Risk factors for heart failure are associated with alterations of the LV end-diastolic pressure-volume relationship in non-heart failure individuals: data from a large-scale, population-based cohort.

AIMS: Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure-volume relationship (EDPVR), which is different in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF patients and their association to risk factors and all-cause mortality in non-HF individuals. METHODS AND RESULTS: Based on clinical and echocardiographic data, participants were divided into 'No HF' (n = 14487), HFrEF (n = 215), and HFpEF (n = 79). We estimated the position of the EDPVR and its stiffness-coefficient ß from echocardiographic data using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with 'No HF', while the stiffness-coefficient ß was increased in both HFrEF and HFpEF. In 'No HF', a higher stiffness-coefficient ß was associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were associated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause mortality. CONCLUSION: In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with increased mortality.

Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock.

BACKGROUND: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. METHODS: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. RESULTS: The analysis included 1116 patients [median age: 70 (IQR 58-79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2-9.5) mmol/l, CRP 17 (IQR 5-71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B-E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3-13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21-1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67-1.26; p = 0.59; p-interaction = 0.01). CONCLUSION: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association.

TRIF is a critical survival factor in viral cardiomyopathy.

TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF(-/-) mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p < 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-ß in the early viremic phase. TRIF(-/-) myocytes displayed a TLR4-dependent suppression of IFN-ß, and pharmacological treatment of CVB3-infected TRIF(-/-) mice with murine IFN-ß led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long-term outcome indexed by reduced mortality (20 versus 100%; p < 0.001). TRIF is essential toward a cardioprotection against CVB3 infection.

CAR links hypoxia signaling to improved survival after myocardial infarction.

The coxsackievirus and adenovirus receptor (CAR) mediates homo- and heterotopic interactions between neighboring cardiomyocytes at the intercalated disc. CAR is upregulated in the hypoxic areas surrounding myocardial infarction (MI). To elucidate whether CAR contributes to hypoxia signaling and MI pathology, we used a gain- and loss-of-function approach in transfected HEK293 cells, H9c2 cardiomyocytes and CAR knockout mice. CAR overexpression increased RhoA activity, HIF-1α expression and cell death in response to chemical and physical hypoxia. In vivo, we subjected cardiomyocyte-specific CAR knockout (KO) and wild-type mice (WT) to coronary artery ligation. Survival was drastically improved in KO mice with largely preserved cardiac function as determined by echocardiography. Histological analysis revealed a less fibrotic, more compact lesion. Thirty days after MI, there was no compensatory hypertrophy or reduced cardiac output in hearts from CAR KO mice, in contrast to control mice with increased heart weight and reduced ejection fraction as signs of the underlying pathology. Based on these findings, we suggest CAR as a therapeutic target for the improved future treatment or prevention of myocardial infarction.

Small animal Look-Locker inversion recovery (SALLI) for simultaneous generation of cardiac T1 maps and cine and inversion recovery-prepared images at high heart rates: initial experience.

PURPOSE: To develop a single magnetic resonance (MR) imaging approach for comprehensive assessment of cardiac function and tissue properties in small animals with high heart rates. MATERIALS AND METHODS: All animal studies were approved by the local animal care committee. Small animal Look-Locker inversion recovery (SALLI) was implemented on a clinical 3.0-T MR unit equipped with a 70-mm solenoid coil. SALLI combines a segmented, electrocardiographically gated, inversion recovery-prepared Look-Locker-type pulse sequence with a multimodal reconstruction framework. Temporal undersampling and radial nonbalanced steady-state free precession enabled acceleration of data acquisition and reduction of motion artifacts, respectively. Nine agarose gel phantoms were used to investigate different sequence settings. For in vivo studies, 10 Sprague-Dawley rats were evaluated to establish normal T1 values before and after injection of gadopentetate dimeglumine. Seven rats with surgically induced acute myocardial infarction were examined to test the feasibility of detecting myocardial injury. In vitro T1 behavior was studied with linear regression analysis, and in vivo T1 differences between infarcted and remote areas were tested by using the Wilcoxon signed rank test. RESULTS: Phantom studies demonstrated systematic behavior of the T1 measurements, and T1 error could be reduced to 1.3% ± 7.4 by using a simple linear correction algorithm. The pre- and postcontrast T1 of myocardium and blood showed narrow normal ranges. In the area of infarction, SALLI demonstrated hypokinesia (on cine images), myocardial edema (on precontrast T1 maps), and myocardial necrosis (on postcontrast T1 maps and late gadolinium enhancement images). CONCLUSION: An MR imaging method enabling simultaneous generation of cardiac T1 maps and cine and inversion recovery-prepared images at high heart rates is presented. SALLI allows for simultaneous and time-efficient assessment of cardiac T1 behavior, function, and late gadolinium enhancement at high heart rates.

Use of sodium-glucose co-transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry.

AIMS: Use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in real-world heart failure (HF) is poorly characterised. In contemporary patients with HF and type 2 diabetes mellitus (T2DM) we assessed over time SGLT2i use, clinical characteristics and outcomes associated with SGLT2i use. METHODS AND RESULTS: Type 2 diabetes patients enrolled in the Swedish HF Registry between 2016-2018 were considered. We performed multivariable logistic regression models to assess the independent predictors of SGLT2i use and Cox regression models in a 1:3 propensity score-matched cohort and relevant subgroups to investigate the association between SGLT2i use and outcomes. Of 6805 eligible HF patients with T2DM, 376 (5.5%) received SGLT2i, whose use increased over time with 12% of patients on treatment at the end of 2018. Independent predictors of SGLT2i use were younger age, HF specialty care, ischaemic heart disease, preserved kidney function, and absence of anaemia. Over a median follow-up of 256 days, SGLT2i use was associated with a 30% lower risk of cardiovascular (CV) death/first HF hospitalisation (hazard ratio 0.70, 95% confidence interval 0.52-0.95), which was consistent regardless of ejection fraction, background metformin treatment and kidney function. SGLT2i use was also associated with a lower risk of all-cause and CV death, HF and CV hospitalisation, and CV death/myocardial infarction/stroke. CONCLUSION: In a contemporary HF cohort with T2DM, SGLT2i use increased over time, was more common with specialist care, younger age, ischaemic heart disease, and preserved renal function, and was associated with lower mortality and morbidity.

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

AIMS: Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials. METHODS AND RESULTS: Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility. CONCLUSION: The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.

Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo.

Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)-induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, virus mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-alpha. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-beta in the heart as a result from viral infection. In conclusion, the MyD88/TNF-alpha axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis.

Switching to Impella 5.0 decreases need for transfusion in patients undergoing temporary mechanical circulatory support.

PURPOSE: Various options of temporary mechanical circulatory support (tMCS) exist for the treatment of cardiogenic shock, however, all forms of tMCS carry a risk of complications. The aim of this study was to compare bleeding complications and thromboembolic events under extracorporeal life support + Impella 2.5/CP (ECMELLA) and isolated Impella 5.0 therapy in the same patient cohort. MATERIAL: We retrospectively analyzed data of patients who underwent ECMELLA implantation and subsequent Impella 5.0 therapy. Implantation strategy and anticoagulation protocol were comparable in both groups. RESULTS: We included 15 patients (mean age 57.2 years; 80% of male patients) who were weaned from ECMELLA undergoing subsequent Impella 5.0 implantation. Mean duration of ECMELLA and Impella 5.0 therapy (10.5 vs. 11.2 days) did not differ significantly (p = .731). The average number of transfused packed red blood cells (PRBC) and thrombocyte concentrates (TC) was significantly decreased during Impella 5.0 treatment (PRBC: 30.3 vs 12.3, p = .001; TC: 5.9 vs 2.2, p = .045). Additionally, the transfusion rates per day were significantly reduced under Impella 5.0 support. CONCLUSIONS: The need for transfusions is significantly lower in the phase of Impella 5.0 therapy compared to the initial phase on ECMELLA. Therefore, we recommend replacing ECMELLA by an Impella 5.0 device early, if possible.

Risk prediction of in-hospital mortality in patients with venoarterial extracorporeal membrane oxygenation for cardiopulmonary support: The ECMO-ACCEPTS score.

PURPOSE: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an increasingly used treatment option for patients in need of mechanical cardiopulmonary support, while available outcome data is limited. The aim of this study was to identify predictors for 30-day in-hospital mortality. MATERIAL AND METHODS: We analyzed baseline characteristics and outcomes of 8351 VA-ECMO procedures performed in Germany from 2007 to 2015. Using a multivariable model, we identified the ten most important variables to allow for prediction of 30-day in-hospital mortality. Based on these variables, we created a mortality prediction score (ECMO-ACCEPTS score) to enhance decision making in patients considered for or treated with VA-ECMO support. RESULTS: Of 8351 patients (71.7% male) 3567 had prior CPR. Mean age was 62 years in the present cohort. The overall 30-day in-hospital mortality was 61%. The ECMO-ACCEPTS score, derived among randomly selected 4175 patients, included ten independent predictors for in-hospital mortality. Internal validation in the remaining 4176 patients confirmed strong differentiation between low and high risk of 30-day in-hospital mortality (r = 0.97 for correlation of predicted with observed mortality, p < .001). CONCLUSIONS: The ECMO-ACCEPTS score might help clinicians to improve risk prediction among VA-ECMO patients for refractory cardiogenic shock.

No effect of thymosin beta-4 on the expression of the transcription factor Islet-1 in the adult murine heart.

The transcription factor Islet-1 marks a progenitor cell population of the second heart field during cardiogenesis. In the adult heart Islet-1 expression is limited to the sinoatrial node, the ventricular outflow tract, and parasympathetic ganglia. The regenerative effect in the injured mouse ventricle of thymosin beta-4 (TB4), a 43-aminoacid peptide, was associated with increased Islet-1 immunostaining, suggesting the induction of an Islet-1-positive progenitor state by TB4. Here we aimed to reassess this effect in a genetic model. Mice from the reporter mouse line Isl1-nLacZ were primed with TB4 and subsequently underwent myocardial infarction. Islet-1 expression was assessed 2, 7, and 14 days after infarction. We detected only a single Islet-1+ cell in 8 TB4 treated and infarcted hearts which located outside of the sinoatrial node, the outflow tract or cardiac ganglia (in ~2500 sections). Two cells were identified in 5 control infarcted hearts. TB4 did not induce LacZ positivity in ventricular explants cultures of Isl1-nLacZ mice nor did it affect the density of LacZ+ cells in explant cultures of nLacZ+ regions of the heart. In summary, we found no evidence that TB4 reactivates Islet-1 expression in adult mouse ventricle.

Adherence to Mediterranean diet, high-sensitive C-reactive protein, and severity of coronary artery disease: Contemporary data from the INTERCATH cohort.

BACKGROUND AND AIMS: Guidelines recommend a healthy diet as a cornerstone of cardiovascular disease (CVD) prevention. Although the Mediterranean diet (MD) is the best studied dietary pattern for CV outcomes, data on association between MD and severity of CAD are limited. Therefore, we analysed dietary data in association with the SYNTAX score in coronary artery disease (CAD) patients from the INTERCATH study. METHODS: The INTERCATH study is an observational study in patients undergoing coronary angiography at the University Heart Center Hamburg. Coronary morphology is assessed by the SYNTAX score. A lifestyle questionnaire collects dietary data with food frequency questions at baseline. Based on seven dietary characteristics, we calculated an established Mediterranean diet score (MDS) with a range of 0-28 points at which 28 points reflect maximal adherence to MD. To investigate the association of MD with severity of CAD, we performed logistic regression analysis after adjustment for confounding factors. RESULTS: Of 1121 patients, 27% were women. The median age was 70.7 years (interquartile range (IQR) 61.1,77.0). CV risk factors were distributed as expected for a CAD cohort (31.3% diabetes, 81.1% arterial hypertension, 34.0% smoking, median BMI 26.6 kg/m2 (IQR 24.1, 30.3), median LDL-C 87 mg/dL (IQR 65.0,116,6). Of all variables included, the strongest correlation with MDS was found for log (hs-CRP) (r = -0.21, p < 0.001). Adherence to MD represented by a higher MDS was significantly associated with a reduced probability for a medium/high risk SYNTAX score of ≥23 with an odds ratio (OR) of 0.923 per point increase of MDS (95% confidence interval 0.869-0.979; p = 0.0079). This association remained significant after adjustment for cardiovascular risk factors (OR 0.934, 95% CI 0.877-0.995, p = 0.035). After further adjustment for log (hs-CRP), the association remained no longer significant (OR 0.955 (0.893-1.022, p = 0.19). CONCLUSIONS: In this contemporary data set, we found an independent association of adherence to MD with a less complex CAD. Hs-CRP correlated significantly with adherence to MD and may be a marker of the vasoprotective effects of MD. These results strengthen the evidence for the protective effect of an MD pattern in CVD prevention.

Percutaneous coronary intervention for ostial and bifurcation lesions using the Szabo technique: a single center experience.

BACKGROUND: Aorto-ostial lesions as well as bifurcation lesions still provide challenges in percutaneous coronary intervention (PCI), as meticulous stent placement is needed. The Szabo-technique, which uses a second wire to anchor the stent at the ostium, may be helpful here. In this article, we will provide detailed information on the technique including video material as well as procedural and long-term follow-up data of a cohort of patients treated with this technique. METHODS: A retrospective single-centre study was performed in patients undergoing Szabo-PCI from 2014 to 2016 (N.=28). RESULTS: Indications for PCI were elective in 53% and urgent/emergent in 47%. Target vessel was the ostial right coronary artery in 43%, the ostial left main artery in 7%, the proximal left anterior descending artery in 29% and the proximal circumflex artery in 21% of the cases. Primary success rate was 86%. In the other 14%, delivery of the stent failed due to a high-grade calcification. There were no periprocedural complications. During the follow-up time (mean 308 days) there was one case of cardiovascular and one case of non-cardiovascular death without any stroke events. In one case target lesions revascularisation was necessary. CONCLUSIONS: The Szabo-technique offers a feasible and safe approach for PCI of ostial and bifurcation lesions. Calcified lesions seem to be a challenging aspect.

Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice.

Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor alpha and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects.