Clinical and Hemodynamic Improvement in Pulmonary Hypertension After Switching to Sacubitril/Valsartan in Patients With Heart Failure With Preserved Ejection Fraction.

ABSTRACT: Patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension have poor survival, and established medical therapies for both conditions are not available. In this retrospective study of 69 patients with HFpEF and either isolated postcapillary pulmonary hypertension (IpcPH, n = 53) or combined postcapillary and precapillary pulmonary hypertension (CpcPH, n = 16), we investigated the effects of sacubitril/valsartan on pulmonary hypertension measured using right heart catheterization at baseline (ie, presacubitril/valsartan) and 99 (94-123) days after switching to sacubitril/valsartan. After switching to sacubitril/valsartan, right heart catheterization showed significantly lower pulmonary artery pressures (systolic/diastolic/mean) in both patient groups compared with presacubitril/valsartan [IpcPH: 44 (38-52)/15 (12-19)/28 (22-33) mm Hg vs. 47 (40-55)/18 (15-23)/31 (26-35) mm Hg, P < 0.01; CpcPH: 54 (43-57)/18 (12-23)/34 (30-36) mm Hg vs. 61 (50-79)/24 (19-30)/40 (31-53) mm Hg, P < 0.05]. The median sacubitril/valsartan dose at follow-up was 24/26 (24/26-49/51) mg twice daily in both patients with IpcPH and CpcPH. Clinically, the New York Heart Association functional class improved by at least 1 class in 32 of 69 patients ( P < 0.01). In conclusion, sacubitril/valsartan therapy improves pulmonary hypertension in patients with HFpEF and either IpcPH or CpcPH. Further prospective randomized trials are needed for confirmation of our results.

Modern gold standard of cardiac output measurement - A simplified bedside measurement of individual oxygen uptake in the cath lab.

OBJECTIVES: Cardiac output (CO) measurements employing the direct Fick principle represent the gold standard in right-sided heart catheterization (RHC). The current widespread approach in hemodynamic workup however uses the indirect Fick principle with assumed values for oxygen uptake (VO2) leading to incorrect CO values in up to 25% of patients. We have tested a contemporary breath-by-breath gas analyzer that allows precise real-time measurements of VO2 with appropriate time and effort to serve the direct Fick principle. METHODS: By means of a small and mobile metabolic cart assembled with widely used components of a standard spiroergometer, we performed bedside measurements of individual VO2. In 33 unselected, consecutive patients with various indications for RHC we compared CO values derived from indirect vs. direct Fick calculations. RESULTS: In 28 of the 33 patients, VO2 measurements were completed with a plausible dataset within a median of 3.2 (interquartile range 2.8-6.2) min. In nine of the 28 patients, CO values based on measured VO2 values differed by more than 20% from CO calculations based on assumed VO2 values with value deviations scattering over a broad range in both directions (maximally +52% to minimally -46%). CONCLUSIONS: The bedside measurement of VO2 for gold standard CO determination is technically feasible within a few min and can thus be easily included in any RHC protocol. As modern therapy for numerus indications demand a precise upfront measurement of hemodynamics, our method might help to correctly identify patients for costly therapies.

[Chronic obstructive pulmonary disease, sleep-disordered breathing and hypoventilation-Influence on the cardiorenal system]. / Chronisch-obstruktive Lungenerkrankung, schlafbezogene Atemstörungen und Hypoventilation ­ Einflüsse auf das kardiorenale System.

Comorbidities are frequently observed in patients suffering from pulmonary diseases due to shared risk factors and intricate interactions between various organ systems. This article aims to characterize the effects of selected diseases of the respiratory system on the cardiovascular system and kidneys. Advanced chronic obstructive pulmonary disease (COPD) often leads to a prognostically unfavorable increased pressure in the pulmonary circulation. In this respect treatment of these patients is primarily aimed at the underlying pulmonary disease and targeted treatment of the pulmonary hypertension should only be carried out according to invasive diagnostics and in an individualized manner. So far, the fact that there is a substantial overlap between COPD and heart failure with preserved ejection fraction has been completely ignored, which should be considered in the diagnostic procedure. Obstructive sleep apnea (OSA) has several unfavorable effects on the cardiovascular system and has been identified as an independent risk factor for cardiovascular diseases. The established treatment of OSA with continuous positive airway pressure (CPAP) has been shown to improve daytime sleepiness and the quality of life; however, an effect of CPAP on the occurrence of cardiovascular events, especially in asymptomatic patients, has so far not been demonstrated in randomized trials. Peripheral edema is frequently observed in patients suffering from chronic hypercapnia, which can be explained by several pathophysiological mechanisms, including pulmonary vasoconstriction and a direct effect of the hypercapnia on renal blood flow. Apart from the administration of diuretics, recompensation of such patients always requires treatment of the hypercapnia by noninvasive ventilation.

Detection of clonal T-cell-receptor (TCR) Vbeta rearrangements in explanted dilated cardiomyopathy hearts by semi-nested PCR, GeneScan, and direct sequencing.

BACKGROUND: Viral infection and anti-cardiac immunity are involved in the pathogenesis of dilated cardiomyopathy (DCM). Immunity targeting particular antigens may evoke expansion of reactive T-cell clones. MATERIAL AND METHODS: Myocardial tissues from explanted hearts were investigated for clonal T-cell-receptor- (TCR-) ß rearrangements by an established semi-nested polymerase chain reaction (PCR), followed by high-resolution GeneScan analysis and direct sequencing. From 17 explanted DCM hearts, 3 myocardial samples each were obtained from the right ventricle, the septum, and the left ventricle (total: 9 myocardial samples per case). Six explanted hearts with non-DCM cardiomyopathy entities served as controls. RESULTS: GeneScan analysis revealed polyclonal TCR-ß rearrangements in all controls. In contrast, at least 1 myocardial sample in 9 out of 17 DCM hearts (total: 20 of the 81 DCM specimens) displayed single dominant TCR-ß PCR products consistent with the presence of clonal T-cell populations. Direct sequencing of the clonal TCR-ß PCR-products disclosed an involvement of Vß 19.01 segments in 14 of the dominant amplificates (70%). Further TCR-Vß segments involved in clonal TCR-ß rearrangements of DCM hearts were Vß 6-1.01 (n=1), Vß 6-3.01 (n=2), Vß 6-5.01 (n=1), Vß 10-3.02 (n=1), and Vß 19.03 (n=1). CONCLUSIONS: The detectability of clonal TCR-ß rearrangements indicates a pathogenic relevance of this finding in DCM. The predominance of Vß 19.01 segments suggests that the immune response in DCM patients targets particular epitopes. However, the partly heterogenic TCR-ß populations in various myocardial samples from the respective cases support the notion that T-cell immunity may target multiple epitopes in human DCM.

Expression of functional T-cell markers and T-cell receptor Vbeta repertoire in endomyocardial biopsies from patients presenting with acute myocarditis and dilated cardiomyopathy.

AIMS: To quantify and functionally characterize the intramyocardial T-cells in endomyocardial biopsies (EMBs) from patients presenting with acute myocarditis (AMC) and dilated cardiomyopathy (DCM). METHODS AND RESULTS: Expression of genes characterizing Th1 [interferon (IFN)γ, Tbet-1, Eomesodermin, interleukin (IL)-27], Th2 (IL-4, IL-5, GATA3), Th17 (IL-17), regulatory [regulatory T-cells (Treg); FoxP3, TGFß, IL-10], anergic (GRAIL), and cytotoxic T-cells (CTLs: Perforin, Granulysin, Granzyme A), as well as of functional T-cell receptor Vbeta (TRBV) families were investigated in EMBs from AMC patients (n= 58) and DCM patients (n= 34) by pre-amplified real-time reverse transcription-polymerase chain reaction. These data were compared with EMBs from n= 19 controls. Expression of CD3d, CD3z, and TRBC (T-cell receptor beta constant region) were associated with the immunohistological diagnosis of inflammatory cardiomyopathy (DCMi). In EMBs from DCM patients with increased CD3d expression, significantly increased markers of Th1 (IFNγ, T-bet, Eomesodermin), regulatory T-cells (Treg; FoxP3, TGFß), and cytotoxic T-cells (CTLs: Perforin, Granulysin, Granzyme A) were present, while no differential polarization of T-cells was found in EMBs form AMC patients. A differential dominance of distinct functional TRBV families was associated with different cardiotropic viruses: TRBV 11 and 24 with Parvovirus B19; TRBV4, 10 and 28 with human herpes virus type 6; and TRBV14 for Coxsackie virus, respectively. CONCLUSIONS: The T-cell infiltrates in human DCMi are characterized by differential expression of functional T-cell markers indicating Th1, Treg, and CTLs, while no major role could be confirmed for Th17. The virus-associated differential TRBV dominance suggests an antiviral specificity of virus-induced T-cell responses in human DCMi.

Digital image analysis system for the quantification of infiltrates and cell adhesion molecules in inflammatory cardiomyopathy.

BACKGROUND: We attempted to develop a digital image analysis (DIA) system for endomyocardial biopsies (EMBs) to reliably quantify a) biopsy quality, b) immunohistochemically-marked infiltrates, and c) cell adhesion molecules (CAMs) in relation to net heart area (HA) for the semi-automated diagnosis of inflammatory cardiomyopathy (InfCM). MATERIAL/METHODS: 140 EMBs from dilated cardiomyopathy (DCM) patients and 14 autopsy heart samples (controls) were immunostained for T-lymphocytes (CD2, CD3, CD4, CD8), beta(2)-integrin+ infiltrates (CD18, LFA-1, Mac-1) and CAMs (immunoglobulin superfamily: ICAM-1, HLA class I, HLA DR, VCAM-1, CD58; selectins: CD62E and CD62P; and the beta(1)-integrin chain CD29). EMB quality was assessed visually on a three-point scale. Infiltrates were quantified visually (per hpf) and by DIA (per mm2 HA). CAM expression was evaluated semiquantitatively and by DIA (area fraction [AF]: stained area relative to HA). RESULTS: DIA-evaluated HA correlated significantly with the visual assessment of EMB quality. The visual evaluation of both infiltrates and CAMs correlated significantly with the respective DIA-based quantification. DIA-quantified CAM-AF and infiltrates were discriminated by the CAM classification (CAMs+: n=87; 62%) compared to controls. DIA-quantified CAM immunoreactivity correlated significantly with the DIA-quantified counter-receptor+ infiltrates. DIA evaluation of biopsy quality, infiltrates, and CAMs was devoid of inter- and intraobserver variability. CONCLUSIONS: The DIA system presented here enables standardized and observer-independent assessment of EMB quality and intramyocardial inflammation (density of infiltrates and CAM expression) in DCM biopsies related to HA. Our data confirm that endothelial CAM count and counter-receptor+ immunocompetent infiltration are interdependent pathogenic and diagnostic hallmarks of InfCM.