Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial.

AIM: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients. METHODS AND RESULTS: In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated. CONCLUSION: In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.

Early-stage health technology assessment of fractional flow reserve coronary computed tomography versus standard diagnostics in patients with stable chest pain in The Netherlands.

OBJECTIVES: The aim of this early-stage Health Technology Assessment (HTA) was to assess the difference in healthcare costs and effects of fractional flow reserve derived from coronary computed tomography (FFRct) compared to standard diagnostics in patients with stable chest pain in The Netherlands. METHODS: A decision-tree model was developed to assess the difference in total costs from the hospital perspective, probability of correct diagnoses, and risk of major adverse cardiovascular events at one year follow-up. One-way sensitivity analyses were conducted to determine the main drivers of the cost difference between the strategies. A threshold analysis on the added price of FFRct analysis (computational analysis only) was conducted. RESULTS: The mean one-year costs were €2,680 per patient for FFRct and €2,915 per patient for standard diagnostics. The one-year probability of correct diagnoses was 0.78 and 0.61, and the probability of major adverse cardiovascular events was 1.92x10-5 and 0.01, respectively. The probability and costs of revascularization and the specificity of coronary computed tomography angiography had the greatest effect on the difference in costs between the strategies. The added price of FFRct analysis should be below €935 per patient to be considered the least costly option. CONCLUSIONS: The early-stage HTA findings suggest that FFRct may reduce total healthcare spending, probability of incorrect diagnoses, and major adverse cardiovascular events compared to current diagnostics for patients with stable chest pain in the Dutch healthcare setting over one year. Future cost-effectiveness studies should determine a value-based pricing for FFRct and quantify the economic value of the anticipated therapeutic impact.

Correction: van Veelen et al. First-in-Human Drug-Eluting Balloon Treatment of Vulnerable Lipid-Rich Plaques: Rationale and Design of the DEBuT-LRP Study. J. Clin. Med. 2023, 12, 5807.

In the original publication [...].

Aortic disease in patients with Marfan syndrome: aortic volume assessment for surveillance.

PURPOSE: To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome. MATERIALS AND METHODS: The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated. RESULTS: Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13). CONCLUSION: Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1.

Clinical features differ substantially between Caucasian and Asian populations of Marfan syndrome.

BACKGROUND: Prevention of aortic dissection and sudden death in patients with Marfan syndrome (MFS) requires accurate diagnosis. MFS is diagnosed by the Ghent criteria, which are primarily based on clinical features of Caucasian MFS populations. We determined whether the Ghent criteria apply to Asian MFS populations. METHODS AND RESULTS: In this multicenter study, we included 255 adult MFS patients according to the Ghent criteria of 2010. Patients were excluded if they were neither Caucasian nor Asian. The Asian MFS population (n=49) had a smaller body surface area (BSA: 1.8 m² vs. 2.0 m², P<0.001), a more severely affected aortic root (absolute aortic diameter: 42.9 mm vs. 43.3mm, P=0.802; corrected for BSA: 24.9 mm vs. 21.7 mm, P<0.001; Z-score: 4.5 vs. 3.6, P=0.013), and more often a positive systemic score (75.5% vs. 60.0%, P=0.045), but less frequently ectopia lentis (24.5% vs. 48.1%, P=0.004) compared with the Caucasian population (n=206). CONCLUSIONS: The Ghent criteria do not necessarily apply to Asian MFS populations, resulting in a more severely affected cardiovascular system. This may be related to under diagnosis of MFS by multiple factors, including the use of Z-score, and genetic and racial differences. The Ghent criteria should be adapted for Asian populations in order to accurately diagnose MFS.

One-year follow-up of patients treated with single antiplatelet therapy directly after percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome.

Graphical AbstractClinical outcomes and treatment adherence during 12 months follow-up. *Second bleeding event in same patient. PCI, percutaneous coronary intervention; TVR, target vessel revascularization.

First-in-Human Drug-Eluting Balloon Treatment of Vulnerable Lipid-Rich Plaques: Rationale and Design of the DEBuT-LRP Study.

Patients with non-obstructive lipid-rich plaques (LRPs) on combined intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) are at high risk for future events. Local pre-emptive percutaneous treatment of LRPs with a paclitaxel-eluting drug-coated balloon (PE-DCB) may be a novel therapeutic strategy to prevent future adverse coronary events without leaving behind permanent coronary implants. In this pilot study, we aim to investigate the safety and feasibility of pre-emptive treatment with a PE-DCB of non-culprit non-obstructive LRPs by evaluating the change in maximum lipid core burden in a 4 mm segment (maxLCBImm4) after 9 months of follow up. Therefore, patients with non-ST-segment elevation acute coronary syndrome underwent 3-vessel IVUS-NIRS after treatment of the culprit lesion to identify additional non-obstructive non-culprit LRPs, which were subsequently treated with PE-DCB sized 1:1 to the lumen. We enrolled 45 patients of whom 20 patients (44%) with a non-culprit LRP were treated with PE-DCB. After 9 months, repeat coronary angiography with IVUS-NIRS will be performed. The primary endpoint at 9 months is the change in maxLCBImm4 in PE-DCB-treated LRPs. Secondary endpoints include clinical adverse events and IVUS-derived parameters such as plaque burden and luminal area. Clinical follow-up will continue until 1 year after enrollment. In conclusion, this first-in-human study will investigate the safety and feasibility of targeted pre-emptive PE-DCB treatment of LRPs to promote stabilization of vulnerable coronary plaque at risk for developing future adverse events.

Single antiplatelet therapy directly after percutaneous coronary intervention in non-ST-segment elevation acute coronary syndrome patients: the OPTICA study.

BACKGROUND: Early P2Y12 inhibitor monotherapy has emerged as a promising alternative to 12 months of dual antiplatelet therapy following percutaneous coronary intervention (PCI). AIMS: In this single-arm pilot study, we evaluated the feasibility and safety of ticagrelor or prasugrel monotherapy directly following PCI in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Patients received a loading dose of ticagrelor or prasugrel before undergoing platelet function testing and subsequent PCI using new-generation drug-eluting stents. The stent result was adjudicated with optical coherence tomography in the first 35 patients. Ticagrelor or prasugrel monotherapy was continued for 12 months. The primary ischaemic endpoint was the composite of all-cause mortality, myocardial infarction, definite or probable stent thrombosis or stroke within 6 months. The primary bleeding endpoint was Bleeding Academic Research Consortium type 2, 3 or 5 bleeding within 6 months. RESULTS: From March 2021 to March 2022, 125 patients were enrolled, of whom 75 ultimately met all in- and exclusion criteria (mean age 64.5 years, 29.3% women). Overall, 70 out of 75 (93.3%) patients were treated with ticagrelor or prasugrel monotherapy directly following PCI. The primary ischaemic endpoint occurred in 3 (4.0%) patients within 6 months. No cases of stent thrombosis or spontaneous myocardial infarction occurred. The primary bleeding endpoint occurred in 7 (9.3%) patients within 6 months. CONCLUSIONS: This study provides first-in-human evidence that P2Y12 inhibitor monotherapy directly following PCI for NSTE-ACS is feasible, without any overt safety concerns, and highlights the need for randomised controlled trials comparing direct P2Y12 inhibitor monotherapy with the current standard of care.

P2Y12-inhibitor monotherapy after coronary stenting: are all P2Y12-inhibitors equal?

INTRODUCTION: P2Y12-inhibitor monotherapy following 1-3 months of dual antiplatelet therapy (DAPT) reduces (major) bleeding without an apparent increase in ischemic events and has therefore emerged as an alternative to 6-12 months of DAPT following percutaneous coronary intervention (PCI). However, there are important differences between the available P2Y12-inhibitors (clopidogrel, prasugrel, and ticagrelor) as agents of choice for P2Y12-inhibitor monotherapy. AREAS COVERED: This review critically appraises the evidence for P2Y12-inhibitor monotherapy after PCI using either clopidogrel, prasugrel, or ticagrelor. Furthermore, we discuss ongoing trials and future directions for research. EXPERT OPINION: P2Y12-inhibitor monotherapy following 1-3 months of DAPT is an alternative to 6-12 months of DAPT following PCI. Ticagrelor may be considered the current preferred option due to its reliable effect on platelet reactivity and its predominant use in clinical trials. Prasugrel could serve as a useful substitute for those not tolerating ticagrelor, but more research into prasugrel monotherapy is warranted. Alternatively, clopidogrel can be used, although there are concerns of high platelet reactivity, especially when genotyping and/or platelet function testing are not used. Future research will need to address the minimal duration of DAPT before switching to P2Y12-inhibitor monotherapy and what the optimal antithrombotic therapy beyond 12 months is.

Spontaneous hypothermia on intensive care unit admission is a predictor of unfavorable neurological outcome in patients after resuscitation: an observational cohort study.

INTRODUCTION: A large number of patients resuscitated for primary cardiac arrest arrive in the intensive care unit (ICU) with a body temperature < 35.0 degrees C. The aim of this observational cohort study was to determine the association between ICU admission temperature and neurological outcome in this patient group. METHODS: Demographics and parameters influencing neurological outcome were retrieved from the charts of all patients resuscitated for primary cardiac arrest and treated with induced mild hypothermia in our ICU from January 2006 until January 2008. Patients were divided into two groups according to their body temperature on ICU admission: a hypothermia group (< 35.0 degrees C) and a non-hypothermia group (>or=35.0 degrees C). Neurological outcome after six months was assessed by means of the Glasgow Outcome Score (GOS), with GOS 1 to 3 defined as unfavorable and GOS 4 to 5 as favorable. A logistic regression model was used to analyze the influence of the different parameters on neurological outcome. RESULTS: The data of 105 consecutive patients resuscitated for primary cardiac arrest and treated with induced mild hypothermia were analyzed. Median ICU admission temperature was 35.1 degrees C (interquartile range (IQR) 34.3 to 35.7). After six months, 61% of the patients had an unfavorable outcome (59% died and 2% were severely disabled), whereas 39% had a favorable outcome (moderate disability or good recovery). Among patients with spontaneous hypothermia on ICU admission, the percentage with unfavorable outcome was higher (69% versus 50%, P = 0.05). Logistic regression showed that age, acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores and spontaneous hypothermia on ICU admission all had an increased odds ratio (OR) for an unfavorable outcome after six months. Spontaneous hypothermia had the strongest association with unfavorable outcome (OR 2.6, 95% CI (confidence interval) 1.1 to 5.9), which became even stronger after adjustment for age, presenting heart rhythm, APACHE II and SOFA scores (OR 3.8, CI 1.3 to 11.0). CONCLUSIONS: In this observational cohort study, spontaneous hypothermia on ICU admission was the strongest predictor of an unfavorable neurological outcome in patients resuscitated for primary cardiac arrest.

The risk for type B aortic dissection in Marfan syndrome.

BACKGROUND: Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome. OBJECTIVES: The purpose of this study was to identify clinical parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome. METHODS: Patients with the diagnosis of Marfan syndrome and magnetic resonance imaging or computed tomographic imaging of the aorta were followed for a median of 6 years for the occurrence of type B dissection or the combined end point of type B aortic dissection, distal aortic surgery, and death. A model using various clinical parameters as well as genotyping was developed to predict the risk for type B dissection in patients with Marfan syndrome. RESULTS: Between 1998 and 2013, 54 type B aortic dissections occurred in 600 patients with Marfan syndrome (mean age 36 ± 14 years, 52% male). Independent variables associated with type B aortic dissection were prior prophylactic aortic surgery (hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.8; p = 0.010) and a proximal descending aorta diameter ≥27 mm (hazard ratio: 2.2; 95% confidence interval: 1.1 to 4.3; p = 0.020). In the risk model, the 10-year occurrence of type B aortic dissection in low-, moderate-, and high-risk patients was 6%, 19%, and 34%, respectively. Angiotensin II receptor blocker therapy was associated with fewer type B aortic dissections (hazard ratio: 0.3; 95% confidence interval: 0.1 to 0.9; p = 0.030). CONCLUSIONS: Patients with Marfan syndrome with prior prophylactic aortic surgery are at substantial risk for type B aortic dissection, even when the descending aorta is only slightly dilated. Angiotensin II receptor blocker therapy may be protective in the prevention of type B aortic dissections.

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

BACKGROUND: It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups. METHODS AND RESULTS: In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197). CONCLUSIONS: Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423.

No beneficial effect of general and specific anti-inflammatory therapies on aortic dilatation in Marfan mice.

AIMS: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1(C1039G/+) Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan. METHODS AND RESULTS: To inhibit inflammation in FBN1(C1039G/+) Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor), methylprednisolone (corticosteroid) or abatacept (T-cell-specific inhibitor). Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-ß) signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage. CONCLUSION: Anti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling.

Circulating transforming growth factor-ß as a prognostic biomarker in Marfan syndrome.

BACKGROUND: Patients with Marfan syndrome (MFS) are at risk for cardiovascular disease. Marfan associated mutations in the FBN1 gene lead to increased transforming growth factor-ß (TGF-ß) activation. The aim of this study was to investigate the role of plasma TGF-ß as a biomarker for progressive aortic root dilatation and dissection. METHODS: Plasma TGF-ß level and aortic root diameter by means of echocardiography were assessed in 99 MFS patients. After 38 months of follow-up measurement of the aortic root was repeated and individual aortic root growth curves were constructed. Clinical events were evaluated. The primary composite endpoint was defined as aortic dissection and prophylactic aortic root replacement. RESULTS: TGF-ß levels were higher in MFS patients as compared to healthy controls (109 pg/ml versus 54 pg/ml, p<0.001). Higher plasma TGF-ß levels correlated with larger aortic root dimensions (r=0.26, p=0.027), previous aortic root surgery (161 pg/ml versus 88 pg/ml, p=0.007) and faster aortic root growth rate (r=0.42, p<0.001). During 38 months of follow-up, 17 events were observed (four type B dissections and 13 aortic root replacements). Patients with TGF-ß levels above 140 pg/ml had a 6.5 times higher risk of experiencing the composite endpoint compared to patients with TGF-ß levels below 140 pg/ml (95% CI: 2.1 to 20.1, p=0.001) with 65% sensitivity and 78% specificity. CONCLUSION: Elevated TGF-ß level in patients with Marfan syndrome is correlated with larger aortic root diameters and faster aortic root growth. Level of plasma TGF-ß predicts cardiovascular events and might serve as a prognostic biomarker in MFS.

Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome.

INTRODUCTION: Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations. Therapeutic strategies, such as prophylactic aortic root surgery and pharmacological therapy, focus on the prevention of aortic dissection. Currently, the standard medicinal treatments targeting aortic dilatation and dissection consist of agents generally used to lower blood pressure and/or the inotropic state of the heart. By these means, the cyclic repetitive forces exerted on the aortic wall are diminished and thus the onset of aortic dilatation is potentially prevented. Although these pharmacological agents may offer some benefit in reduction of aortic aneurysm expansion rate, they do not target the underlying cause of the progressive aortic degradation. AREAS COVERED: This review discusses the effectiveness of frequently prescribed medications used to prevent and delay aortic complications in Marfan syndrome. New insights on the biochemical pathways leading to aortic disease are also discussed to highlight new targets for pharmacological therapy. EXPERT OPINION: Recent insights in the transforming growth factor beta signaling pathway and inflammatory mechanisms in a well-established mouse model of Marfan syndrome, have led to studies exploring new pharmacological treatment strategies with doxycycline, statins and angiotensin II receptor blockers. Pharmacological therapy is focused more on prevention than on delay of aortic wall pathology in Marfan syndrome. Of the new pharmacological treatment strategies targeting aortic pathology in Marfan syndrome, angiotensin receptor type 1 blockers are promising candidates, with several clinical trials currently ongoing.

The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest.

INTRODUCTION: Treatment with hypothermia has been shown to improve outcome after cardiac arrest (CA). Current consensus is to rewarm at 0.25-0.5 °C/h and avoid fever. The aim of this study was to investigate whether active rewarming, the rate of rewarming or development of fever after treatment with hypothermia after CA was correlated with poor outcome. METHODS: This retrospective cohort study included adult patients treated with hypothermia after CA and admitted to the intensive care unit between January 2006 and January 2009. The average rewarming rate from end of hypothermia treatment (passive rewarming) or start active rewarming until 36 °C was dichotomized in a high (≥ 0.5 °C/h) or normal rate (<0.5 °C/h). Fever was defined as >38 °C within 72 h after admission. Poor outcome was defined as death, vegetative state, or severe disability after 6 months. RESULTS: From 128 included patients, 56% had a poor outcome. Actively rewarmed patients (38%) had a higher risk for poor outcome, OR 2.14 (1.01-4.57), p<0.05. However, this effect disappeared after adjustment for the confounders age and initial rhythm, OR 1.51 (0.64-3.58). A poor outcome was found in 15/21 patients (71%) with a high rewarming rate, compared to 54/103 patients (52%) with a normal rewarming rate, OR 2.61 (0.88-7.73), p = 0.08. Fever was not associated with outcome, OR 0.64 (0.31-1.30), p = 0.22. CONCLUSIONS: This study showed that patients who needed active rewarming after therapeutic hypothermia after CA did not have a higher risk for a poor outcome. In addition, neither speed of rewarming, nor development of fever had an effect on outcome.