of follow-up (reverse remodeling). The initial therapeutic effect persisted during 12-month follow-up independently of time of follow-up and QRS width. No significant decrease of LV end-diastolic size during chronic resynchronization was detected in contrast to previous studies with resynchronization by biventricular pacing.

In-vivo coronary flow profiling based on biplane angiograms: influence of geometric simplifications on the three-dimensional reconstruction and wall shear stress calculation.

BACKGROUND: Clinical studies suggest that local wall shear stress (WSS) patterns modulate the site and the progression of atherosclerotic lesions. Computational fluid dynamics (CFD) methods based on in-vivo three-dimensional vessel reconstructions have recently been shown to provide prognostically relevant WSS data. This approach is, however, complex and time-consuming. Methodological simplifications are desirable in porting this approach from bench to bedside. The impact of such simplifications on the accuracy of geometry and wall shear stress calculations has to be investigated. METHODS: We investigated the influence of two methods of lumen reconstruction, assuming circular versus elliptical cross-sections and using different resolutions for the cross-section reconstructions along the vessel axis. Three right coronary arteries were used, of which one represented a normal coronary artery, one with "obstructive", and one with "dilated" coronary atherosclerosis. The vessel volume reconstruction was performed with three-dimensional (3D) data from a previously validated 3D angiographic reconstruction of vessel cross-sections and vessel axis. RESULTS: The difference between the two vessel volumes calculated using the two evaluated methods is less than 1 %. The difference, of the calculated pressure loss, was between 2.5% and 8.5% for the evaluated methods. The distributions of the WSS histograms were nearly identical and strongly cross-correlated (0.91-0.95). The good agreement of the results was confirmed by a Chi-square test. CONCLUSION: A simplified approach to the reconstruction of coronary vessel lumina, using circular cross-sections and a reduced axial resolution of about 0.8 mm along the vessel axis, yields sufficiently accurate calculations of WSS.

Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases.

Clopidogrel pharmacokinetics and pharmacodynamics in out-of-hospital cardiac arrest patients with acute coronary syndrome undergoing target temperature management.

BACKGROUND: Target temperature management (TTM) after cardiac arrest (CA) improves outcome in patients with acute coronary syndrome (ACS). Previous data point to an interaction between hypothermia and drug metabolism, potentially impacting on platelet function in patients on antiplatelet therapy. PURPOSE: To compare clopidogrel metabolism and platelet function in clopidogrel naïve ACS patients treated with TTM (33°C, n=15) and in ACS patients (troponin positive) without TTM (n=18). METHODS: Platelet function was measured by multiple electrode platelet aggregometry (MEA), light transmittance aggregometry (LTA) and VASP analysis before and after administration of a 600mg clopidogrel loading dose. Plasma levels of clopidogrel and its metabolites were measured. All patients were screened for CYP2C19*2 polymorphism and scheduled for PCI. TTM was carried out for 24h at a target temperature of 33°C using a computer feedback surface cooling device in cardiac arrest patients. RESULTS: Plasma concentration of clopidogrel and metabolites was lower in the TTM group after 2 and 4h, respectively (all p<0.005 vs. controls), and platelet function tests revealed an attenuated response to clopidogrel with respect to baseline platelet activity in the TTM group. This was significant for MEA, LTA and VASP analysis (all p<0.05). Moreover, there was no significant difference in genotype and platelet function determined ex vivo at 33 or 37°C, respectively. CONCLUSION: Inhibition of platelet function is significantly lessened in TTM at 33°C, likely due to reduced clopidogrel absorption. Patients with TTM might thus have a higher risk for further cardiovascular events despite antiplatelet therapy with clopidogrel.

Effects of Renal Denervation on Renal Artery Function in Humans: Preliminary Study.

AIM: To study the effects of RD on renal artery wall function non-invasively using magnetic resonance. METHODS AND RESULTS: 32 patients undergoing RD were included. A 3.0 Tesla magnetic resonance of the renal arteries was performed before RD and after 6-month. We quantified the vessel sharpness of both renal arteries using a quantitative analysis tool (Soap-Bubble®). In 17 patients we assessed the maximal and minimal cross-sectional area of both arteries, peak velocity, mean flow, and renal artery distensibility. In a subset of patients wall shear stress was assessed with computational flow dynamics. Neither renal artery sharpness nor renal artery distensibility differed significantly. A significant increase in minimal and maximal areas (by 25.3%, p = 0.008, and 24.6%, p = 0.007, respectively), peak velocity (by 16.9%, p = 0.021), and mean flow (by 22.4%, p = 0.007) was observed after RD. Wall shear stress significantly decreased (by 25%, p = 0.029). These effects were observed in blood pressure responders and non-responders. CONCLUSIONS: RD is not associated with adverse effects at renal artery level, and leads to an increase in cross-sectional areas, velocity and flow and a decrease in wall shear stress.

NT-proBNP and diastolic left ventricular function in patients with Marfan syndrome.

AIMS: Subclinical diastolic dysfuntion in patients with preclinical heart failure with preserved ejection fraction (HFpEF) has been demonstrated in patients with Marfan syndrome (MFS). We investigated the relationship between diastolic dysfunction and NT-proBNP levels in patients with MFS. METHODS AND RESULTS: NT-proBNP, C-reactive protein (CRP) and diastolic function were assessed in 217 patients with MFS (31 ± 16 y, 110 f. and in 339 patients referred for suspected MFS in whom the diagnosis was ruled out according to the Ghent nosology (30 ± 15 y, 154 f). Assessment of cardiovascular remodeling, diastolic function in echocardiography, and NT-proBNP was analyzed with univariate analysis and multi-parameter analysis of covariance (MANCOVA). NT-proBNP was 70.6 ± 74.8 pg/ml in patients with Marfan syndrome and 58.4 ± 100.3 pg/ml in controls (p = 0.002, Kolmogorov-Smirnov). There were significant intergroup differences regarding end-diastolic left ventricular volume (p < 0.001), and aortic diameter (p < 0.001). The ratio of early diastolic mitral flow velocity (E) to early relaxation velocity in tissue Doppler (e'), E/e' (p < 0.001) was significantly higher in patients with Marfan syndrome than in controls, whereas e' (p < 0.001) and the ratio of E to inflow velocity during atrial contraction (A), E/A (p = 0.012) was significantly lower. Besides age and gender, diagnosis of MFS, diastolic function (e' and E/e'), Z-Score of aortic diameter, and left ventricular size were identified as significant independent parameters with impact on NT-proBNP levels. CONCLUSIONS: MFS patients presenting with normal ejection fraction show disturbed diastolic function and higher NT-proBNP levels, which is partly explained by aortic Z-score. Assessment of diastolic function and NT-proBNP levels may therefore detect early abnormalities and guide surveillance and prevention management of patients with MFS.

Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a fatal disease with limited therapeutic options. Pathophysiological changes comprise obliterative vascular remodelling of small pulmonary arteries, elevated mean pulmonary arterial systolic pressure (PASP) due to elevated resistance of pulmonary vasculature, adverse right ventricular remodelling, and heart failure. Recent findings also indicate a role of increased inflammation and insulin resistance underlying the development of PAH. We hypothesized that treatment of this condition with the peroxisome proliferator-activated receptor-γ (PPARγ) activator pioglitazone, known to regulate the expression of different genes addressing insulin resistance, inflammatory changes, and vascular remodelling, could be a beneficial approach. PAH was induced in adult rats by a single subcutaneous injection of monocrotaline (MCT). Pioglitazone was administered for 2 weeks starting 3 weeks after MCT-injection. At day 35, hemodynamics, organ weights, and -indices were measured. We performed morphological and molecular characterization of the pulmonary vasculature, including analysis of the degree of muscularization, proliferation rates, and medial wall thickness of the small pulmonary arteries. Furthermore, markers of cardiac injury, collagen content, and cardiomyocyte size were analyzed. Survival rates were monitored throughout the experimental period. Pioglitazone treatment improved survival, reduced PASP, muscularization of small pulmonary arteries, and medial wall thickness. Further, MCT-induced right ventricular hypertrophy and fibrosis were attenuated. This was accompanied with reduced cardiac expression of brain natriuretic peptide, as well as decreased cardiomyocyte size. Finally, pulmonary macrophage content and osteopontin gene expression were attenuated. Based on the beneficial impact of pioglitazone, activation of PPARγ might be a promising treatment option in PAH.

Magnetic resonance low-dose dobutamine test is superior to SCAR quantification for the prediction of functional recovery.

BACKGROUND: Low-dose dobutamine challenge (DSMR) by MRI was compared with delayed enhancement imaging with Gd-DTPA (SCAR) as a predictor of improvement of wall motion after revascularization (RECOVERY). METHODS AND RESULTS: In 29 patients with coronary artery disease (68+/-7 years of age, 2 women, 32+/-8% ejection fraction), wall motion was evaluated semiquantitatively by MRI before and 3 months after revascularization. SCAR and DSMR were performed before revascularization. The transmural extent of scar was assessed semiquantitatively. Binary prediction of RECOVERY was performed by logistic regression in 288 segments with wall motion abnormalities at rest. Receiver operating characteristic-area under curve (AUC) statistics were used to compare different models. Low-dose DSMR (AUC 0.838) was superior to SCAR (AUC 0.728) in predicting RECOVERY. SCAR did not improve accuracy of prediction by DSMR. Subgroup analysis showed superiority of DSMR for 1% to 74% transmural extent of infarction. CONCLUSIONS: Low-dose DSMR is superior to SCAR in predicting RECOVERY. This advantage is largest in segments with a delayed enhancement of 1% to 74%.

Noninvasive determination of coronary blood flow velocity with cardiovascular magnetic resonance in patients after stent deployment.

BACKGROUND: In patients with coronary artery stents, no direct noninvasive coronary artery imaging is possible with magnetic resonance (MR). A well-established method for the assessment of the functional significance of a coronary lesion is the measurement of coronary flow reserve by invasive intracoronary Doppler. The purpose of the study was to determine coronary flow velocity reserve (CFVR) with MR after stent deployment. METHODS AND RESULTS: Thirty-eight patients after successful PTCA and stent deployment were included. CFVR was measured perpendicular to the artery distal to the stent using phase-contrast velocity quantification at rest and during adenosine-stimulated hyperemia with a 1.5T MR tomograph (ACS NT, Philips). Measurements were repeated after 3 months and compared with invasive coronary angiography. In 18 patients, additional invasive Doppler flow measurements were obtained. CFVR could be determined in 29 of 38 (76%) of the patients. After 3 months, significant differences were obtained between coronary arteries with and without restenosis. Using a threshold of 1.2, a sensitivity of 83% with a specificity of 94% was achieved for > or =75% stenoses. CFVR with CMR was similar to Doppler results (r=0.87), with a mean relative difference of 7.5%. CONCLUSIONS: In patients with preserved coronary microcirculating vasoreactivity that are suitable for MR coronary angiography and flow assessments, CMR measures of coronary blood flow velocities reserve may be used to detect in-stent restenosis.