Adverse events and drug-drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure.

INTRODUCTION: Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. AREAS COVERED: Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. EXPERT OPINION: Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.

Cannabidiol's impact on drug-metabolization.

IMPORTANCE: Products containing cannabidiol(CBD) are easily accessible. CBD is reported to inhibit the drug-metabolizing proteins(DMP) Cytochrome P450(CYP)3A4/5, CYP2C9, CYP2B6, CYP2D6, CYP2E1, CYP1A2, CYP2C19, carboxylesterase 1(CES1), uridine 5'diphospho-glucoronosyltransferase(UGT)1A9, UGT2B7, P-glycoprotein(P-gp) and Breast Cancer Resistance Protein(BCRP). The relevance of CBD-drug interactions is largely unknown. Aim of the study was to identify drugs, potentially interacting with orally ingested CBD, to assess whether CBD-drug interactions have been reported, and if substrates of DMP are frequently prescribed drugs. OBSERVATIONS: Identified were 403 drugs as substrates of DMP. CBD-drug interactions were reported for 53/403 substrates in humans (n = 25), in vivo (n = 13) or in vitro (n = 15). In 31/53 substrates, CBD induced an increase, in 1/53 a decrease, in 4/53 no change in the substrate level. For 5/53 substrates, the results were controversial, and in 12/53 no substrate levels were reported. Among the 30 most frequently prescribed drugs in Germany were 67% substrates of DMP and among the 50 most frequently prescribed drugs in the USA 68%. RELEVANCE AND CONCLUSIONS: There is an urgent need for pharmacologic studies on CBD-drug interactions. Patients should be educated on the potential risk and awareness should be increased among physicians. Regulatory authorities should become aware of the problem and start an initiative on an international level to increase the safety of CBD.

Surgical Transmitral Thrombectomy to Prevent Recurrent Stroke in Acute Myocardial Infarction.

Left ventricular (LV)-thrombi occur in up to 14 % of patients with acute myocardial infarction (AMI) in the era of primary percutaneous coronary intervention. For these patients, anticoagulant therapy (AC) is recommended by AMI-guidelines. When, despite AC, LV-thrombi lead to embolism, surgical thrombectomy is an option, which is not mentioned or not recommended in AMI-guidelines. We report a 46-year old female patient with AMI. An 80 % stenosis of the proximal left anterior descending coronary artery was treated by a drug-eluting stent. Thrombi within the akinetic LV-apex became mobile despite AC and dual antiplatelet therapy, and a cerebellar stroke occurred. By a transmitral surgical approach with endoscopic assistance the thrombi were completely removed. Postoperative course and 12-months follow-up were uneventful. LV-thrombi should be observed carefully regarding changes in morphology. Surgical thrombectomy of LV-thrombi is a rare treatment option to prevent imminent embolism. Benefits versus risks of surgical removal of LV-thrombi need to be carefully weighted.

Aortic root replacement for aortic root aneurysm with severe aortic regurgitation and incidentally detected left ventricular hyper-trabeculation/noncompaction.

A 54-year-old male with severe aortic regurgitation (AR), aortic root aneurysm, left ventricular hyper-trabeculation/noncompaction (LVHT) and systolic dysfunction with a left ventricular ejection fraction (LVEF) of 52% underwent successful aortic root replacement. Intraoperative video-endoscopy confirmed LVHT. At 3-year follow-up, he remains in an excellent clinical condition and echocardiography shows an improvement of the systolic function, LVHT and LVEF of 66%. Timely surgical correction of severe AR may also lead to improvement of systolic function in a patient with LVHT.

Correlation between pathoanatomic findings, imaging modalities, and genetic findings in patients with left ventricular hypertrabeculation/noncompaction.

Introduction: Left ventricular hypertrabeculation, also named 'noncompaction' (LVHT) is a cardiac abnormality which is detected by pathoanatomic investigation or during cardiac surgery. Imaging techniques visualize LVHT by ventriculography, echocardiography, cardiac magnetic resonance imaging (CMRI) and computed tomography (CT).Areas covered: We aimed to assess 1) how often the definition of LVHT was validated against a criterion standard, 2) if inter- and intra-observer agreement was assessed, and 3) how often LVHT was associated with genetic diseases. A literature search disclosed 58 cases whose hearts were investigated pathoanatomically and by ≥1 imaging technique. Echocardiography was most frequently (95%) compared with pathoanatomy, followed by cMRI (31%), ventriculography (7%) and CT (5%). Intra- and inter-observer agreement was more frequently assessed for cMRI definitions and yielded more consistent results than for echocardiographic definitions. Since genetic findings were only reported from 4 of the 58 cases, no association with imaging findings could be carried out.Expert opinion: Correlation between pathoanatomic investigations with imaging techniques will hopefully contribute to reliable and uniformly accepted definitions of LVHT. Most probably, the echocardiographic definition of LVHT will be a synthesis of the currently used definitions, integrating short axis and four-chamber views. A refinement of cMRI definitions, considering pathoanatomic and echocardiographic investigations, seems necessary to avoid overdiagnosis.

Effect of music on patients with cardiovascular diseases and during cardiovascular interventions : A systematic review.

BACKGROUND: The therapeutic effects of music have been known for thousands of years. Recently, studies with music interventions in patients with cardiovascular diseases yielded controversial results. The aim of this review is to provide an overview of the effects of receptive music intervention on the cardiovascular system. METHODS: We searched in PubMed, SCOPUS and CENTRAL for publications between January 1980 and May 2018. Primary endpoints were heart rate, heart rate variability and blood pressure. Secondary endpoints comprised respiratory rate, anxiety and pain. The quality of the studies was assessed by using the CONSORT statement and the Cochrane risk of bias assessment tool. A meta-analysis and subgroup analyses concerning music style, gender and region were planned. RESULTS: A total of 29 studies comprising 2579 patients were included and 18 studies with 1758 patients investigated the effect of music on patients undergoing coronary angiography or open heart surgery. Other studies applied music to children with congenital heart diseases, pregnant women with hypertension or patients with unstable angina. Due to high methodological study heterogeneity, a meta-analysis was not performed. The study quality was assessed as medium to low. In ten studies with higher quality comprising 1054 patients, music intervention was not associated with significant changes in the cardiovascular endpoints compared to the control group. The subgroup analyses did not demonstrate any relevant results. CONCLUSION: Currently no definite effect of receptive music intervention on the cardiovascular system can be verified. Further research is needed to assess music as an inexpensive and easy applicable form of therapy.

Anterograde Amnesia as a Manifestation of Acute Type A Aortic Dissection.

Objectives Memory impairment has been only rarely reported in association with acute aortic dissection type A. We report a patient with pure anterograde amnesia and memory impairment of contents occurring after the event, accompanying acute aortic dissection type A. Case Report A previously healthy 53-year-old Caucasian male was admitted because of sudden chest pain after having lifted a heavy object. Clinical examination and electrocardiogram showed no abnormalities. Since blood tests showed leukocytosis, anemia, and elevated D-dimer level, either pulmonary embolism or aortic dissection was suspected; therefore, computed tomography was suggested. The patient seemed disoriented to time, and neurologic investigation confirmed that the patient was disoriented to time; short time memory was severely impaired and concentration was reduced. An amnestic episode with anterograde amnesia was diagnosed. Computed tomography showed type A aortic dissection. A supracoronary replacement of the ascending aorta was performed. The patient was discharged on the 7th postoperative day. Three months postoperatively, the patient is clinically stable; however, amnesia for the interval between pain onset and cardiac surgery persists. Conclusions Transient amnesia, usually considered a benign syndrome, may be more common than generally recognized in aortic dissection. The suspicion for aortic dissection or other cardiovascular emergencies is substantiated when amnesia is associated with sudden onset of chest pain, leukocytosis, and elevated D-dimer levels. Computed tomography of the aorta with contrast medium is the imaging method of choice to confirm or exclude the diagnosis.

Multisystem Myotilinopathy, including Myopathy and Left Ventricular Noncompaction, due to the MYOT Variant c.179C>T.

Left ventricular hypertrabeculation/noncompaction is a myocardial abnormality of unknown etiology/pathogenesis, which is frequently associated with neuromuscular disorders or chromosomal defects. LVHT in association with a MYOT mutation has not been reported. The patient is a 72-year-old male with a history of strabismus in childhood, asymptomatic creatine-kinase elevation since age 42 years, slowly progressive lower limb weakness since age 60 years, slowly progressive dysarthria and dysphagia since age 62 years, and recurrent episodes of arthralgias and myalgias since age 71 years. He also had arterial hypertension, diverticulosis, hyperlipidemia, coronary heart disease, and a hiatal hernia with reflux esophagitis. Clinical exam revealed mild quadruparesis and proximal wasting of the legs. Whole exome sequencing revealed a known variant in the MYOT gene. Muscle biopsy, previously assessed as inclusion body myopathy, was compatible with the genotype after revision. Cardiologic work-up revealed a left anterior hemiblock, mild myocardial thickening, and noncompaction. This case shows that myotilinopathy may manifest as a multisystem disease, including noncompaction.

Reversible myocardial oedema due to acute myocardial infarction as differential diagnosis of cardiac transthyretin amyloidosis.

Using bone-avid radiotracers, cardiac transthyretin (TTR) amyloidosis can be diagnosed by scintigraphy, thus obviating endomyocardial biopsy. Radiotracer accumulation, however, may also be due to other causes. A 68-year-old male with acute myocardial infarction underwent recanalization of the left anterior descending coronary artery (LAD). Postinterventionally, transthoracic echocardiography showed hypokinesia of the septum and anterior wall and a thickened myocardium with granular sparkling appearance. Cardiac amyloidosis was suspected. A 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid whole-body scan 4 days after LAD recanalization showed Perugini 2 myocardial tracer uptake. Monoclonal gammopathy was excluded, and cardiac TTR amyloidosis was diagnosed. Three months later, 99m-Tc-hydroxydiphosphate scan showed no myocardial tracer uptake. Cardiac magnetic resonance imaging revealed late gadolinium enhancement within the LAD supply area. No mutation of the TTR gene was found. Suspicion of amyloidosis should consider not only echocardiography but also history and clinical findings. Myocardial oedema due to reperfusion should be acknowledged as a differential diagnosis for cardiac uptake of bone-avid radiotracers.

Variants in HNRNPDL and SETX Not Necessarily Indicate Familial Amyotrophic Lateral Sclerosis or Limb Girdle Muscular Dystrophy 1G in Acute Muscular Respiratory Failure.

Genetic work-up is useful for the identification of a primary myopathy. However, even sophisticated genetic methods may fail to detect the underlying cause of myopathy as in the following case. The patient is a 52-year-old female with a history of epilepsy, arterial hypertension, atrial flutter requiring cardioversion, ablation, and anticoagulation, coronary heart disease, hyperlipidemia, and hyper-CKemia. At age 52 years, she was referred for heart failure due to ischemic cardiomyopathy requiring appropriate medication and implantation of an ICD. During hospitalization she developed acute muscular respiratory failure requiring mechanical ventilation. Genetic panels for myopathy, neuropathy, and cardiomyopathy revealed variants of unknown significance in the HNRNPDL and SETX genes respectively. Clinical presentation and muscle biopsy, however, suggested metabolic myopathy. Acute muscular respiratory failure may require traditional diagnostic work-up for primary myopathy and long-term invasive and non-invasive ventilation. Panel investigations not necessarily lead to a conclusive diagnosis. The multisystem nature of the condition rather suggests a metabolic defect than LGMD-1G or fALS as genetic findings suggested.

Left Ventricular Thrombi and Embolic Events in Takotsubo Syndrome despite Therapeutic Anticoagulation.

INTRODUCTION: Takotsubo syndrome (TTS) may be complicated by left-ventricular (LV) thrombus formation in 1.3-5.3% of patients. Risk factors for thrombi comprise apical TTS, elevated levels of C-reactive protein and troponine, thrombocytosis, persisting ST segment elevation and right-ventricular involvement. Embolic risk appears high, and anticoagulation is recommended. CASE PRESENTATION: We present 3 females, aged 60-82 years, with TTS-associated LV thrombi and cerebral embolism despite therapeutic anticoagulation. Two patients showed apical and 1 patient midventricular ballooning. In 2 patients LV thrombi had not been present at the first echocardiographic examination. LV thrombi were multiple and highly mobile in 2 patients; 1 patient had a single immobile thrombus associated with spontaneous echocardiographic contrast (SEC). In each case, 3 of the described risk factors for LV thrombus formation were identified. The embolic stroke occurred 41-120 h after TTS symptom onset and 21-93 h after the initiation of therapeutic anticoagulation. Two patients were discharged with a neurological deficit, and 1 of them eventually died as a consequence of the stroke. LV thrombectomy to prevent embolism, which has been reported in a small number of cases, had not been considered in our patients. CONCLUSION: At present, the management of patients with TTS-related thrombi is still unclear, and further studies are urgently needed to assess the best methods for imaging and anticoagulation and to determine the role of thrombolysis and cardiac surgery. Until these studies are available, we suggest the following approach: patients with a TTS-related thrombus should be monitored by echocardiography while receiving anticoagulation. In case of highly mobile LV thrombi, the heart team may consider cardiac surgery to prevent systemic embolism. The role of SEC in TTS remains to be determined.

Unusual Phenotype and Disease Trajectory in Kearns-Sayre Syndrome.

OBJECTIVE: To describe unusual course and unusual phenotypic features in an adult patient with Kearns-Sayre syndrome (KSS). Case Report. The patient is a 49-year-old male with KSS, diagnosed clinically upon the core features, namely, onset before the age 20 of years, pigmentary retinopathy, and ophthalmoparesis, and the complementary features, namely, elevated CSF protein, cardiac conduction defects, and cerebellar ataxia. The patient presented also with other previously described features, such as diabetes, short stature, white matter lesions, hypoacusis, migraine, hepatopathy, steatosis hepatis, hypocorticism (hyponatremia), and cataract. Unusual features the patient presented with were congenital anisocoria, severe caries, liver cysts, pituitary enlargement, desquamation of hands and feet, bone chondroma, aortic ectasia, dermoidal cyst, and sinusoidal polyposis. The course was untypical since most of the core phenotypic features developed not earlier than in adulthood. CONCLUSIONS: KSS is a multisystem disease, but the number of tissues affected is higher than so far anticipated. KSS should be considered even if core features develop not earlier than in adulthood and if unusual features accompany the presentation.

Noncompaction and Takotsubo Syndrome in a Neuromuscular Disorder.

BACKGROUND: Takotsubo syndrome (TTS) in patients with left ventricular hypertrabeculation/noncompaction (LVHT) has been reported in four patients, and a TTS plus LVHT plus a neuromuscular disorder (NMD) was only reported once so far. Here, we present the fifth patient with LVHT and TTS and the second patient with LVHT, TTS, and a NMD. METHODS AND RESULTS: The patient is a 68 yo female hobby choir singer with a history of skin dermatofibroma, skin fibrokeratoma, arterial hypertension, hyperlipidemia, hypothyroidism, anemia, hyponatremia, diverticulosis, LVHT detected at age 60 y, five syncopes, a liver cyst, and carotid endarterectomy 2 months prior to admission because of sudden-onset chest pain. Workup revealed ST elevation, troponin elevation, and mild coronary artery sclerosis. Ventriculography and transthoracic echocardiography (TTE) showed the apical type of a TTS. ECG normalised within 10 w and TTE within 6 w under beta-blockers and ATII-blockers. The TTS was triggered by being offended of being unable to sing anymore after endarterectomy. Neurological workup suggested the presence of a NMD. CONCLUSIONS: This case shows that LVHT occurs in NMD patients and that patients with LVHT and a NMD may develop a TTS. Whether patients with LVHT and a NMD are particularly prone to develop a TTS requires further confirmation. NMD patients with LVHT should avoid stress not to trigger a TTS.

Understanding left ventricular hypertrabeculation/noncompaction: pathomorphologic findings and prognostic impact of neuromuscular comorbidities.

INTRODUCTION: When >3 trabeculations associated with interventricular recesses are found, this is termed 'left ventricular hypertrabeculation/noncompaction' (LVHT). Cardiac-imaging methods detect LVHT in all ages, isolated or associated with extracardiac, especially neuromuscular disorders (NMDs). Many issues about LVHT are unclear. The review gives an update about pathomorphologic findings in patients >14 years and the role of NMDs in LVHT. Areas covered: A PubMed-search for the terms "noncompaction" or "non-compaction" or "hypertrabeculation" AND "autopsy" or 'biopsy' or 'ultrastructure' or 'electron microscopy' AND 'neuromuscular' or 'myopathy' or 'neuropathy' was carried out from 1985 to July 2018. Expert commentary: Macroanatomic (n = 65), histopathologic (n = 59) and ultrastructural (n = 7) reports were found. A comparison with echocardiography was described in 45 cases. Measurements of non-compacted and compacted layer were only given from hearts investigated in short-axis cuts after formaldehyde-fixation. Endocardial, subendocardial and interstitial fibrosis were frequent findings. When LVHT-patients were systematically investigated, a NMD was found in 80%, most frequently mitochondrial disorders, Barth syndrome, zaspopathy, and myotonic dystrophy type 1. LVHT does not seem to be a special type of cardiac involvement of NMDs. NMDs affect prognosis in LVHT as well as LVHT affects prognosis in patients with Duchenne muscular dystrophy.

Side effects of and contraindications for whole-body electro-myo-stimulation: a viewpoint.

Whole-body electro-myo-stimulation (WB-EMS) has been introduced as an alternative to physical training. Data about side effects and contraindications of WB-EMS are summarised. From healthy subjects, elevation of creatine-kinase (CK) activity with inter-individual variability was reported after WB-EMS. No data about applied current types, stimulation frequency and risk factors were given. In randomised trials investigating WB-EMS, CK activity was not measured. Seven cases of rhabdomyolysis after WB-EMS were found, and it remains open whether WB-EMS was the only risk factor. In healthy subjects, WB-EMS does not seem to affect blood pressure, heart rate and oxygen uptake. The lists of exclusion criteria are, in part, contradictory between different studies, especially regarding malignancy and heart failure. Risk factors for rhabdomyolysis are not mentioned as contraindications for WB-EMS. Scientific research should concentrate on muscle damage as a side effect of WB-EMS considering current types applied, stimulation frequency and risk factors for rhabdomyolysis. Research about WB-EMS should include longitudinal muscle force measurements and MRI. Subjects, intending to perform WB-EMS, should undergo investigations by a physician comprising a screen for risk factors for rhabdomyolysis. The education of operators working in gyms with WB-EMS should be regulated and improved. Regulatory authorities should become aware of the problem. Those working in the field should start an initiative on an international level to increase the safety of WB-EMS.

Respiratory insufficiency from myasthenia gravis and polymyositis due to malignant thymoma triggering Takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TTS) is a non-ischaemic cardiomyopathy with sudden but transient systolic dysfunction. TTS mimics myocardial infarction clinically, chemically, and electrocardiographically but echocardiography typically shows apical ballooning and coronary angiography is normal. TTS has not been reported in a patient with myasthenia gravis (MG) and polymyositis due to a malignant thymoma. CASE REPORT: Two weeks prior to admission, a 76-year-old female developed dysarthria, chronic coughing and disabling myalgias of the entire musculature. Since there was hyper-CKemia and elevated troponin, myocardial infarction was suspected. During swallowing of the antithrombotic medication on admission, she experienced apnoea, requiring cardio-pulmonary resuscitation with intubation and mechanical ventilation. Further diagnostic work-up precluded coronary heart disease but revealed TTS. Upon neurologic work-up, MG and polymyositis were diagnosed but the response to cholinergic drugs and plasmapheresis was poor. TTS was attributed to stress and anxiety from MG-associated respiratory insufficiency. The further course was complicated by recurrent supraventricular bradyarrhythmias and respiratory insufficiency. Upon thoracic CT a thymoma was suspected. Two months after admission, the mediastinal tumour was resected and malignant thymoma WHO BII infiltrating the mediastinum (modified Masaoka-Koga II/2) was diagnosed. CONCLUSIONS: This case shows that TTS may be triggered by stress from respiratory insufficiency during a myasthenic crisis, MG may be associated with polymyositis, cholinergic medication may trigger bradyarrhythmias, and cholinergic drugs and plasmapheresis may exhibit a poor effect if malignant thymoma and polymyositis are present.

Muscular and cardiac manifestations in a Duchenne-carrier harboring a dystrophin deletion of exons 12-29.

Female carriers of mutations in the dystrophin gene (DMD-carriers) may manifest clinically in the skeletal muscle, the heart, or both. Cardiac involvement may manifest before, after, or together with the muscle manifestations. A 46y female developed slowly progressive weakness of the lower and upper limbs with left-sided predominance since age 26y. Muscle enzymes were repeatedly elevated and muscle biopsy showed absence of dystrophin. MLPA analysis revealed a deletion of exons 12-29. After starting steroids at age 39y, she developed palpitations and exertional dyspnoea. Cardiac MRI at age 41y revealed mildly reduced systolic function, a slightly enlarged left ventricle, mild hypokinesia of the entire myocardium, and focal, transmural late gadolinium enhancement (LGE) of the midventricular lateral wall. She did not tolerate beta-blockers but profited from ivabradine and lisinopril. In conclusion, muscle manifestations in DMD-carriers with deletions of exons 12-29 may start years before cardiac involvement becomes clinically apparent. Progressive worsening of systolic function in DMD-carriers is attributable to progressive myocardial fibrosis, as demonstrated by LGE. Steroids may trigger the development of cardiac disease in DMD-carriers.