Cardiovascular manifestations of type IV Ehlers-Danlos syndrome - A case report.

Type IV Ehlers-Danlos syndrome (vascular) is a rare connective tissue disease caused by COL3A1 gene mutation on type III collagen. Clinical presentation is related to vascular fragility and risk of rupture of the arterial wall. Definite diagnosis is given by genetic study and the approach to these patients requires a multidisciplinary team and effective blood pressure control. There is currently only one medication with potential benefit in prevention of cardiovascular events: celiprolol. This article describes the case of a 41-year-old female patient, diagnosed with vascular Ehlers-Danlos syndrome after multiple major cardiovascular events: aortic, coronary and carotid dissections and venous and arterial thrombosis. These required multiple surgical interventions and long-term admission in intensive care units leading to complete functional recovery. This case report seeks to stress the need for an early diagnosis to prevent the severe cardiovascular complications of this rare syndrome.

Biomarkers of Myocardial Fibrosis: Revealing the Natural History of Fibrogenesis in Fabry Disease Cardiomyopathy.

BACKGROUND: Cardiomyopathy is a major determinant of overall Fabry disease (FD) prognosis, with the worst outcomes in patients with myocardial fibrosis. Late gadolinium enhancement is currently the gold standard for evaluation of replacement myocardial fibrosis; however, this event is irreversible, thus identification of biomarkers of earlier diffuse fibrosis is paramount. METHODS AND RESULTS: Type I collagen synthesis and degradation biomarkers (PICP [carboxyterminal propeptide of procollagen type I], ICTP [carboxyterminal telopeptide of type I collagen], and MMP1 [matrix metalloproteinase 1] and MMP2) and markers of bone synthesis and degradation were evaluated (to adjust type I collagen metabolism to bone turnover) in FD patients and controls. FD patients were grouped by cardiomyopathy severity, according to echocardiogram: (1) normal, (2) tissue Doppler abnormalities, (3) left ventricular hypertrophy. A significant increase in PICP and a significant decrease in matrix metalloproteinases were observed in FD patients; even the group with normal echocardiogram had a significant increase in PICP. We also found a significant correlation between left ventricular mass and PICP (ρ=0.378, P=0.003) and MMP1 (ρ=-0.484, P<0.001). PICP (adjusted for bone turnover) was the better predictor of left ventricular mass in multivariable regression, and its diagnostic accuracy to predict late gadolinium enhancement was also significant. CONCLUSIONS: Collagen type I synthesis is increased in FD cardiomyopathy, even in the earlier stages of the disease, and this profibrotic state has good predictive value for and is likely to be critical to the development of overt left ventricular hypertrophy. Moreover, inhibition of enzymes involved in collagen type I cleavage also seems crucial to myocardial collagen deposition.

New biomarkers defining a novel early stage of Fabry nephropathy: A diagnostic test study.

BACKGROUND: Renal involvement in Fabry disease is a major determinant of overall disease prognosis and early enzyme replacement therapy seems effective in preventing progression of kidney injury. Gb3 storage, glomerular sclerosis and tubulo-interstitial fibrosis may occur with minimal or no changes on standard renal tests, hence alternative markers of renal dysfunction are crucial. In this study we compared several biomarkers with albuminuria in the identification of incipient Fabry nephropathy and their diagnostic accuracy to identify chronic kidney disease (CKD) stage≥2. METHODS: In this multicentre, prospective, cross-sectional and diagnostic test study, a cohort of 78 Fabry patients and 25 healthy controls was consecutively recruited. Patients were grouped by severity of nephropathy: 1) albuminuria<30mg/g; 2) albuminuria 30-299mg/g; 3) albuminuria>300mg/g; 4) glomerular filtration rate (GFR)<60mL/min/1.73m2. Several index tests, namely biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-ß-glucosaminidase and alanine aminopeptidase) dysfunction were compared with the reference standard (albuminuria). RESULTS: Significant increase of all tested biomarkers in Fabry patients, even in the subgroup of patients without evidence of nephropathy. We also found inverse significant correlations between estimated GFR and collagen type IV (ρ=-0.289; p=0.003) or N-acetyl-ß-glucosaminidase (ρ=-0.448; p<0.001), which were stronger than with albumin (ρ=-0.274; p=0.019). There was also better diagnostic accuracy of N-acetyl-ß-glucosaminidase to predict CKD stage≥2. CONCLUSIONS: These results suggest that studied biomarkers may overcome the limitations of albuminuria as sensitive marker of early renal dysfunction and as marker for CKD progression risk. These biomarkers may also define novel early stages of nephropathy characterized by mesangial expansion and/or tubular damage.

Hypocalcemic cardiomyopathy.

The association between hypocalcemia and heart failure is rare. There are few reported cases in the literature of this association, which is termed hypocalcemic cardiomyopathy. We report the case of a 61-year-old woman with no relevant medical history, admitted for progressively worsening exertional dyspnea, orthopnea and edema of the lower limbs for a previous month. Physical examination showed diffuse muscle spasms, with no signs of latent tetany.Further investigation revealed ionized calcium 0.54 mmol/l (normal 1.12-1.30), phosphorus 9.8 mg/dl, parathyroid hormone <2.5 pg/ml and CK >3000 U/l, with normal thyroid function. The electrocardiogram showed long QT interval and a pattern of left ventricular overload, and myocardial biomarkers were negative. The echocardiogram revealed regional wall motion abnormalities, coronary angiography was normal and a cranial CT scan detected calcification of basal ganglia and white matter. She started diuretic and calcium replacement therapy which resulted in complete clinical recovery, with no need for heart failure therapy after normalization of serum calcium.

[Subvalvular aortic stenosis associated with 8p23 deletion]. / Estenose aórtica subvalvular associada à deleção 8p23.

We report the case of a 35-year-old man admitted due to heart failure, who had had moderate cognitive deficit, craniofacial dysmorphism, epilepsy, panic attacks and congenital heart disease (subvalvular aortic stenosis) associated with chronic atrial fibrillation since childhood. In view of his facial dysmorphism and clinical presentation, karyotype analysis was performed and revealed a de novo interstitial deletion in chromosome 8 in the region p23.1-p23.2. This is a rare chromosomal anomaly (about 50 descriptions in the literature), whose most common manifestations include heart defects, cognitive retardation and behavioral disturbances. In this paper we present the first case with associated subvalvular aortic stenosis and review the literature on this chromosomal abnormality.

Extended remission of metastatic epithelioid angiosarcoma of the heart with liposomal doxorubicin.

Angiosarcoma is the most common primary malignant tumour of the heart. It is a rare and aggressive neoplasm that almost always has a short and fatal evolution. By the time it produces symptoms it has usually progressed to a mass causing haemodynamic compromise. Initial presentation with metastatic disease is unusual. We report the case of a 72-year-old man who presented with painful skin lesions on both hands. The skin biopsy was diagnosed as intravascular metastasis of epithelioid angiosarcoma. Body computed tomography scan disclosed a solid mass in the left atrium. The tumour was judged unresectable and the patient was treated with systemic chemotherapy, consisting of liposomal doxorubicin, which resulted in a complete clinical response. The patient remains free of disease after 48 months of follow-up. The excellent clinical evolution of our patient verifies that liposomal doxorubicin may be effective in the treatment of these tumours and significantly prolong patients' lifespan.

The Valsalva maneuver revisited by wavelets.

The Valsalva maneuver is an autonomic test that evokes short sharp cardiovascular fluctuations mediated by the autonomic nervous system. Numerous spectral analysis methods have been proposed to analyze biological signals. When applied to heart rate (HR) variability, two major bands related to autonomic influence have been defined: LF (mainly sympathetic) and HF (parasympathetic). However, conventional spectral approaches are based on the assumption of stationarity, and most require at least five minutes of recording. These two requirements cannot be fulfilled when analysis of dynamic processes such as the regulatory action of the autonomic nervous system is required. Wavelet transform is a mathematical tool that, by determining the temporal localization of the changes, the frequencies involved and their contribution to the entire signal, overcomes the limitations imposed by conventional methods. In the present work, we use wavelets to evaluate autonomic influence through the LF and HF band powers on acute changes in systolic blood pressure (sBP) and RR intervals (RRI) during the Valsalva maneuver. Eighteen healthy volunteers performed the maneuver by blowing, after a deep inspiration and with a closed glottis, against a pressure of 40 mmHg for 15 seconds. Data were analyzed in three different periods: 1) the last minute just prior to the test (CTR); 2) the 15 seconds of the Valsalva maneuver (VM); 3) during the next 35 seconds after the maneuver (aVM). We observed that LF power increased in sBP and RRI in both VM and ower only increased after Valsalva. The data showed a marked increase in sympathetic activity during and after the maneuver and an increase in parasympathetic outflow after aVM. In conclusion, the ability of wavelets to analyze short non-stationary signals makes wavelet transform a promising tool to evaluate physiological and pathological autonomic conditions.

Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy.

A middle age Portuguese woman was investigated for renal amyloidosis. She presented with progressive renal failure, proteinuria, hypertension, and sensory symptoms in the feet. Clinical and neurophysiological evaluation disclosed sensory-autonomic neuropathy. Cardiovascular tests and 123-MIBG investigation showed parasympathetic dysfunction and decrease of myocardial innervation, in accordance with small fiber neuropathy, as usually observed in amyloidosis. Immunohistochemical studies revealed AFib amyloidosis and genetic studies the amino acid exchange Glu526Val of the fibrinogen Aalpha-chain mutation, which was also present in one of her sons. The mutant gene in this patient was associated with the same haplotype as all other reported cases of Glu526Val mutations. This is the first reported AFibamyloidosis in Portugal, and the first case of AFib in which sensory and autonomic nerve fiber dysfunction is described, indicating that small nerve fiber lesion can occur in the fibrinogen Aalpha chain mutation. This can be important for prognosis, in particular when liver transplantation is considered for treatment.

[Acute disautonomia associated to Hodgkin lymphoma]. / Disautonomia aguda associada a linfoma de Hodgkin.

The case of a 31 man with acute disautonomia envolving the parasympathetic and sympathetic systems but sparing sympathetic cholinergic division is presented. A Hodgkin lymphoma was diagnosed allowing the diagnosis of a paraneoplastic syndrome.