Publications by authors named "Frank Ruschitzka"

365 Publications

MMP-2 knockdown blunts age-dependent carotid stiffness by decreasing elastin degradation and augmenting eNOS activation.

Cardiovasc Res 2021 09 29. Epub 2021 Sep 29.

Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.

Aims: Arterial stiffness is a hallmark of vascular aging that precedes and strongly predicts the development of cardiovascular diseases. Age-dependent stiffening of large elastic arteries is primarily attributed to increased levels of matrix metalloproteinase-2 (MMP-2). However, the mechanistic link between age-dependent arterial stiffness and MMP-2 remains unclear. Thus, we aimed to investigate the efficacy of MMP-2 knockdown using small interfering RNA (siRNA) on age-dependent arterial stiffness.

Methods And Results: Pulse wave velocity (PWV) was assessed in right carotid artery of wild type (WT) mice from different age groups. MMP-2 levels in the carotid artery and plasma of young (3 months) and old (20-25 months) WT mice were determined. Carotid PWV as well as vascular and circulating MMP-2 were elevated with increasing age in mice. Old WT mice (18-21-month-old) were treated for 4 weeks with either MMP-2 or scrambled (Scr) siRNA via tail vein injection. Carotid PWV was assessed at baseline, 2 and 4 weeks after start of the treatment. MMP-2 knockdown reduced vascular MMP-2 levels and attenuated age-dependent carotid stiffness. siMMP-2 treated mice showed increased elastin to collagen ratio, lower plasma desmosine (DES), enhanced phosphorylation of endothelial nitric oxide synthase (eNOS) and higher levels of vascular cyclic guanosine monophosphate (cGMP). An age-dependent increase in direct protein-protein interaction between MMP-2 and eNOS was also observed. Lastly, DES, an elastin breakdown product, was measured in a patient cohort (n = 64, 23-86 years old), where carotid-femoral PWV was also assessed; here, plasma levels of DES directly correlated with age and arterial stiffness.

Conclusion: MMP-2 knockdown attenuates age-dependent carotid stiffness by blunting elastin degradation and augmenting eNOS bioavailability. Given the increasing clinical use of siRNA technology, MMP2 knockdown should be investigated further as a possible strategy to mitigate age-dependent arterial stiffness and related CV diseases.

Translational Perspective: Arterial stiffness is a hallmark of vascular aging that precedes and strongly predicts the development of cardiovascular diseases. This study provides translational evidence to support a key role for MMP-2 on the development of age-associated arterial stiffness. Silencing of MMP-2 using siRNA technology shows an effect on aged mice where it attenuates age-dependent carotid stiffness by reducing elastin degradation and increasing eNOS bioavailability. Additionally, in humans we show that elastin breakdown increases with age and increased PWV. These findings indicate MMP-2 knockdown as a promising novel strategy to attenuate age-dependent arterial stiffness and cardiovascular diseases.
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http://dx.doi.org/10.1093/cvr/cvab300DOI Listing
September 2021

HFA of the ESC position paper on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider Part 3: at the hospital and discharge.

ESC Heart Fail 2021 Sep 28. Epub 2021 Sep 28.

Heart Failure and Heart Transplantation Unit, Onassis Cardiac Surgery Center, Athens, Greece.

The growing population of left ventricular assist device (LVAD)-supported patients increases the probability of an LVAD- supported patient hospitalized in the internal or surgical wards with certain expected device related, and patient-device interaction complication as well as with any other comorbidities requiring hospitalization. In this third part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, definitions and structured approach to the hospitalized LVAD-supported patient are presented including blood pressure assessment, medical therapy of the LVAD supported patient, and challenges related to anaesthesia and non-cardiac surgical interventions. Finally, important aspects to consider when discharging an LVAD patient home and palliative and end-of-life approaches are described.
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http://dx.doi.org/10.1002/ehf2.13590DOI Listing
September 2021

Heart failure in COVID-19: the multicentre, multinational PCHF-COVICAV registry.

ESC Heart Fail 2021 Sep 17. Epub 2021 Sep 17.

Division of Infectious Diseases, Azienda ULSS 9, M. Magalini Hospital, Verona, Italy.

Aims: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations.

Methods And Results: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P < 0.001). After adjusting, HF remained associated with in-hospital mortality (OR 1.45 [95% confidence interval: 1.01-2.06], P = 0.041). Importantly, 186 of 1282 [15%] patients had an acute HF event during hospitalization (76 [40%] with de novo HF), which was associated with higher in-hospital mortality (89 [48%] vs. 220 [23%]) than in patients without HF event (OR 3.10 [2.24-4.29], P < 0.001).

Conclusions: Hospitalized COVID-19 patients with HF are at increased risk for in-hospital death. In-hospital worsening of HF or acute HF de novo are common and associated with a further increase in in-hospital mortality.
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http://dx.doi.org/10.1002/ehf2.13549DOI Listing
September 2021

Heart Failure Association of the European Society of Cardiology position paper on the management of left ventricular assist device-supported patients for the non-left ventricular assist device specialist healthcare provider: Part 2: at the emergency department.

ESC Heart Fail 2021 Sep 14. Epub 2021 Sep 14.

Ziekenhuis Oost-Limburg, Genk, Belgium.

The improvement in left ventricular assist device (LVAD) technology and scarcity of donor hearts have increased dramatically the population of the LVAD-supported patients and the probability of those patients to present to the emergency department with expected and non-expected device-related and patient-device interaction complications. The ageing of the LVAD-supported patients, mainly those supported with the 'destination therapy' indication, increases the risk for those patients to suffer from other co-morbidities common in the older population. In this second part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, definitions and structured approach to the LVAD-supported patient presenting to the emergency department with bleeding, neurological event, pump thrombosis, chest pain, syncope, and other events are presented. The very challenging issue of declaring death in an LVAD-supported patient, as the circulation is artificially preserved by the device despite no other signs of life, is also discussed in detail.
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http://dx.doi.org/10.1002/ehf2.13587DOI Listing
September 2021

HFA of the ESC Position paper on the management of LVAD supported patients for the non LVAD specialist healthcare provider Part 1: Introduction and at the non-hospital settings in the community.

ESC Heart Fail 2021 Sep 14. Epub 2021 Sep 14.

Department of Cardiology, Ege University Hospital, Izmir, Turkey.

The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of the LVAD-supported patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. The expected and non-expected device-related and patient-device interaction complications impose a significant burden on the medical system exceeding the capacity of the LVAD implanting centres. The ageing of the LVAD-supported patients, mainly those supported with the 'destination therapy' indication, increases the risk for those patients to experience comorbidities common in the older population. The probability of an LVAD-supported patient presenting with medical emergency to a local emergency department, internal, or surgical ward of a non-LVAD implanting centre is increasing. The purpose of this trilogy is to supply the immediate tools needed by the non-LVAD specialized physician: ambulance clinicians, emergency ward physicians, general cardiologists, internists, anaesthesiologists, and surgeons, to comply with the medical needs of this fast-growing population of LVAD-supported patients. The different issues discussed will follow the patient's pathway from the ambulance to the emergency department and from the emergency department to the internal or surgical wards and eventually to the discharge home from the hospital back to the general practitioner. In this first part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, after the introduction on the assist devices technology in general, definitions and structured approach to the assessment of the LVAD-supported patient in the ambulance and emergency department is presented including cardiopulmonary resuscitation for LVAD-supported patients.
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http://dx.doi.org/10.1002/ehf2.13588DOI Listing
September 2021

Treatment of Advanced Heart Failure-Focus on Transplantation and Durable Mechanical Circulatory Support: What Does the Future Hold?

Heart Fail Clin 2021 Oct;17(4):697-708

Department of Cardiology, University Hospital of Zürich, Rämistrasse 100, Zürich 8091, Switzerland.

Heart transplantation (HTx) is the treatment of choice in patients with late-stage advanced heart failure (Advanced HF). Survival rates 1, 5, and 10 years after transplantation are 87%, 77%, and 57%, respectively, and the average life expectancy is 9.16 years. However, because of the donor organ shortage, waiting times often exceed life expectancy, resulting in a waiting list mortality of around 20%. This review aims to provide an overview of current standard, recent advances, and future developments in the treatment of Advanced HF with a focus on long-term mechanical circulatory support and HTx.
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http://dx.doi.org/10.1016/j.hfc.2021.05.013DOI Listing
October 2021

Impact of epicardial adipose tissue on cardiovascular haemodynamics, metabolic profile, and prognosis in heart failure.

Eur J Heart Fail 2021 Aug 23. Epub 2021 Aug 23.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Aims: We evaluated the impact of echocardiographic epicardial adipose tissue (EAT) on cardiovascular haemodynamics, metabolic profile and prognosis in heart failure (HF) using combined cardiopulmonary-echocardiography exercise stress.

Methods And Results: We analysed EAT thickness of HF patients with reduced (HFrEF, n = 205) and preserved (HFpEF, n = 188) ejection fraction, including 44 controls. HFpEF patients displayed the highest EAT, while HFrEF patients had lower values than controls. EAT showed an inverse correlation with natriuretic peptides, troponin T and C-reactive protein in HFrEF, while having a direct association with troponin T and C-reactive protein in HFpEF. EAT was independently associated with peak oxygen consumption (VO ) and peripheral extraction (AVO diff), regardless of body mass index. EAT was inversely correlated with peak VO and AVO diff in HFpEF, while a direct association was observed in HFrEF, where lower EAT values were associated with worse left ventricular systolic dysfunction. In HFpEF, increased EAT was related to right ventriculo-arterial (tricuspid annular plane systolic excursion/systolic pulmonary artery pressure) uncoupling. After 21 months of follow-up, 146 HF hospitalizations and 34 cardiovascular deaths were recorded in the HF population. Cox multivariable analysis supported an independent differential role of EAT in HF cohorts (interaction P = 0.01): higher risk of adverse events for increasing EAT in HFpEF [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.37] and for decreasing EAT in HFrEF (HR 0.75, 95% CI 0.54-0.91).

Conclusion: In HFpEF, EAT accumulation is associated with worse haemodynamic and metabolic profile, also affecting survival. Conversely, lower EAT values imply higher left ventricular dysfunction, global functional impairment and adverse prognosis in HFrEF.
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http://dx.doi.org/10.1002/ejhf.2337DOI Listing
August 2021

Guidance on the management of left ventricular assist device (LVAD) supported patients for the non-LVAD specialist healthcare provider: executive summary.

Eur J Heart Fail 2021 Aug 18. Epub 2021 Aug 18.

Department of Cardiology, Ege University Hospital, Izmir, Turkey.

The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD supported patients. Device-related, and patient-device interaction complications impose a significant burden on the medical system exceeding the capacity of LVAD implanting centres. The probability of an LVAD supported patient presenting with medical emergency to a local ambulance team, emergency department medical team and internal or surgical wards in a non-LVAD implanting centre is increasing. The purpose of this paper is to supply the immediate tools needed by the non-LVAD specialized physician - ambulance clinicians, emergency ward physicians, general cardiologists, and internists - to comply with the medical needs of this fast-growing population of LVAD supported patients. The different issues discussed will follow the patient's pathway from the ambulance to the emergency department, and from the emergency department to the internal or surgical wards and eventually back to the general practitioner.
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http://dx.doi.org/10.1002/ejhf.2327DOI Listing
August 2021

Right ventricular only pacing for cardiac resynchronization therapy.

Europace 2021 Aug 14. Epub 2021 Aug 14.

Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1093/europace/euab145DOI Listing
August 2021

Impact of Atrial Fibrillation on Outcome in Takotsubo Syndrome: Data From the International Takotsubo Registry.

J Am Heart Assoc 2021 08 28;10(15):e014059. Epub 2021 Jul 28.

Department of Cardiology Intensive Care Medicine and Angiology Vincentius-Diakonissen-Hospital Karlsruhe Germany.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (<0.001), and there were fewer women (=0.046) in the AF than in the non-AF group. Left ventricular ejection fraction was significantly lower (=0.001), and cardiogenic shock was more often observed (<0.001) in the AF group. Both in-hospital (<0.001) and long-term mortality (<0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long-term mortality (hazard ratio, 2.31; 95% CI, 1.50-3.55; <0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in-hospital and long-term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in-hospital and long-term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01947621.
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http://dx.doi.org/10.1161/JAHA.119.014059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475688PMC
August 2021

The effect of intravenous ferric carboxymaltose on health-related quality of life in iron-deficient patients with acute heart failure: the results of the AFFIRM-AHF study.

Eur Heart J 2021 Jun 3. Epub 2021 Jun 3.

Robertson Center for Biostatistics, University of Glasgow, Boyd Orr Building University Avenue, Glasgow G12 8QQ, UK.

Aims: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population.

Methods And Results: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM.

Conclusion: In iron-deficient patients with HF and left ventricular ejection fraction ≤50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24.
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http://dx.doi.org/10.1093/eurheartj/ehab234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370759PMC
June 2021

TNF-α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm-ageing.

Eur J Clin Invest 2021 Nov 2;51(11):e13600. Epub 2021 Jun 2.

Center for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.

Aims: Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm-aging as a mediator and potential therapeutic target.

Methods: 3 months- (young) and 18-20 months-old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF-α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF- α were assessed in patients with ischemic stroke and correlated with age and outcome.

Results: Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood-brain barrier in old mice, i.e. increased post-stroke degradation of endothelial tight junctions and expression of tight junctions-digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF-α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF-α plasma levels which correlated with worsened short-term neurological outcome as well as with age.

Conclusions: This study identifies TNF-α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm-aging as a mechanism of age-related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.
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http://dx.doi.org/10.1111/eci.13600DOI Listing
November 2021

Optimized implementation of cardiac resynchronization therapy: a call for action for referral and optimization of care.

Europace 2021 08;23(8):1324-1342

Cardiologie, CHU Rennes - LTSI Inserm UMR 1099, Université Rennes-1, Rennes, France.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heart failure hospitalization rates and all-cause mortality. Nevertheless, up to two-thirds of eligible patients are not referred for CRT. Furthermore, post-implantation follow-up is often fragmented and suboptimal, hampering the potential maximal treatment effect. This joint position statement from three European Society of Cardiology Associations, Heart Failure Association (HFA), European Heart Rhythm Association (EHRA) and European Association of Cardiovascular Imaging (EACVI), focuses on optimized implementation of CRT. We offer theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on four actionable domains: (i) overcoming CRT under-utilization, (ii) better understanding of pre-implant characteristics, (iii) abandoning the term 'non-response' and replacing this by the concept of disease modification, and (iv) implementing a dedicated post-implant CRT care pathway.
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http://dx.doi.org/10.1093/europace/euaa411DOI Listing
August 2021

Improving 1-year mortality prediction in ACS patients using machine learning.

Eur Heart J Acute Cardiovasc Care 2021 May 20. Epub 2021 May 20.

Department of Cardiology, University Heart Center, University Hospital of Zurich, Switzerland.

Background: The Global Registry of Acute Coronary Events (GRACE) score is an established clinical risk stratification tool for patients with acute coronary syndromes (ACS). We developed and internally validated a model for 1-year all-cause mortality prediction in ACS patients.

Methods: Between 2009 and 2012, 2'168 ACS patients were enrolled into the Swiss SPUM-ACS Cohort. Biomarkers were determined in 1'892 patients and follow-up was achieved in 95.8% of patients. 1-year all-cause mortality was 4.3% (n = 80). In our analysis we consider all linear models using combinations of 8 out of 56 variables to predict 1-year all-cause mortality and to derive a variable ranking.

Results: 1.3% of 1'420'494'075 models outperformed the GRACE 2.0 Score. The SPUM-ACS Score includes age, plasma glucose, NT-proBNP, left ventricular ejection fraction (LVEF), Killip class, history of peripheral artery disease (PAD), malignancy, and cardio-pulmonary resuscitation. For predicting 1-year mortality after ACS, the SPUM-ACS Score outperformed the GRACE 2.0 Score which achieves a 5-fold cross-validated AUC of 0.81 (95% CI 0.78-0.84). Ranking individual features according to their importance across all multivariate models revealed age, trimethylamine N-oxide, creatinine, history of PAD or malignancy, LVEF, and haemoglobin as the most relevant variables for predicting 1-year mortality.

Conclusions: The variable ranking and the selection for the SPUM-ACS Score highlight the relevance of age, markers of heart failure, and comorbidities for prediction of all-cause death. Before application, this score needs to be externally validated and refined in larger cohorts.

Clinical Trial Registration: NCT01000701.
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http://dx.doi.org/10.1093/ehjacc/zuab030DOI Listing
May 2021

Ethnic comparison in takotsubo syndrome: novel insights from the International Takotsubo Registry.

Clin Res Cardiol 2021 May 19. Epub 2021 May 19.

Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Background: Ethnic disparities have been reported in cardiovascular disease. However, ethnic disparities in takotsubo syndrome (TTS) remain elusive. This study assessed differences in clinical characteristics between Japanese and European TTS patients and determined the impact of ethnicity on in-hospital outcomes.

Methods: TTS patients in Japan were enrolled from 10 hospitals and TTS patients in Europe were enrolled from 32 hospitals participating in the International Takotsubo Registry. Clinical characteristics and in-hospital outcomes were compared between Japanese and European patients.

Results: A total of 503 Japanese and 1670 European patients were included. Japanese patients were older (72.6 ± 11.4 years vs. 68.0 ± 12.0 years; p < 0.001) and more likely to be male (18.5 vs. 8.4%; p < 0.001) than European TTS patients. Physical triggering factors were more common (45.5 vs. 32.0%; p < 0.001), and emotional triggers less common (17.5 vs. 31.5%; p < 0.001), in Japanese patients than in European patients. Japanese patients were more likely to experience cardiogenic shock during the acute phase (15.5 vs. 9.0%; p < 0.001) and had a higher in-hospital mortality (8.2 vs. 3.2%; p < 0.001). However, ethnicity itself did not appear to have an impact on in-hospital mortality. Machine learning approach revealed that the presence of physical stressors was the most important prognostic factor in both Japanese and European TTS patients.

Conclusion: Differences in clinical characteristics and in-hospital outcomes between Japanese and European TTS patients exist. Ethnicity does not impact the outcome in TTS patients. The worse in-hospital outcome in Japanese patients, is mainly driven by the higher prevalence of physical triggers.

Trial Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01947621.
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http://dx.doi.org/10.1007/s00392-021-01857-4DOI Listing
May 2021

Secondary attack rates from asymptomatic and symptomatic influenza virus shedders in hospitals: Results from the TransFLUas influenza transmission study.

Infect Control Hosp Epidemiol 2021 May 6:1-7. Epub 2021 May 6.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital and University of Zurich, Zurich, Switzerland.

Objective: Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care.

Design: Prospective surveillance study during 2 influenza seasons.

Setting: Tertiary-care hospital.

Participants: Volunteer sample of inpatients on medical wards and healthcare workers (HCWs).

Methods: Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission.

Results: In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals.

Conclusions: Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.
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http://dx.doi.org/10.1017/ice.2021.112DOI Listing
May 2021

[The Role of Percutaneous Coronary Revascularization in Chronic Coronary Syndromes].

Praxis (Bern 1994) 2021 Apr;110(6):313-323

Klinik für Kardiologie, Universitäres Herzzentrum, Universitätsspital Zürich, Zürich.

The Role of Percutaneous Coronary Revascularization in Chronic Coronary Syndromes Coronary heart disease represents the leading cause of morbidity and mortality worldwide. Optimal management of these patients is therefore crucial and includes lifestyle changes, optimal medical therapy, and coronary revascularization. This review summarizes diagnostic and therapeutic strategies of patients with chronic coronary syndromes, focusing on the 2019 European Society of Cardiology (ESC) guidelines for the diagnosis and management of chronic coronary syndromes. In particular, the role of invasive assessment and coronary revascularization in chronic coronary syndromes is discussed.
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http://dx.doi.org/10.1024/1661-8157/a003648DOI Listing
April 2021

Multimodal Multiparametric Three-dimensional Image Fusion in Coronary Artery Disease: Combining the Best of Two Worlds.

Radiol Cardiothorac Imaging 2020 Apr 16;2(2):e190116. Epub 2020 Apr 16.

Institute of Diagnostic and Interventional Radiology (J.v.S., M.M., H.M., H.A., R.M.) and Department of Cardiology, University Heart Center (F.R., R.M.), University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland; Siemens Healthineers, Forchheim, Germany (C.S.); and Institute for Biomedical Engineering, ETH Zurich and University of Zurich, Zurich, Switzerland (J.v.S., S.K., R.M.).

Purpose: To allow for comprehensive noninvasive diagnostics of coronary artery disease (CAD) by using three-dimensional (3D) image fusion of CT coronary angiography, CT-derived fractional flow reserve (CT FFR), whole-heart dynamic 3D cardiac MRI perfusion, and 3D cardiac MRI late gadolinium enhancement (LGE).

Materials And Methods: Seventeen patients (54 years ± 10 [standard deviation], one female) who underwent cardiac CT and cardiac MRI were included (combined subcohort of three prospective trials). Software facilitating multimodal 3D image fusion was developed. Postprocessing of CT data included segmentation of the coronary tree and heart contours, calculation of CT FFR values, and color coding of the coronary tree according to CT FFR. Postprocessing of cardiac MRI data included segmentation of the left ventricle (LV) in cardiac MRI perfusion and cardiac MRI LGE, co-registration of cardiac MRI to CT data, and projection of cardiac MRI perfusion and LGE values onto the high spatial resolution LV from CT.

Results: Image quality was rated as good to excellent (scores: 2.5-2.6; 3 = excellent). CT coronary angiography revealed significant stenoses in seven of 17 cases (41%). CT FFR was possible in 16 of 17 cases (94%) and showed pathologic flow in seven of 17 cases (41%), six of which coincided with cases revealing significant stenoses at CT coronary angiography. Cardiac MRI perfusion identified eight of 17 patients (47%) with hypoperfusion (ischemic burden of 17% ± 5). Cardiac MRI LGE showed myocardial scar in three of 17 cases (18%, scar burden of 7% ± 4). Conventional two-dimensional readout of CT coronary angiography and cardiac MRI resulted in eight of 17 cases (47%) with uncertain findings. Most of these divergent findings could be solved when adding information from CT FFR and 3D image fusion (six of eight, 75%).

Conclusion: Multimodal 3D cardiac image fusion is feasible and may help with comprehensive noninvasive CAD diagnostics.© RSNA, 2020.
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http://dx.doi.org/10.1148/ryct.2020190116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977970PMC
April 2020

The management of secondary mitral regurgitation in patients with heart failure: a joint position statement from the Heart Failure Association (HFA), European Association of Cardiovascular Imaging (EACVI), European Heart Rhythm Association (EHRA), and European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Eur Heart J 2021 Mar 18. Epub 2021 Mar 18.

Department of Cardiology, Inselspital, University of Bern, Bern, Switzerland.

Secondary (or functional) mitral regurgitation (SMR) occurs frequently in chronic heart failure (HF) with reduced left ventricular (LV) ejection fraction, resulting from LV remodelling that prevents coaptation of the valve leaflets. Secondary mitral regurgitation contributes to progression of the symptoms and signs of HF and confers worse prognosis. The management of HF patients with SMR is complex and requires timely referral to a multidisciplinary Heart Team. Optimization of pharmacological and device therapy according to guideline recommendations is crucial. Further management requires careful clinical and imaging assessment, addressing the anatomical and functional features of the mitral valve and left ventricle, overall HF status, and relevant comorbidities. Evidence concerning surgical correction of SMR is sparse and it is doubtful whether this approach improves prognosis. Transcatheter repair has emerged as a promising alternative, but the conflicting results of current randomized trials require careful interpretation. This collaborative position statement, developed by four key associations of the European Society of Cardiology-the Heart Failure Association (HFA), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Association of Cardiovascular Imaging (EACVI), and European Heart Rhythm Association (EHRA)-presents an updated practical approach to the evaluation and management of patients with HF and SMR based upon a Heart Team approach.
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http://dx.doi.org/10.1093/eurheartj/ehab086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014526PMC
March 2021

Prognostic impact of acute pulmonary triggers in patients with takotsubo syndrome: new insights from the International Takotsubo Registry.

ESC Heart Fail 2021 06 13;8(3):1924-1932. Epub 2021 Mar 13.

Department of Cardiology, Charité, Campus Rudolf Virchow, Berlin, Germany.

Aims: Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes.

Methods And Results: Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33-3.38; P = 0.002).

Conclusions: The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.
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http://dx.doi.org/10.1002/ehf2.13165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120351PMC
June 2021

Protective effects of SGLT-2 inhibitors across the cardiorenal continuum: two faces of the same coin.

Eur J Prev Cardiol 2021 Feb 28. Epub 2021 Feb 28.

Cardiology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

The cardiovascular and renal systems are closely interconnected in health and disease. Disorders affecting one of these systems frequently involve the other. Both diseases progress through a continuous chain of events, defined as the 'cardiorenal continuum', which is initiated by risk factors that lead to subclinical disease, clinical events, and ultimately to heart failure and end-stage kidney disease. Previous studies have shown that interventions anywhere along this chain of events can interrupt the pathophysiological cascade and provide cardiovascular and/or kidney 'protection'. More recently, clinical trials with SGLT-2 inhibitors (SGLT2i) have shown a significant reduction in cardiovascular and kidney outcomes. Evidence from EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, VERTIS-CV, CREDENCE, and more recently DAPA-HF, EMPEROR-Reduced, and DAPA-CKD show that the beneficial effects of SGLT2i are observed across all stages of the cardiorenal continuum, ranging from patients with diabetes and multiple risk factors to those with established cardiovascular disease and even independently of diabetes status. This review provides a critical appraisal of the efficacy and safety of SGLT2i, demonstrating that this is a novel way to disrupt the chain of pathological events in the cardiorenal continuum and prevent cardiovascular and kidney disease in patients with and without diabetes.
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http://dx.doi.org/10.1093/eurjpc/zwab034DOI Listing
February 2021

Prognostic value of inflammatory biomarkers and GRACE score for cardiac death and acute kidney injury after acute coronary syndromes.

Eur Heart J Acute Cardiovasc Care 2021 May;10(4):445-452

Department of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.

Aims : The aim of this study was to analyse the role of inflammation and established clinical scores in predicting acute kidney injury (AKI) after acute coronary syndromes (ACS).

Methods And Results : In a prospective multicentre cohort including 2034 patients with ACS undergoing percutaneous coronary intervention, high-sensitivity C-reactive protein (hsCRP), neutrophil count, neutrophil-to-lymphocyte ratio (NL-ratio), and creatinine were measured at the index procedure. AKI (n = 39, defined according to RIFLE criteria) and major cardiovascular and cerebrovascular events were adjudicated after 1 year. Associations between inflammation, AKI, and cardiac death (CD) were assessed by C-statistics and Cox proportional hazard models with log-rank test to compare survival. Patients with ACS with elevated neutrophil count >7.8 × 109/L, NL-ratio >5, combined neutrophil-count/creatinine, or NL-ratio/creatinine at baseline showed a higher incidence of AKI (all P < 0.05) and CD (all P < 0.001). The risk of AKI, CD, and their combination was increased in patients with higher neutrophil count/creatinine (heart rate (HR) = 3.7, 95% cardiac index (CI) 1.9-7.1; HR = 2.7, 95% CI 1.6-4.6; HR = 3.2, 95% CI 2.1-4.9); NL-ratio/creatinine (HR = 2.1, 95% CI 1.6-4.1; HR = 2.2, 95% CI 1.3-3.8; HR = 2.3, 95% CI 1.5-3.5); and hsCRP (HR = 1.8, 95% CI 0.9-3.5; HR = 2.2, 95% CI 1.3-3.6; HR = 1.9, 95% CI 1.2-2.8) after adjustment for age, diabetes, hypertension, previous heart failure, kidney function, haemodynamic instability at admission, statin, and renin-angiotensin-aldosterone antagonists use. Subjects with higher GRACE score 1.0/NL-ratio had higher rate of AKI, CD, and both (HR = 1.4, 95% CI 0.5-4.2; HR = 2.7, 95% CI 1.3-5.9; HR = 2.1, 95% CI 1-4.3).

Conclusions : Inflammation markers may predict AKI after correction for renal function at the index procedure. hsCRP performed better than the NL-ratio. However, the integration of inflammation markers to traditional risk factors or scores does not add prognostic information.

Trial Registration : ClinicalTrials.gov, NCT01000701.
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http://dx.doi.org/10.1093/ehjacc/zuab003DOI Listing
May 2021

The FAST-FURO study: effect of very early administration of intravenous furosemide in the prehospital setting to patients with acute heart failure attending the emergency department.

Eur Heart J Acute Cardiovasc Care 2021 Jun;10(5):487-496

The GREAT (Global REsearch in Acute cardiovascular conditions Team) Network, Madrid, Spain.

Aims: The effect of early administration of intravenous (IV) furosemide in the emergency department (ED) on short-term outcomes of acute heart failure (AHF) patients remains controversial, with one recent Japanese study reporting a decrease of in-hospital mortality and one Korean study reporting a lack of clinical benefit. Both studies excluded patients receiving prehospital IV furosemide and only included patients requiring hospitalization. To assess the impact on short-term outcomes of early IV furosemide administration by emergency medical services (EMS) before patient arrival to the ED.

Methods And Results: In a secondary analysis of the Epidemiology of Acute Heart Failure in Emergency Departments (EAHFE) registry of consecutive AHF patients admitted to Spanish EDs, patients treated with IV furosemide at the ED were classified according to whether they received IV furosemide from the EMS (FAST-FURO group) or not (CONTROL group). In-hospital all-cause mortality, 30-day all-cause mortality, and prolonged hospitalization (>10 days) were assessed. We included 12 595 patients (FAST-FURO = 683; CONTROL = 11 912): 968 died during index hospitalization [7.7%; FAST-FURO = 10.3% vs. CONTROL = 7.5%; odds ratio (OR) = 1.403, 95% confidence interval (95% CI) = 1.085-1.813; P = 0.009], 1269 died during the first 30 days (10.2%; FAST-FURO = 13.4% vs. CONTROL = 9.9%; OR = 1.403, 95% CI = 1.146-1.764; P = 0.004), and 2844 had prolonged hospitalization (22.8%; FAST-FURO = 25.8% vs. CONTROL = 22.6%; OR = 1.189, 95% CI = 0.995-1.419; P = 0.056). FAST-FURO group patients had more diabetes mellitus, ischaemic cardiomyopathy, peripheral artery disease, left ventricular systolic dysfunction, and severe decompensations, and had a better New York Heart Association class and had less atrial fibrillation. After adjusting for these significant differences, early IV furosemide resulted in no impact on short-term outcomes: OR = 1.080 (95% CI = 0.817-1.427) for in-hospital mortality, OR = 1.086 (95% CI = 0.845-1.396) for 30-day mortality, and OR = 1.095 (95% CI = 0.915-1.312) for prolonged hospitalization. Several sensitivity analyses, including analysis of 599 pairs of patients matched by propensity score, showed consistent findings.

Conclusion: Early IV furosemide during the prehospital phase was administered to the sickest patients, was not associated with changes in short-term mortality or length of hospitalization after adjustment for several confounders.
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http://dx.doi.org/10.1093/ehjacc/zuaa042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245147PMC
June 2021

Exercise intolerance - from spiroergometry to transdiaphragmatic myocardial punch biopsy: a case report of isolated cardiac sarcoidosis.

Eur Heart J Case Rep 2021 Jan 4;5(1):ytaa121. Epub 2021 Jan 4.

Department of Cardiology, University Heart Centre, University Hospital Zurich, Zurich, Switzerland.

Background: Several aetiologies account for exercise intolerance, with cardiac sarcoidosis (CS) constituting a rare cause thereof. The pathogenesis of CS is still unresolved and its diagnosis still difficult to establish, in the absence of any extracardiac manifestations in particular.

Case Summary: A 49-year-old amateur athlete presented with exercise intolerance during running over a 3-week period. Coronary artery and structural lung disease were excluded by coronary angiography and computer tomography. The symptoms could be reproduced during spiroergometry during which an exercise-induced high-degree atrioventricular (AV) block was documented. During electrocardiographic monitoring, a 2:1 AV block was observed. Different imaging modalities showed inferobasal septal inflammation and fibrosis. Transthoracic and transoesophageal echocardiography-guided endomyocardial biopsies were inconclusive and only subsequent epicardial biopsy performed by transdiaphragmatic minimally invasive surgery lead to the histological diagnosis of non-caseating granuloma, confirming CS. The patient was treated with high-dose steroids 1 week after implantation of a primary prevention dual-chamber implantable cardioverter-defibrillator (ICD). While tapering steroids, recurrence of myocardial inflammation occurred. However, no tachytherapies and <0.1% right ventricular pacing were needed after 2 years of follow-up.

Discussion: Differential diagnoses were either an infiltrative disease, a tumour, or an infectious disease. Due to the different treatment options, we had to establish definite diagnosis by myocardial biopsy. Retrospectively, the implantation of the ICD can be discussed. However, cardiac magnetic resonance imaging showed fibrosis which is usually irreversible and substrate for potentially lethal ventricular arrhythmia. Confirming the diagnosis of isolated CS is challenging. Long-term management should be guided individually based on clinical and imaging findings.
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http://dx.doi.org/10.1093/ehjcr/ytaa121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850611PMC
January 2021

Optimized Implementation of cardiac resynchronization therapy - a call for action for referral and optimization of care.

Europace 2021 Feb 5. Epub 2021 Feb 5.

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction and leads to improved quality of life, reductions in heartfailure hospitalization rates and reduces all-cause mortality. Nevertheless, up to two-thirds ofeligible patients are not referred for CRT. Furthermore, post implantation follow-up is oftenfragmented and suboptimal, hampering the potential maximal treatment effect. This jointposition statement from three ESC Associations, HFA, EHRA and EACVI focuses onoptimized implementation of CRT. We offer theoretical and practical strategies to achievemore comprehensive CRT referral and post-procedural care by focusing on four actionabledomains; (I) overcoming CRT under-utilization, (II) better understanding of pre-implantcharacteristics, (III) abandoning the term 'non-response' and replacing this by the concept ofdisease modification, and (IV) implementing a dedicated post-implant CRT care pathway.
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http://dx.doi.org/10.1093/europace/euab035DOI Listing
February 2021

TNFα induces endothelial dysfunction in rheumatoid arthritis via LOX-1 and arginase 2: reversal by monoclonal TNFα antibodies.

Cardiovasc Res 2021 Jan 23. Epub 2021 Jan 23.

Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Switzerland.

Aims: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and blood vessels. Despite low levels of low-density lipoprotein cholesterol (LDL-C), RA patients exhibit endothelial dysfunction and are at increased risk of death from cardiovascular (CV) complications, but the molecular mechanism of action is unknown.We aimed in the present study to identify the molecular mechanism of endothelial dysfunction in a mouse model of RA and in patients with RA.

Methods And Results: Endothelium-dependent relaxations to acetylcholine were reduced in aortae of two TNFα transgenic mouse lines with either mild (Tg3647) or severe (Tg197) forms of RA in a time- and severity-dependent fashion as assessed by organ chamber myograph. In Tg197, TNFα plasma levels were associated with severe endothelial dysfunction. LOX-1 receptor was markedly upregulated leading to increased vascular oxLDL uptake and NFκB-mediated enhanced Arg2 expression via direct binding to its promoter resulting in reduced NO bioavailability and vascular cGMP levels as shown by ELISA and chromatin immunoprecipitation. Anti-TNFα treatment with infliximab normalized endothelial function together with LOX-1 and Arg2 serum levels in mice. In RA patients, soluble LOX-1 serum levels were also markedly increased and closely related to serum levels of C-reactive protein. Similarly, ARG2 serum levels were increased. Similarly, anti-TNFα treatment restored LOX-1 and ARG2 serum levels in RA patients.

Conclusions: Increased TNFα levels not only contribute to RA, but also to endothelial dysfunction by increasing vascular oxLDL content and activation of the LOX-1/NFκB/Arg2 pathway leading to reduced NO bioavailability and decreased cGMP levels. Anti-TNFα treatment improved both articular symptoms and endothelial function by reducing LOX-1, vascular oxLDL and Arg2 levels.
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http://dx.doi.org/10.1093/cvr/cvab005DOI Listing
January 2021

Acute heart and brain failure: a case report.

Eur Heart J Case Rep 2020 Dec 29;4(6):1-8. Epub 2020 Nov 29.

Department of Cardiology, University Heart Center Zurich, University Hospital Zurich, Raemistrasse 100, 8006 Zurich, Switzerland.

Background: Takotsubo syndrome (TTS) is characterized by often reversible but acute heart failure occurring after an emotional or physical trigger event. The 'brain failure' counterpart is posterior reversible encephalopathy syndrome (PRES) characterized by often reversible but acute neurological symptoms. This case report elaborates on a complex clinical scenario with co-existence of coronary artery disease, TTS and PRES and discusses the pathophysiology, differential diagnosis, and management.

Case Summary: An 82-year-old woman presented with acute heart failure and generalized tonic-clonic seizures following an acute exacerbation of her chronic back pain. Brain magnetic resonance imaging demonstrated vasogenic oedema consistent with the diagnosis of PRES. Focal wall motion abnormalities on echocardiography without causal coronary stenoses on angiography were consistent with the diagnosis of TTS. After an interdisciplinary approach to differential diagnosis and treatment, the patient was discharged to geriatric rehabilitation without heart failure or neurological defects 4 weeks later.

Discussion: TTS and PRES share significant similarities in proposed pathogenesis, epidemiology, management, and clinical outcome. This case report highlights the need for early recognition of this rare association and multidisciplinary approach to diagnosis and treatment as both heart and brain disease may require early intervention up to rapid intensive care support.
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http://dx.doi.org/10.1093/ehjcr/ytaa352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793236PMC
December 2020

SARS-CoV-2 leads to a small vessel endotheliitis in the heart.

EBioMedicine 2021 Jan 7;63:103182. Epub 2021 Jan 7.

Department of Pathology and Molecular Pathology, University Hospital Zürich, University of Zurich, Schmelzbergstrasse 12., Zurich CH-8091, Switzerland. Electronic address:

Background: SARS-CoV-2 infection (COVID-19 disease) can induce systemic vascular involvement contributing to morbidity and mortality. SARS-CoV-2 targets epithelial and endothelial cells through the ACE2 receptor. The anatomical involvement of the coronary tree is not explored yet.

Methods: Cardiac autopsy tissue of the entire coronary tree (main coronary arteries, epicardial arterioles/venules, epicardial capillaries) and epicardial nerves were analyzed in COVID-19 patients (n = 6). All anatomical regions were immunohistochemically tested for ACE2, TMPRSS2, CD147, CD45, CD3, CD4, CD8, CD68 and IL-6. COVID-19 negative patients with cardiovascular disease (n = 3) and influenza A (n = 6) served as controls.

Findings: COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction.

Interpretation: ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19.

Funding: No external funding was necessary for this study.
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http://dx.doi.org/10.1016/j.ebiom.2020.103182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808909PMC
January 2021
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