Jörn Tongers

Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges

In the absence of effective endogenous repair mechanisms after cardiac injury, cell-based therapies have rapidly emerged as a potential novel therapeutic approach in ischaemic heart disease. After the initial characterization of putative endothelial progenitor cells and their potential to promote cardiac neovascularization and to attenuate ischaemic injury, a decade of intense research has examined several novel approaches to promote cardiac repair in adult life. A variety of adult stem and progenitor cells from different sources have been examined for their potential to promote cardiac repair and regeneration. Although early, small-scale clinical studies underscored the potential effects of cell-based therapy largely by using bone marrow (BM)-derived cells, subsequent randomized-controlled trials have revealed mixed results that might relate, at least in part, to differences in study design and techniques, e.g. differences in patient population, cell sources and preparation, and endpoint selection. Recent meta-analyses have supported the notion that administration of BM-derived cells may improve cardiac function on top of standard therapy. At this stage, further optimization of cell-based therapy is urgently needed, and finally, large-scale clinical trials are required to eventually proof its clinical efficacy with respect to outcomes, i.e. morbidity and mortality. Despite all promises, pending uncertainties and practical limitations attenuate the therapeutic use of stem/progenitor cells for ischaemic heart disease. To advance the field forward, several important aspects need to be addressed in carefully designed studies: comparative studies may allow to discriminate superior cell populations, timing, dosing, priming of cells, and delivery mode for different applications. In order to predict benefit, influencing factors need to be identified with the aim to focus resources and efforts. Local retention and fate of cells in the therapeutic target zone must be improved. Further understanding of regenerative mechanisms will enable optimization at all levels. In this context, cell priming, bionanotechnology, and tissue engineering are emerging tools and may merge into a combined biological approach of ischaemic tissue repair.

Growth Differentiation Factor-15 in Idiopathic Pulmonary Arterial Hypertension

RATIONALE Growth-differentiation factor (GDF)-15 is a stress-responsive, transforming growth factor-beta-related cytokine. Circulating levels of GDF-15 provide independent prognostic information in patients with acute pulmonary embolism and chronic left-sided heart failure. OBJECTIVES To assess the prognostic value of GDF-15 in idiopathic pulmonary arterial hypertension. METHODS GDF-15 levels were determined in 76 treatment-naive patients at the time of baseline right heart catheterization. Patients were monitored for a median (range) of 48 (0-101) months (first cohort). Twenty-two additional patients were studied at baseline and 3 to 6 months after initiation of therapy (second cohort). MEASUREMENTS AND MAIN RESULTS Fifty-five percent of the patients in the first cohort presented with GDF-15 levels above 1,200 ng/L, the previously defined upper reference limit. The risk of death or transplantation at 3 years was 15 and 44% in patients with GDF-15 levels below or above 1,200 ng/L, respectively (P = 0.006). Elevated levels of GDF-15 were associated with increased mean right atrial and pulmonary capillary wedge pressures, a lower mixed venous oxygen saturation (Sv(O(2))), and higher levels of uric acid and N-terminal pro-brain natriuretic peptide (NT-proBNP). After adjustment for hemodynamic and biochemical variables, GDF-15 remained an independent predictor of adverse outcomes (P = 0.002). GDF-15 provided prognostic information in clinically relevant patient subgroups, and added prognostic information to hemodynamic variables and NT-proBNP. Changes in GDF-15 over time in the second cohort were related to changes in NT-proBNP (P = 0.031) and inversely related to changes in Sv(O(2)) (P < 0.001). CONCLUSIONS GDF-15 is a promising new biomarker in idiopathic pulmonary arterial hypertension.

Atrial flutter and fibrillation in patients with pulmonary hypertension

BACKGROUND Atrial flutter and fibrillation are being increasingly reported in patients with pulmonary hypertension but little is known about their clinical implications. We sought to determine the incidence and clinical impact of these arrhythmias in patients with pulmonary hypertension. METHODS In a 5-year, prospective study, we assessed the incidence of new-onset atrial flutter and fibrillation as well as risk factors, clinical consequences, management, and impact on survival in patients with pulmonary arterial hypertension (PAH, n=157) or inoperable chronic thromboembolic pulmonary hypertension (CTEPH, n=82). RESULTS The cumulative 5-year incidence of new-onset atrial flutter and fibrillation was 25.1% (95% confidence interval, 13.8-35.4%). The development of these arrhythmias was frequently accompanied by clinical worsening (80%) and signs of right heart failure (30%). Stable sinus rhythm was successfully re-established in 21/24 (88%) of patients initially presenting with atrial flutter and in 16/24 (67%) of patients initially presenting with atrial fibrillation. New-onset atrial flutter and fibrillation were an independent risk factor of death (p=0.04, simple Cox regression analysis) with a higher mortality in patients with persistent atrial fibrillation when compared to patients in whom sinus rhythm was restored (estimated survival at 1, 2 and 3 years 64%, 55%, and 27% versus 97%, 80%, and 57%, respectively; p=0.01, log rank analysis). CONCLUSIONS Atrial flutter and fibrillation develop in a sizable number of patients with PAH or inoperable CTEPH and often lead to clinical deterioration and right heart failure. Mortality is high when sinus rhythm cannot be restored.

Mortality in patients with cardiogenic shock treated with the Impella CP microaxial pump for isolated left ventricular failure

Aims: Cardiogenic shock is still associated with high mortality rates of around 50%. Intra-aortic counterpulsation had been frequently used in cardiogenic shock, but was previously found to provide no mortality benefit. We investigated the effect of an interdisciplinary and multiprofessional routine strategy of early invasive haemodynamic support in combination with complete revascularization in patients with cardiogenic shock before admission to our intensive care unit. Methods and results: We analysed all cardiogenic shock patients (mean age 62±13 years) presenting at our institution between 2013 and mid 2016, who received an Impella CP microaxial pump for isolated left ventricle support (n=61). Sixty-one per cent (n=37) had been resuscitated before Impella insertion. Overall mortality was 48% (n=29/61) at 30 days. Thirty-day mortality was higher in resuscitated patients (resuscitated: 65% (n=24/37); non-resuscitated: 21% (n=5/24)). When applying the inclusion/exclusion criteria of the SHOCK-II trial, eligible patients (n=25) had a markedly lower mortality (24% (n=6/25) at 30 days) compared with the published trial (~40% in both arms). The observed mortality of SHOCK-II-like patients in the registry was also lower compared with their predicted mortality using IABP-Shock II score (49%) and CardShock score (36%). Conclusion: The results of this registry suggest that using a standardized protocol including early active haemodynamic support with Impella CP in cardiogenic shock in patients with isolated left ventricle failure may be associated with improved outcomes and lower than previously reported or predicted mortality rates. Pre-implantation cardiac arrest critically influences observed mortality. The results support the case for a randomized trial.

Acquired von Willebrand syndrome in cardiogenic shock patients on mechanical circulatory microaxial pump support

Early use of mechanical circulatory support, e.g. veno-arterial extracorporeal membrane oxygenation (ECMO) or left ventricular unloading by microaxial pump in refractory cardiogenic shock is recommended in current guidelines. Development of acquired von Willebrand Syndrome (AVWS) in patients with left ventricular assist devices (LVADs) and ECMO has been reported. There is an increasing number of patients treated with the Impella® CP microaxial pump for left ventricular unloading. However, the prevalence of AVWS in these high risk patients is unknown and needs to be determined. We therefore screened 21 patients (68 ± 11years) treated with Impella® (17 for cardiogenic shock, 4 for protected PCI) for the presence of AVWS by determining von Willebrand factor multimers, VWF collagen binding capacity and VWF antigen. During the time course of Impella® support, 20/21 patients (95%) developed AVWS (mean duration of support: 135 ± 114 hours, mean time from device implantation to first diagnosis of AVWS: 10.6 ± 10.8 hours). Our data indicate that AVWS is a common phenomenon during left ventricular unloading via microaxial pump support. Thus, AVWS has to be considered as contributing factor for potential bleeding complications in this high risk patient population, especially in the context of dual antiplatelet therapy.

Cell-Based Therapy in Ischemic Heart Disease

Despite continuous advances in primary prevention and secondary management of arteriosclerotic disease, ischemic cardiovascular disease constitute an increasing socioeconomic burden. A solid body of evidence has previously indicated a regenerative capacity of stem and progenitor cell-based therapy in preclinical and early-phase clinical studies. Clinical application of stem and progenitor cells in ischemic heart disease have included patients with coronary artery disease after revascularized acute myocardial infarction, ischemic cardiomyopathy, or refractory angina. Larger scale clinical studies subsequently generated mixed data partly due to differences in study design and employed techniques. While the therapeutic application of different cell populations appears safe, therapeutic efficacy of stem and progenitor cells needs yet to be proven at a larger scale in properly designed randomized-controlled trials. Vast efforts have been undertaken to overcome practical limitations and conceptual challenges that were encountered in praxis over time. Multiple strategies such as supportive use of biomaterials, combination of different cell sources, genetic modification of cells prior to application, and addition of factors turned out to be promising overly in the preclinical evaluation To optimize and fully leverage the regenerative potential of cell-based therapies further aspects including identification of a potentially ideal cell linage as well as timing, repetition and dosing of cell delivery need to be addressed.

Cardiogenic shock complicating peripartum cardiomyopathy: Importance of early left ventricular unloading and bromocriptine therapy

Introduction: Acute peripartum cardiomyopathy complicated by cardiogenic shock is a rare but life-threatening disease. A prolactin fragment is considered causal for the pathogenesis of peripartum cardiomyopathy. This analysis sought to investigate the role of early percutaneous mechanical circulatory support with micro-axial flow-pumps and/or veno-arterial extracorporeal membrane oxygenation in combination with the prolactin inhibitor bromocriptine in refractory cardiogenic shock complicating peripartum cardiomyopathy. Methods and results: In this single-centre analysis, five peripartum cardiomyopathy patients with refractory cardiogenic shock received mechanical circulatory support with either Impella CP microaxial pump only (n=2) or in combination with veno-arterial extracorporeal membrane oxygenation (n=3) in the setting of biventricular failure. All patients were mechanically ventilated. In all cases mechanical circulatory support was combined with bromocriptine therapy and early administration of levosimendan. All patients survived the acute phase of refractory cardiogenic shock. Mechanical circulatory support using a micro-axial pump allowed to significantly reduce catecholamine dosage. Remarkably, early left ventricular support with micro-axial flow-pumps resulted in myocardial recovery whereas delayed Impella (mechanical circulatory support) implantation was associated with poor left ventricular recovery. Conclusion: Mechanical circulatory support in patients with refractory cardiogenic shock complicating peripartum cardiomyopathy was associated with a 30-day survival of 100% and a favourable outcome. Notably, early left ventricular unloading combined with bromocriptine therapy was associated with left ventricular recovery. Therefore, an immediate transfer to a tertiary hospital experienced in mechanical circulatory support in combination with bromocriptine treatment seems indispensable for successful treatment of peripartum cardiomyopathy complicated by cardiogenic shock.

First-in-Man Fully Percutaneous Complete Bypass of Heart and Lung

A 24-year-old man was admitted to a regional hospital after an attempted suicide by taking 9 g of the antidepressant venlafaxine. After initial seizures, overnight progressive cardiogenic shock developed [(1,2)][1] and resulted in cardiac arrest from electromechanical dissociation (EMD) 12 h after

Angiographic detection of fatal acute aortic dissection Stanford type A under resuscitation

After resuscitation for out-of-hospital cardiac arrest (OHCA), emergent cardiac catheterization is recommended in patients with ST-segment elevation, and should be considered early in those without [1, 2]. Here, we present a patient with OHCA and inferior ST-segment elevation who inadvertently had fatal acute aortic dissection, which is only rarely documented by angiography. A 77-year-old female with know atrial fibrillation on phenprocoumon and arterial hypertension was admitted to our emergency department after cardiopulmonary resuscitation (CPR) for OHCA. The patient had suffered from angina for 24 h and collapsed in the waiting room, while expecting an appointment with a general practitioner. After 20 min of CPR for asystole, spontaneous circulation returned. Electrocardiogram (ECG) demonstrated ST-segment elevation in leads II, III, aVF and V6. The ventilated patient, who was then stable with vasopressors, was immediately transferred to our hospital. After arrival in the emergency department, ECG confirmed ST-segment elevations, Q waves in leads II, III, aVF and V6, and incomplete right bundle branch block (Fig. 1A). Fast-track echocardiography showed mild aortic regurgitation but no pericardial effusion or severe right ventricular dysfunction. Therefore, the patient was transferred to the cathlab. On the way, hypotension occurred and CPR was performed with a mechanical resuscitation device (LUCAS, Physio-Control). Aortography revealed acute aortic dissection Stanford type A (AADA) extending to both iliac arteries, with the brachiocephalic trunk and the left carotid artery originating from the false lumen (Fig. 1B, C; Supplementary Video 1 — see journal website). Due to prolonged resuscitation and fatal neurological prognosis, resuscitation was terminated. Autopsy confirmed AADA with an entry in the aortic bulb (Fig. 1D) without affecting the right coronary artery ostium, as well as an aneurysm of the abdominal aorta (Fig. 1E). Prognosis of AADA is poor with 50% mortality after 48 h without surgery and 17.1% mortality after 30 days with surgery [3]. In our case, the clinical picture and ECG findings were indeed suggestive of inferior myocardial infarction, and typical echocardiographic signs of AADA, such as pericardial effusion or relevant aortic regurgitation were missing. Incidence of AADA is low compared to that of ST-segment elevation myocardial infarction, but is probably underestimated [4]. The prevalence of ST-segment elevation in AADA is 3.2% [5], and fast rule-out echocardiography in patients with ST-segment elevation in inferior leads is useful [6] and allowed by current guidelines, as long as it does not delay angiography [1, 7]. The present case prototypically illustrates fatal AADA and reminds us of considering AADA in cases of chest pain and ST-segment elevation in inferior leads, and further points to the eminent role of computed tomography in cases of successful resuscitation for OHCA [1]. clinical cardiology

Two vascular arteriovenous malformations with left-to-right shunting and right-heart failure in a single patient

Arteriovenous malformations may lead to right-heart failure in cases of hemodynamically significant left-to-right shunting. Here, we report the case of a 37-year-old female who presented with congestive heart failure related to an isolated anomalous connection of the left pulmonary vein to the left brachiocephalic vein (partial anomalous pulmonary venous connection). After successful reconnection to the left appendage and clinical improvement, the patient once again developed progressive signs of heart failure. Several arteriovenous malformations were identified in the liver as the underlying cause of the patients high-output heart failure, and the patient was retrospectively diagnosed with hereditary hemorrhagic telangiectasia. Target embolization led to right-ventricular remodeling, and persistent clinical improvement. To our knowledge, this is the first report of two rare AV-malformations with left-to-right shunting and progressive right-heart failure in a single individual.