Nitrous oxide abuse leading to extreme homocysteine levels and thrombosis in young adults: a case series.

BACKGROUND: Neurologic complications from recreational use of nitrous oxide (N2O), which are attributed to vitamin B12 deficiency, have been well documented. With increasing dosages and frequency of N2O use, an additional association with thromboembolisms is becoming apparent. OBJECTIVES: To assess thrombotic complications of recreational N2O use. METHODS: All medical charts at the largest hospital in Amsterdam were searched for N2O use and subsequent neurologic and/or thrombotic events. For patients with thrombotic events, we extracted data on the risk factors for arterial and venous thrombosis as well as serum vitamin B12 and homocysteine concentrations. RESULTS: Between January 2015 and May 2021, 326 patients who reported recreational use of N2O were identified; of these, 17 (5%) patients presented with severe thrombotic events associated with N2O (71% men; median age, 26 years [range, 18-53 years]), 5 patients presented with arterial thrombosis (3 with acute coronary syndrome, 1 with femoral artery thrombosis, and 1 with middle cerebral artery thrombus), and 12 patients presented with venous thromboembolisms (10 with pulmonary embolisms, 1 with portal vein thrombosis and 1 with cerebral vein thrombosis). Additionally, homocysteine were concentrations severely increased (median, 125 µmol/L [range, 22-253 µmol/L]; reference, <15 µmol/L). Patients reported use of 400 to 6000 g (ie, 50-750 balloons) of N2O in 1 day. Fifty percent of these patients had experienced neurologic symptoms before the thrombotic event. CONCLUSION: We describe an alarming incidence of serious thrombotic events among young adults after excessive recreational use of N2O, accompanied by extremely high homocysteine concentrations. The upward trend in the recreational use of N2O warrants more awareness of its dangers among both users and medical professionals. Furthermore, these findings could reopen the discussion on possible associations between hyperhomocysteinemia and thrombosis mediated through N2O.

Thrombosis within the left anterior descending coronary artery and left ventricle after high-dose nitrous oxide use.

We present a man in his 30s with acute anterior myocardial infarction due to thrombotic occlusion of the left anterior descending artery and subsequent left ventricular thrombus formation after high-dose recreational use of nitrous oxide (N2O). Initial questioning for use of illicit substances was negative, but low vitamin B12 levels and severely elevated homocysteine levels prompted us to interrogate for the use of laughing gas. On questioning, the patient admitted to have used this substance, which he presumed to be innocent. Neither percutaneous coronary intervention with balloon dilatation nor intravenous glycoprotein IIb/IIIa receptor antagonist, nor continuous use of anticoagulation and double antiplatelet therapy resulted in thrombus resolution. Due to a severely reduced left ventricular function, despite 3 months on heart failure therapy, the patient is being counselled for intracardiac defibrillator implantation. We conclude that N2O, notably when consumed in conjunction with other proatherogenic substances, is associated with thrombosis: a relation possibly mediated by severe hyperhomocysteinaemia.

Cardiac arrest resulting from an unidentified foreign object, later identified as a balloon cover, within the left anterior descending coronary artery.

A 31-year-old man with a history of hypertrophic cardiomyopathy and alcohol septal ablation one week before was presented after an out of hospital cardiac arrest in the setting of an anterior wall ST-elevation myocardial infarction. Immediate coronary angiography showed an unidentified foreign object within the left anterior descending coronary artery (LAD), later identified as the cover of a balloon that had been unintentionally inserted and abandoned within the LAD during the alcohol septum ablation one week earlier. Intracoronary imaging confirmed the presence of endothelial damage and thrombus formation within the LAD explaining acute myocardial infarction. The patient was treated by surgical retrieval of the balloon cover, extended septal myectomy and coronary artery bypass grafting (CABG) of the LAD. This case is both an example of unintentional neglect of unexpected objects, and the importance of multimodality imaging and multidisciplinary teamwork to get to a correct diagnosis and treatment.

Essential Thrombocytosis in Patients <40 Years Old With Acute Coronary Syndromes: A Not So Uncommon Underlying Diagnosis Often Overlooked.

BACKGROUND: In patients under <40 years, traditional cardiovascular (CV)-risk factors are a less likely cause of acute coronary syndromes (ACS) compared to older counterparts. AIMS: To estimate the prevalence of essential thrombocytosis (ET), a hematological disorder and less-prevalent risk factor, in young patients presenting with ACS. METHODS: We constructed a retrospective database of all patients <40 years (n=271) that had consecutively undergone coronary angiography (CAG) after their first ACS within our hospital within the last ten years (2010-2020) and had known thrombocyte counts (n=241). Patients with thrombocytes >450x10*9/L were screened for this hematological disorder. RESULTS: In our database, we identified 15 subjects with thrombocytosis. One was previously known as ET. Of the remaining 14 patients, five were considered reactive/secondary thrombocytosis, and four were lost to follow-up, four were eventually diagnosed with ET, one remains uncertain. The diagnosis was newly established before the initiation of this study in two patients (average delay: six years). Two patients were identified as a result of this study.  Conclusion: With a prevalence of at least 2.1%, ET appears not uncommon in patients <40 years with ACS. Moreover, screening patients with ACS and elevated thrombocytes yielded a novel diagnosis of ET in 27% of patients. The diagnosis was initially missed in all cases. Since the timing of revascularization should be adjusted to thrombocyte count/initiation of ET therapy to prevent thrombotic complications, cardiologists should know, recognize and screen for this pathology in ACS-patients, notably in those with absent traditional CV-risk factors: an 'ACS-protocol' aimed at less-prevalent risk factors could support this.

Non-bacterial thrombotic endocarditis manifested by ventricular fibrillation in a patient with low grade ovarian carcinoma: case report and literature review.

BACKGROUND: Non-bacterial thrombotic endocarditis (NBTE) is a rare form of endocarditis notably described in patients with advanced malignancy and auto-immune diseases. It is characterized by the formation of sterile, fibrin-containing vegetations on cardiac endothelium, in the absence of positive blood cultures. It is predominantly located on the mitral- and aortic valve (AV). Vegetations in NBTE are prone to embolize. Trousseau syndrome (TS) is defined as unexplained thrombotic events that precede the diagnosis of malignancy. CASE SUMMARY: A 49-year-old pre-menopausal woman with a history of visual disturbances, recurrent deep vein thrombosis (DVT) with concurrent pulmonary emboli (PE), and uterine myomas with dysfunctional uterine bleeding was resuscitated for ventricular fibrillation. While echocardiography revealed vegetations on the AV, blood cultures remained negative. Additional work-up for the aetiology of sterile vegetations revealed a low-grade ovarian carcinoma. Cardiac analysis showed evidence of myocardial infarction in the absence of coronary atherosclerosis as a cause for ventricular fibrillation. DISCUSSION: Unexplained thrombotic events (venous, arterial, or both) warrant further investigation, e.g., with regard to TS. NBTE is a potential source of thromboembolism in TS and a rare ante-mortem finding, which prompts additional investigation of the underlying cause. In our patient, a triad of (suspected) (i) arterial/systemic embolization (i.e. visual disturbances, splenic infarction, coronary embolism), (ii) peripheral thrombophlebitis/hypercoagulability (i.e. DVT and PE), and (iii) malignancy (i.e. gynaecological abnormalities) raised suspicion of NBTE in the setting of TS. Early diagnosis and treatment of NBTE is of importance due to the high incidence of embolization, with possible fatal outcome.

[Thromboembolisms due to recreational use of nitrous oxide]. / Trombo-embolieën door recreatief lachgasgebruik.

Nitrous oxide (N2O) is increasingly used as a recreational drug, and is presumed relatively safe and innocent. The risks for neurological complications are often known, however the risks of serious thromboembolic events are not. We describe three cases of acute thromboembolic events resulting in serious cardiovascular complications after N2O abuse: one case of myocardial infarction that resulted in a reduced ejection fraction, one case of peripheral arterial occlusion that led to limb amputation and one case of pulmonary embolism that resulted in hemodynamic instability requiring extracorporeal membrane oxygenation (ECMO) and surgical removal. All patients were young adults with a low cardiovascular risk profile. N2O inactivates vitamin B12, leading to vitamin B12 deficiency and subsequent to hyperhomocysteinemia, which is associated with the formation of fibrinolysis-resistant blood thrombi. In conclusion, we contest the safety and innocence of recreational N2O (ab)use. Our three cases illustrate that, next to previously described neurological complications, the use of nitrous oxide is associated with thromboembolic cardiovascular complications, presumably mediated by hyperhomocysteinemia.

Cardiovascular complications of Streptococcus pneumoniae bacteraemia.

The incidence of Streptococcus pneumoniae bacteraemia has risen due to a worldwide increase in immunocompromised patients and antibiotic resistance. We describe three patients who experienced severe, including cardiovascular, complications of pneumococcal bacteraemia. Cardiovascular complications related to pneumococci may run a fulminant course. However, some of these life-threatening complications (eg, endocarditis and aortitis) may long remain unnoticed or be misdiagnosed and therefore delay correct treatment. We review the literature with regards to the incidence, diagnosis and treatment of these rare but possibly lethal and hence important cardiovascular complications.

Transulnar coronary intervention complicated by compartment syndrome.

We describe a case of a compartment syndrome after transulnar coronary intervention. As far as we are aware of, this is the first report of such a complication after a transulnar approach described in the literature. Compartment syndrome is a very rare but possibly devastating complication of coronary angiography and percutaneous coronary interventions. We retrospectively observed an incidence rate of 0.007% after 13,948 coronary angiographies or 0.013% after 7532 interventions performed through the wrist in our centre in the last 5 years. Rapid recognition and treatment of this rare complication may prevent long-term morbidity and are thus of utmost importance. General measures should be taken to reduce this incidence of this serious complication.

Case report of an acute myocardial infarction after high-dose recreational nitrous oxide use: a consequence of hyperhomocysteinaemia?

BACKGROUND: Nitrous oxide (N2O, laughing gas) is increasingly used as a recreational drug and is presumed relatively safe and innocent. It is often being used in combination with other substances, such as cannabis. CASE SUMMARY: A young adult attended the emergency room because of chest pain after recreational use of very high-dose nitrous oxide in combination with cannabis. Electrocardiography demonstrated ST-elevation in the anterior leads. Coronary angiography showed thrombus in the proximal and thrombotic occlusion of the distal left anterior descending coronary artery for which primary percutaneous coronary intervention was attempted. Thrombus aspiration was unsuccessful and the patient was further treated with a glycoprotein IIb/IIIa in addition to dual platelet therapy. Blood results showed low vitamin B12 and folic acid status with concomitant hyperhomocysteinaemia, a known cause of hypercoagulation. Transthoracic echocardiogram showed a moderately reduced left ventricular ejection fraction (LVEF). Three months later, an improvement in LVEF and no recurrent angina or symptoms of heart failure were noticed. DISCUSSION: We report a case of acute myocardial infarction secondary to very high-dose nitrous oxide abuse in combination with cannabis and possible hypoxia. We propose that severe hyperhomocysteinaemia secondary to nitrous oxide-induced vitamin B12 deficiency together with the vasoconstrictive effects of cannabis might pose a seriously increased risk for intracoronary, among others, thrombus formation. In conclusion, we contest the safety and innocence of recreational nitrous oxide (ab)use, notably in the context of other factors increasing the risk of coagulation.

A Perforated Mitral Valve Aneurysm: A Rare but Serious Complication of Aortic Valve Endocarditis Resulting From a Regurgitant Jet Lesion.

Infective endocarditis has high morbidity and mortality rates. The aortic valve is most often affected in native valve endocarditis. Complications of aortic valve endocarditis range from local abscess and fistula formation, systemic complications secondary to thromboembolism and septic embolization, to congestive heart failure resulting from conduction system involvement and valve damage. A rare complication of aortic valve endocarditis is the occurrence of a 'jet lesion' on the mitral valve. Such a lesion, caused by an impinging regurgitant jet stream from a damaged aortic valve, can become directly and indirectly inoculated and evolve into a local infected aneurysm which might eventually rupture causing acute severe congestive heart failure and/or peripheral thromboembolism. We present the case of a 63-year-old man who presented with aortic valve endocarditis complicated by a perforated mitral valve aneurysm, congestive heart failure, and peripheral thromboembolism.

Rupturing Abdominal Aneurysm Presenting as Acute Coronary Syndrome.

A 61-year-old male presented to the emergency ward with pain in his upper abdomen. Due to an abnormal electrocardiogram (ECG) and elevated cardiac enzymes the cardiologist was consulted to exclude cardiac pathology. The consulting cardiologist advised to exclude an abdominal diagnosis before treating the condition as an acute coronary syndrome (ACS). Before noninvasive imaging had been performed, the clinical situation deteriorated and an emergency laparotomy revealed a ruptured aortic aneurysm. Despite immediate revascularization multiple organ failure ensued and the patient died a few days later. This case illustrates that the suspicion of ACS should never delay the investigation of other life-threatening disorders. Contrarily angina, ECG abnormalities, and myocardial ischemia are all well known to concur with major vascular, intra-abdominal, intra-cranial, and pulmonary pathology; hence these other life-threatening conditions should always be considered and preferably be ruled out prior to further investigation and treatment of ACS.

Case report of a 'snake thrombus' in the right heart: a rare finding on echocardiography.

BACKGROUND: A right heart thrombus originating from an inferior vena cava thrombosis (IVCT) is a rare entity. In accordance with venous thromboembolism (VTE), IVCT can be categorized as primary or secondary. Secondary ICVT can be the result of a predisposing hypercoagulable state and/or from external compression on the inferior vena cava (IVC) such as in case of malignancies. Renal cell carcinoma (RCC), amongst others, has been described in the context of secondary IVCT. CASE SUMMARY: An 80-year-old man was presented in our emergency department with complaints of dyspnoea and oedema. Echocardiography revealed a large snake-like thrombus in the IVC extending into the right atrium. Subsequent computed tomography resulted in a diagnosis of an RCC. The patient was considered to be in too poor clinical condition for surgical removal. In the next days, his condition deteriorated, after which palliative care was initiated and the patient deceased at day 12 of admission. CONCLUSION: A right heart thrombus is a rare finding during echocardiography. This case demonstrates an incidental finding of a 'snake thrombus' in the IVC and right heart secondary to RCC. This case illustrates the importance and additional value of echocardiography in the setting of suspected right-sided heart failure.

NewProt - a protein engineering portal.

The NewProt protein engineering portal is a one-stop-shop for in silico protein engineering. It gives access to a large number of servers that compute a wide variety of protein structure characteristics supporting work on the modification of proteins through the introduction of (multiple) point mutations. The results can be inspected through multiple visualizers. The HOPE software is included to indicate mutations with possible undesired side effects. The Hotspot Wizard software is embedded for the design of mutations that modify a proteins' activity, specificity, or stability. The NewProt portal is freely accessible at http://newprot.cmbi.umcn.nl/ and http://newprot.fluidops.net/.

CorNet: Assigning function to networks of co-evolving residues by automated literature mining.

CorNet is a web-based tool for the analysis of co-evolving residue positions in protein super-family sequence alignments. CorNet projects external information such as mutation data extracted from literature on interactively displayed groups of co-evolving residue positions to shed light on the functions associated with these groups and the residues in them. We used CorNet to analyse six enzyme super-families and found that groups of strongly co-evolving residues tend to consist of residues involved in a same function such as activity, specificity, co-factor binding, or enantioselectivity. This finding allows to assign a function to residues for which no data is available yet in the literature. A mutant library was designed to mutate residues observed in a group of co-evolving residues predicted to be involved in enantioselectivity, but for which no literature data is available yet. The resulting set of mutations indeed showed many instances of increased enantioselectivity.

A fish is not a fish: patterns in fatty acid composition of aquatic food may have had implications for hominin evolution.

From c. 2 Ma (millions of years ago) onwards, hominin brain size and cognition increased in an unprecedented fashion. The exploitation of high-quality food resources, notably from aquatic ecosystems, may have been a facilitator or driver of this phenomenon. The aim of this study is to contribute to the ongoing debate on the possible role of aquatic resources in hominin evolution by providing a more detailed nutritional context. So far, the debate has focused on the relative importance of terrestrial versus aquatic resources while no distinction has been made between different types of aquatic resources. Here we show that Indian Ocean reef fish and eastern African lake fish yield on average similarly high amounts of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA). Hence a shift from exploiting tropical marine to freshwater ecosystems (or vice versa) would entail no material difference in dietary long-chain polyunsaturated fatty acid (LC-PUFA) availability. However, a shift to marine ecosystems would likely mean a major increase in access to brain-selective micronutrients such as iodine. Fatty fish from marine temperate/cold waters yield twice as much DHA and four times as much EPA as tropical fish, demonstrating that a latitudinal shift in exploitation of African coastal ecosystems could constitute a significant difference in LC-PUFA availability with possible implications for brain development and functioning. We conclude that exploitation of aquatic food resources could have facilitated the initial moderate hominin brain increase as observed in fossils dated to c. 2 Ma, but not the exceptional brain increase in later stages of hominin evolution. We propose that the significant expansion in hominin brain size and cognition later on may have been aided by strong directional selecting forces such as runaway sexual selection of intelligence, and nutritionally supported by exploitation of high-quality food resources in stable and productive aquatic ecosystems.

Saturated fatty acid (SFA) status and SFA intake exhibit different relations with serum total cholesterol and lipoprotein cholesterol: a mechanistic explanation centered around lifestyle-induced low-grade inflammation.

We investigated the relations between fatty acid status and serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol and total cholesterol/HDL cholesterol ratio in five Tanzanian ethnic groups and one Dutch group. Total cholesterol/HDL cholesterol ratio is a widely used coronary artery disease (CAD) risk factor. Fatty acid status was determined by measurement of fatty acids in serum cholesterol esters and erythrocytes. Data reflecting the influence of fatty acid intakes on serum total cholesterol and lipoprotein cholesterol were obtained from documented intervention studies. We found that 14:0, 16:0 and saturated fatty acid (SFA) status correlates positively with total cholesterol/HDL cholesterol ratio, while their intakes were unrelated. Linoleic acid and polyunsaturated fatty acid (PUFA) status and PUFA intake exhibited negative relations with the total cholesterol/HDL cholesterol ratio. These data suggest that a high SFA status, not a high SFA intake, is associated with increased CAD risk, while both high linoleic acid status and PUFA status are associated with reduced CAD risk. Consequently, the total cholesterol/HDL cholesterol ratio is a questionable risk marker since meta-analyses of randomized controlled trials show that partial dietary replacement of SFA for linoleic acid, the dominating dietary PUFA, does not change CAD risk. We conclude that many lifestyle factors, not SFA intake alone, determine SFA status, and suggest that interaction with many other lifestyle factors determines whether SFA status has a relevant contributing effect in low-grade inflammation, lipoprotein changes and CAD risk. The present outcome may teach us to consider the health effects of the entire diet together with many nondietary lifestyle factors, opposite to the reductionist approach of studying the effects of single nutrients, SFA and PUFA included.

DHA status is positively related to motor development in breastfed African and Dutch infants.

OBJECTIVES: Docosahexaenoic (DHA) and arachidonic (AA) acids are important for neurodevelopment. We investigated the relation between erythrocyte (RBC) DHA and AA contents and neurological development, by assessment of General Movements (GMs), in populations with substantial differences in fish intakes. METHODS: We included 3-month-old breastfed infants of three Tanzanian tribes: Maasai (low fish, n = 5), Pare (intermediate fish, n = 32), and Sengerema (high fish, n = 60); and a Dutch population (low-intermediate, fish, n = 15). GMs were assessed by motor optimality score (MOS) and the number of observed movement patterns (OMP; an MOS sub-score). RBC-DHA and AA contents were determined by capillary gas chromatography. RESULTS: We found no between-population differences in MOS. OMP of Sengerema infants (high fish) was higher than OMP of Dutch infants (low-intermediate fish). MOS related to age. OMP related positively to infant age (P < 0.001) and RBC-DHA (P = 0.015), and was unrelated to ethnicity and RBC-AA. DISCUSSION: The positive relation between RBC-DHA and the number of observed movement patterns of 3-month old infants might reflect the connection of DHA with motor development.

Interrelationships between maternal DHA in erythrocytes, milk and adipose tissue. Is 1 wt% DHA the optimal human milk content? Data from four Tanzanian tribes differing in lifetime stable intakes of fish.

Little is known about the interrelationships between maternal and infant erythrocyte-DHA, milk-DHA and maternal adipose tissue (AT)-DHA contents. We studied these relationships in four tribes in Tanzania (Maasai, Pare, Sengerema and Ukerewe) differing in their lifetime intakes of fish. Cross-sectional samples were collected at delivery and after 3 d and 3 months of exclusive breast-feeding. We found that intra-uterine biomagnification is a sign of low maternal DHA status, that genuine biomagnification occurs during lactation, that lactating mothers with low DHA status cannot augment their infants' DHA status, and that lactating mothers lose DHA independent of their DHA status. A maternal erythrocyte-DHA content of 8 wt% was found to correspond with a mature milk-DHA content of 1·0 wt% and with subcutaneous and abdominal (omentum) AT-DHA contents of about 0·39 and 0·52 wt%, respectively. Consequently, 1 wt% DHA might be a target for Western human milk and infant formula that has milk arachidonic acid, EPA and linoleic acid contents of 0·55, 0·22 and 9·32 wt%, respectively. With increasing DHA status, the erythrocyte-DHA content reaches a plateau of about 9 wt%, and it plateaus more readily than milk-DHA and AT-DHA contents. Compared with the average Tanzanian-Ukerewe woman, the average US woman has four times lower AT-DHA content (0·4 v. 0·1 wt%) and five times lower mature milk-DHA output (301 v. 60 mg/d), which contrasts with her estimated 1·8-2·6 times lower mobilisable AT-DHA content (19 v. 35-50 g).