Takotsubo syndrome: getting closer to its causes.

Takotsubo syndrome (TTS) accounts for between 1 and 4% of cases presenting clinically as an acute coronary syndrome. It typically presents as a transient cardiac phenotype of left ventricular dysfunction with spontaneous recovery. More dramatic presentations may include cardiogenic shock or cardiac arrest. Despite progress in the understanding of the condition since its first description in 1990, considerable questions remain into understanding underlying pathomechanisms. In this review article, we describe the current published data on potential underlying mechanisms associated with the onset of TTS including sympathetic nervous system over-stimulation, structural and functional alterations in the central nervous system, catecholamine secretion, alterations in the balance and distribution of adrenergic receptors, the additive impact of hormones including oestrogen, epicardial coronary or microvascular spasm, endothelial dysfunction, and genetics as potentially contributing to the cascade of events leading to the onset. These pathomechanisms provide suggestions for novel potential therapeutic strategies in patients with TTS including the role of cognitive behavioural therapy, beta-blockers, and endothelin-A antagonists. The underlying mechanism of TTS remains elusive. In reality, physical or emotional stressors likely trigger through the amygdala and hippocampus a central neurohumoral activation with the local and systemic secretion of excess catecholamine and other neurohormones, which exert its effect on the myocardium through a metabolic switch, altered cellular signalling, and endothelial dysfunction. These complex pathways exert a regional activation in the myocardium through the altered distribution of adrenoceptors and density of autonomic innervation as a protective mechanism from myocardial apoptosis. More research is needed to understand how these different complex mechanisms interact with each other to bring on the TTS phenotype.

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the TTN Gene.

BACKGROUND: Truncating variants in the TTN gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers. METHODS: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%). RESULTS: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; P=0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; P=0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; P<0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (P=0.07). CONCLUSIONS: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.

Hidden in Heart Failure.

Current diagnostic strategies fail to illuminate the presence of rare disease in the heart failure population. One-third of heart failure patients are categorised as suffering an idiopathic dilated cardiomyopathy, while others are labelled only as heart failure with preserved ejection fraction. Those affected frequently suffer from delays in diagnosis, which can have a significant impact on quality of life and prognosis. Traditional rhetoric argues that delineation of this patient population is superfluous to treatment, as elucidation of aetiology will not lead to a deviation from standard management protocols. This article emphasises the importance of identifying genetic, inflammatory and infiltrative causes of heart failure to enable patients to access tailored management strategies.

Effectiveness of the 2014 European Society of Cardiology guideline on sudden cardiac death in hypertrophic cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: In 2014, the European Society of Cardiology (ESC) recommended the use of a novel risk prediction model (HCM Risk-SCD) to guide use of implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We sought to determine the performance of HCM Risk-SCD by conducting a systematic review and meta-analysis of articles reporting on the prevalence of SCD within 5 years of evaluation in low, intermediate and high-risk patients as defined by the 2014 guidelines (predicted risk <4%, 4%-<6% and ≥6%, respectively). METHODS: The protocol was registered with PROSPERO (registration number: CRD42017064203). MEDLINE and manual searches for papers published from October 2014 to December 2017 were performed. Longitudinal, observational cohorts of unselected adult patients, without history of cardiac arrest were considered. The original HCM Risk-SCD development study was included a priori. Data were pooled using a random effects model. RESULTS: Six (0.9%) out of 653 independent publications identified by the initial search were included. The calculated 5-year risk of SCD was reported in 7291 individuals (70% low, 15% intermediate; 15% high risk) with 184 (2.5%) SCD endpoints within 5 years of baseline evaluation. Most SCD endpoints (68%) occurred in patients with an estimated 5-year risk of ≥4% who formed 30% of the total study cohort. Using the random effects method, the pooled prevalence of SCD endpoints was 1.01% (95% CI 0.52 to 1.61) in low-risk patients, 2.43% (95% CI 1.23 to 3.92) in intermediate and 8.4% (95% CI 6.68 to 10.25) in high-risk patients. CONCLUSIONS: This meta-analysis demonstrates that HCM Risk-SCD provides accurate risk estimations that can be used to guide ICD therapy in accordance with the 2014 ESC guidelines. REGISTRATION NUMBER: PROSPERO CRD42017064203;Pre-results.

Percutaneous extraction of an embolized progesterone contraceptive implant from the pulmonary artery.

The Nexplanon® implant is a commonly used radiopaque contraceptive device that contains progestogen associated with an ethylene vinyl-acetate copolymer resulting in a slow release of the active hormonal ingredient. It is inserted into the subdermal connective tissue and provides contraceptive efficacy for up to 3 years. Device removal for clinical, personal or device "end-of-life span" reasons is straightforward. In rare cases, implant migration can occur locally within centimeters of the insertion site. Distant device embolization is extremely rare and can result in complications including chest pain, dyspnoea, pneumothorax and thrombosis or prevent conception until the active ingredient is depleted. We present one such case, where a Nexplanon® implant embolized into the pulmonary artery of a young female patient. We describe the initial "missed" diagnosis of embolized device on a chest radiograph and subsequent successful percutaneous removal once distant embolization was diagnosed.

Percutaneous balloon aortic valvuloplasty in the era of transcatheter aortic valve implantation: a narrative review.

The role of percutaneous balloon aortic valvuloplasty (BAV) in the management of severe symptomatic aortic stenosis has come under the spotlight following the development of the transcatheter aortic valve implantation (TAVI) technique. Previous indications for BAV were limited to symptom palliation and as a bridge to definitive therapy for patients undergoing conventional surgical aortic valve replacement (AVR). In the TAVI era, BAV may also be undertaken to assess the 'therapeutic response' of a reduction in aortic gradient in borderline patients often with multiple comorbidities, to assess symptomatic improvement prior to consideration of definitive TAVI intervention. This narrative review aims to update the reader on the current indications and practical techniques involved in undertaking a BAV procedure. In addition, a summary of the haemodynamic and clinical outcomes, as well as the frequently encountered procedural complications is presented for BAV procedures conducted during both the pre-TAVI and post-TAVI era.

The failing heart: a bad case of the 'flu'.

A 24-year-old Nepali man presented to hospital with a short history of feeling unwell with a flu-like illness. He subsequently went into acute renal failure requiring several sessions of renal replacement therapy by haemofiltration. The underlying aetiology of his renal failure was unclear. His renal function recovered following haemofiltration and he was discharged home with a plan for outpatient follow-up and investigations. He re-presented to hospital 6 days later with severe fluid overload. Echocardiogram was suggestive of impaired left ventricular systolic function; subsequent cardiac MRI confirmed this and was indicative of a dilated cardiomyopathy. A diagnosis of dilated cardiomyopathy with cardiorenal syndrome was made, most likely secondary to viral myocarditis in view of his initial presentation. He was diuresed and treated with prognostic medications for heart failure. His symptoms resolved and on subsequent outpatient review he was feeling well.

Ulcerative colitis: a case of steroid refractory disease.

A 21-year-old lady was admitted to a hospital with an 8-week history of bloody diarrhoea. She had been diagnosed with ulcerative colitis 2 years previously and had remained in remission until the gradual onset of bloody diarrhoea. Her bowel frequency was 20 times per day and associated with significant abdominal pain and weight loss. She was started on intravenous steroids, topical therapy and anti-tumour necrosis factor therapy; however, this failed to achieve symptom control. Histology of tissue obtained from flexible sigmoidoscopy eventually demonstrated cytomegalovirus (CMV)-associated colitis. Intravenous anti-viral valganciclovir was initiated and the patient made a rapid recovery. This case discusses the differentials for steroid-refractory ulcerative colitis, including the common pitfall of inflammatory bowel disease management and CMV infection. This case also discusses CMV pathophysiology including histological features, appropriate investigations and current management guidelines.

Interstitial keratitis and sensorineural hearing loss as a manifestation of rheumatoid arthritis: clinical lessons from a rare complication.

Cogan's syndrome or non-syphilitic interstitial keratitis with vestibule-auditory dysfunction is a serious and under-recognised complication of rheumatoid arthritis. It is an autoimmune condition characterised by inflammatory infiltrates on the cornea and extensive vestibulocochlear damage. If left untreated, patients progress to develop profound hearing loss. We present a case that was incorrectly diagnosed and treated as conjunctivitis by several emergency departments prior to being correctly recognised as Cogan's syndrome.

Ganfort, a blinding drug to the physician.

Ganfort eye drops are indicated for adult patients with open-angle glaucoma who have poor response to topical ß-blockers or prostaglandin analogues. They contain 0.3 mg of bimatoprost (a prostaglandin) and 5 mg of timolol (ß-blocker). The authors present a case of a 45-year-old man with glaucoma presenting with shortness of breath. On admission, he had a normal heart rate, pulse oximetry and examination. Despite being of low risk stratification using the Wells score and the Modified Geneva Score for pulmonary emboli, CT pulmonary angiogram scan subsequently showed extensive bilateral multiple large pulmonary emboli. This case demonstrates that the systemic absorption of ocular ß blockers is extremely high and it bypasses the first pass metabolism. Therefore, even one drop of Ganfort into each eye once a day was sufficient to disguise the tachycardia of a large pulmonary emboli.

Diaphoresis and abdominal pain caused by extra-adrenal paragangliomas.

A 63-year-old lady presented with suprapelvic pain, weight loss and night sweats. On examination, she was noted to be hypertensive with a distended abdomen. Imaging (CT) revealed a 9.5 cm retroperitoneal mass with a high degree of vascularity and necrotic centre. The patient's urinary and plasma catecholamines were significantly raised and subsequent radio-isotope scan suggested the tumour was likely to be of a neuroendocrine nature. A diagnosis of a malignant paraganglioma was made. Malignant paragangliomas derive from sympathetic tissue and secrete catecholamines. Diagnostic uncertainty might lead to biopsy of tumour but this carries a high-risk of catecholamine-induced complications such as hypertensive crisis, cardiac arrhythmias and cardiac ischaemia and must be avoided.

An unusual cause of blackout with transient loss of consciousness: Prinzmetal angina.

The authors present the case of a 61-year-old woman who was troubled by regular episodes of throat discomfort, headache, dyspnoea and tingling sensation in the upper limbs. These were associated with occasional episodes of transient loss of consciousness accompanied by urinary incontinence over a period of 5 years. As these episodes became increasingly frequent, she was referred to a neurologist. Initial neurological assessment and investigations had a negative diagnostic yield and she was therefore referred for cardiac review. A repeat 24 h Holter revealed intermittent episodes of significant ST-segment elevation associated with a Mobitz type II atrio-ventricular block correlating with her symptoms. Her echocardiography and coronary angiography were normal; hence a diagnosis of Prinzmetal angina was made. She was treated appropriately with nitrates and a calcium channel blocker and followed up in cardiology clinic with no further recurrence of symptoms.

Managing unstable angina and non-ST elevation MI.

Acute coronary syndrome (ACS), encompassing unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI), is often the result of an acute thrombotic occlusion of the coronary vessels, associated with atheromatous plaque rupture or erosion. ACS is associated with a severely impaired prognosis and requires prompt and efficient specialist treatment. The clinical presentation may be identical across all three components of ACS. Establishing an accurate diagnosis without delay is of paramount importance to start treatment promptly. Patients with suspected ACS need to be referred immediately to A&E. Prehospital treatment, which includes aspirin, nitrates, morphine and oxygen (if hypoxic), should be initiated rapidly. Important features pointing towards a diagnosis of ACS include: typical characteristics of chest pain, presence of risk factors, and ECG changes suggestive of myocardial ischaemia. Chest discomfort in patients with ACS typically occurs at rest, is anginal in character and can range from mild tightness to central crushing chest pain. It may be associated with nausea, dyspnoea or diaphoresis. The chest pain may radiate to the arms, back or jaw and is often >20 minutes in duration. An accurate clinical history and a detailed examination are vital. Initial investigations are the same for all ACS events, with the need for urgent serial ECGs and the measurement of cardiac troponin levels, to assess myocardial damage. In NSTEMI, ECG changes suggestive of ischaemia are often present and associated with elevated cardiac troponin. In UA, there is a considerable reduction in myocardial perfusion leading to symptoms; but there is no rise in cardiac troponin. Risk stratification is imperative in assessment of ACS to allow efficient delivery of specialist care. Treatment includes: antiplatelets; antithrombotic agents; angina drugs; analgesia, and PCI.