Current Treatment of Heart Failure with Preserved Ejection Fraction: Should We Add Life to the Remaining Years or Add Years to the Remaining Life?

According to the ejection fraction, patients with heart failure may be divided into two different groups: heart failure with preserved or reduced ejection fraction. In recent years, accumulating studies showed that increased mortality and morbidity rates of these two groups are nearly equal. More importantly, despite decline in mortality after treatment in regard to current guideline in patients with heart failure with reduced ejection fraction, there are still no trials resulting in improved outcome in patients with heart failure with preserved ejection fraction so far. Thus, novel pathophysiological mechanisms are under development, and other new viewpoints, such as multiple comorbidities resulting in increased non-cardiac deaths in patients with heart failure and preserved ejection fraction, were presented recently. In this review, we will focus on the tested as well as the promising therapeutic options that are currently studied in patients with heart failure with preserved ejection fraction, along with a brief discussion of pathophysiological mechanisms and diagnostic options that are helpful to increase our understanding of novel therapeutic strategies

Differential Expression of Matrix Metalloproteases in Human Fibroblasts with Different Origins

Fibroblasts are widely distributed cells and are responsible for the deposition of extracellular matrix (ECM) components but also secrete ECM-degrading matrix metalloproteases. A finely balanced equilibrium between deposition and degradation of ECM is essential for structural integrity of tissues. In the past, fibroblasts have typically been understood as a uniform cell population with comparable functions regardless of their origin. Here, we determined growth curves of fibroblasts derived from heart, skin, and lung and clearly show the lowest proliferation rate for cardiac fibroblasts. Furthermore, we examined basal expression levels of collagen and different MMPs in these three types of fibroblasts and compared these concerning their site of origin. Interestingly, we found major differences in basal mRNA expression especially for MMP1 and MMP3. Moreover, we treated fibroblasts with TNF-α and observed different alterations under these proinflammatory conditions. In conclusion, fibroblasts show different properties in proliferation and MMP expression regarding their originated tissue

Protective Function of STAT3 in CVB3-Induced Myocarditis

The transcription factor signal transducer and activator of transcription 3 (STAT3) is an important mediator of the inflammatory process. We investigated the role of STAT3 in viral myocarditis and its possible role in the development to dilated cardiomyopathy. We used STAT3-deficent mice with a cardiomyocyte-restricted knockout and induced a viral myocarditis using Coxsackievirus B3 (CVB3) which induced a severe inflammation during the acute phase of the viral myocarditis. A complete virus clearance and an attenuated inflammation were examined in both groups WT and STAT3 KO mice 4 weeks after infection, but the cardiac function in STAT3 KO mice was significantly decreased in contrast to the infected WT mice. Interestingly, an increased expression of collagen I was detected in STAT3 KO mice compared to WT mice 4 weeks after CVB3 infection. Furthermore, the matrix degradation was reduced in STAT3 KO mice which might be an explanation for the observed matrix deposition. Consequently, we here demonstrate the protective function of STAT3 in CVB3-induced myocarditis. Since the cardiomyocyte-restricted knockout leads to an increased fibrosis, it can be assumed that STAT3 signalling in cardiomyocytes protects the heart against increased fibrosis through paracrine effects

Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation

Aims: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in pre‐transplant characteristics and outcomes after HTx. Methods and results: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in all‐cause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46–62; 24.6% women), 49 732 events occurred during a median follow‐up of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11–3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44–0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12–1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17–1.32; P < 0.001) or VAD (OR 1.53, CI 1.45–1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13–1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62–2.00; P < 0.001). There were no differences in all‐cause mortality, cardiovascular mortality, and graft failure between sexes. Conclusions: In this US transplant registry, men and women differed in pre‐transplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized post‐HTx management and care

Superior Ventriculo-Arterial Coupling with Decellularized Allografts Compared with Conventional Prostheses

Background To date, no experimental or clinical study provides detailed analysis of vascular impedance changes after total aortic arch replacement. This study investigated ventriculoarterial coupling and vascular impedance after replacement of the aortic arch with conventional prostheses vs. decellularized allografts. Methods After preparing decellularized aortic arch allografts, their mechanical, histological and biochemical properties were evaluated and compared to native aortic arches and conventional prostheses in vitro. In open-chest dogs, total aortic arch replacement was performed with conventional prostheses and compared to decellularized allografts (n = 5/group). Aortic flow and pressure were recorded continuously, left ventricular pressure-volume relations were measured by using a pressure- conductance catheter. From the hemodynamic variables end-systolic elastance (Ees), arterial elastance (Ea) and ventriculoarterial coupling were calculated. Characteristic impedance (Z) was assessed by Fourier analysis. Results While Ees did not differ between the groups and over time (4.1±1.19 vs. 4.58±1.39 mmHg/mL and 3.21±0.97 vs. 3.96±1.16 mmHg/mL), Ea showed a higher increase in the prosthesis group (4.01±0.67 vs. 6.18±0.20 mmHg/mL, P<0.05) in comparison to decellularized allografts (5.03±0.35 vs. 5.99±1.09 mmHg/mL). This led to impaired ventriculoarterial coupling in the prosthesis group, while it remained unchanged in the allograft group (62.5±50.9 vs. 3.9±23.4%). Z showed a strong increasing tendency in the prosthesis group and it was markedly higher after replacement when compared to decellularized allografts (44.6±8.3dyn·sec·cm−5 vs. 32.4±2.0dyn·sec·cm−5, P<0.05). Conclusions Total aortic arch replacement leads to contractility-afterload mismatch by means of increased impedance and invert ventriculoarterial coupling ratio after implantation of conventional prostheses. Implantation of decellularized allografts preserves vascular impedance thereby improving ventriculoarterial mechanoenergetics after aortic arch replacement

Total Aortic Arch Replacement: Superior Ventriculo-Arterial Coupling with Decellularized Allografts Compared with Conventional Prostheses.

BACKGROUND: To date, no experimental or clinical study provides detailed analysis of vascular impedance changes after total aortic arch replacement. This study investigated ventriculoarterial coupling and vascular impedance after replacement of the aortic arch with conventional prostheses vs. decellularized allografts. METHODS: After preparing decellularized aortic arch allografts, their mechanical, histological and biochemical properties were evaluated and compared to native aortic arches and conventional prostheses in vitro. In open-chest dogs, total aortic arch replacement was performed with conventional prostheses and compared to decellularized allografts (n = 5/group). Aortic flow and pressure were recorded continuously, left ventricular pressure-volume relations were measured by using a pressure-conductance catheter. From the hemodynamic variables end-systolic elastance (Ees), arterial elastance (Ea) and ventriculoarterial coupling were calculated. Characteristic impedance (Z) was assessed by Fourier analysis. RESULTS: While Ees did not differ between the groups and over time (4.1+/-1.19 vs. 4.58+/-1.39 mmHg/mL and 3.21+/-0.97 vs. 3.96+/-1.16 mmHg/mL), Ea showed a higher increase in the prosthesis group (4.01+/-0.67 vs. 6.18+/-0.20 mmHg/mL, P<0.05) in comparison to decellularized allografts (5.03+/-0.35 vs. 5.99+/-1.09 mmHg/mL). This led to impaired ventriculoarterial coupling in the prosthesis group, while it remained unchanged in the allograft group (62.5+/-50.9 vs. 3.9+/-23.4%). Z showed a strong increasing tendency in the prosthesis group and it was markedly higher after replacement when compared to decellularized allografts (44.6+/-8.3dyn.sec.cm-5 vs. 32.4+/-2.0dyn.sec.cm-5, P<0.05). CONCLUSIONS: Total aortic arch replacement leads to contractility-afterload mismatch by means of increased impedance and invert ventriculoarterial coupling ratio after implantation of conventional prostheses. Implantation of decellularized allografts preserves vascular impedance thereby improving ventriculoarterial mechanoenergetics after aortic arch replacement

Human Cardiac-Derived Adherent Proliferating Cells Reduce Murine Acute Coxsackievirus B3-Induced Myocarditis

BACKGROUND: Under conventional heart failure therapy, inflammatory cardiomyopathy typically has a progressive course, indicating a need for alternative therapeutic strategies to improve long-term outcomes. We recently isolated and identified novel cardiac-derived cells from human cardiac biopsies: cardiac-derived adherent proliferating cells (CAPs). They have similarities with mesenchymal stromal cells, which are known for their anti-apoptotic and immunomodulatory properties. We explored whether CAPs application could be a novel strategy to improve acute Coxsackievirus B3 (CVB3)-induced myocarditis. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the safety of our approach, we first analyzed the expression of the coxsackie- and adenovirus receptor (CAR) and the co-receptor CD55 on CAPs, which are both required for effective CVB3 infectivity. We could demonstrate that CAPs only minimally express both receptors, which translates to minimal CVB3 copy numbers, and without viral particle release after CVB3 infection. Co-culture of CAPs with CVB3-infected HL-1 cardiomyocytes resulted in a reduction of CVB3-induced HL-1 apoptosis and viral progeny release. In addition, CAPs reduced CD4 and CD8 T cell proliferation. All CAPs-mediated protective effects were nitric oxide- and interleukin-10-dependent and required interferon-γ. In an acute murine model of CVB3-induced myocarditis, application of CAPs led to a decrease of cardiac apoptosis, cardiac CVB3 viral load and improved left ventricular contractility parameters. This was associated with a decline in cardiac mononuclear cell activity, an increase in T regulatory cells and T cell apoptosis, and an increase in left ventricular interleukin-10 and interferon-γ mRNA expression. CONCLUSIONS: We conclude that CAPs are a unique type of cardiac-derived cells and promising tools to improve acute CVB3-induced myocarditis

The role of TIR-domain-containing adaptor protein inducing Interferon-ß (TRIF) in experimental viral-induced myocarditis in mice

In der hier entstandenen Studie wird erstmals die Evidenz des Adaptermoleküls TRIF als ein essentieller kardioprotektiver Effektor des TLR-Systems in der CVB3-induzierten Myokarditis anhand eines experimentellen Mausmodells wissenschaftlich belegt. Zugleich wird eine neue Bedeutung des TLR-Systems für die virale Myokarditis sichtbar gemacht. Im Rahmen der erforderlichen Experimente wurden TRIF-/- Mäuse und WT-Mäuse verwendet und durch eine CVB3-Infektion dem gut etablierten experimentellen Mausmodell der viralen Myokarditis zugeführt. Sieben Tage nach der CVB3-Infektion, in der virämischen Phase der Myokarditis, wurde die linksventrikuläre Pumpfunktion charakterisiert und das Herzgewebe mittels immunhistologischer und molekularbiologischer Verfahren tiefergehend untersucht. Im Anschluss hieran wurde das Überleben nach CVB3-Infektion und IFN-ß Substitution der unterschiedlichen Tiergruppen nähergehend beleuchtet. Von allen in die Studie eingegliederten Tieren wurde die Herzfunktion mittels der Konduktanz- Kathetertechnik bestimmt, und es wurde eine signifikant verschlechterte systolische und globale linksventrikuläre Pumpfunktion in der Tiergruppe der TRIF-/- CVB3 Mäusen im Vergleich zu den WT-CVB3 Mäusen festgestellt. Die Ergebnisse der immunhistologischen und molekularbiologischen Untersuchungen liegen im Abgleich zu den WT-CVB3 Mäusen eine signifikant erhöhte kardiale Inflammation in den TRIF-/- CVB3 Mäusen erkennen. Weiterhin wurde in der Gruppe der induzierten TRIF-/-Mäuse ein erhöhter Gehalt infiltrativer Immunzellen (Makrophagen, T- und B-Lymphozyten, zytotoxischen T-Zellen) im myokardialen Gewebe aufgefunden. Überdies war eine gesteigerte Expression pro- inflammatorischer Zytokine und auch erhöhte Expressionen der Zelladhäsionsmoleküle wie VCAM und ICAM nach CVB3- Infektion in TRIF-/- Mäusen verglichen mit den WT-CVB3 Mäusen zu verifizieren. Schließlich konnten eine erhöhte Viruslast, eine gleichbleibende spezifsche Rezeptorfunktion und signifikant gesteigerte Apoptoseraten und in TRIF-/- CVB3 Mäusen im Vergleich zu WTCVB3 Mäusen nach CVB3-Infektion verzeichnet werden. In summa lässt sich aus den von uns erhobenen Daten ableiten, dass eine TRIF-Defizienz zu einer deutlichen Exazerbation der viralen Myokarditis einschließlich des Verlust der kardialen Viruskontrolle einhergehend mit der Entwicklung einer LV-Dysfunktion und einer schwerwiegenden myokardialen Schädigung führt. Darüber hinaus führt eine TRIF-Defizienz zur erhöhten Induktion der Mortalitätsrate nach CVB3-Infektion, die maßgeblich durch eine insuffiziente kardiale IFN-ß Antwort induziert wurde. Die vorliegende Studie analysiert und beschreibt auf der Grundlage breit angelegter Untersuchungsreihen im Mausmodell erstmalig und eingehend die Evidenz von TRIF als einen essentiellen kardioprotektiven TLR- Effektor im Krankheitsbild der viralen Myokarditis und indiziert eine neuartige Relevanz des TLR-Systems hinsichtlich dieser myokardialen Erkrankung.In summary, the current study shows that TRIF is essential in virus control of CVB3 in the heart. Loss of TRIF leads to exacerbation of viral replication, severe heart failure, and mortality in viral myocarditis. This work suggest that early impaired IFN-β response may contrubute to the consequences of TRIF deficiency seen in CVB3-induced murine myocarditis. To our knowledge, the present study provides the first evidence for TRIF as an essential cardioprotective TLR adaptor in viral myocarditis and anticipates a novel role for the TLR system concerning this disease