Comparison of digital color fundus imaging and fluorescein angiographic findings for the early detection of diabetic retinopathy in young type 1 diabetic patients.

PURPOSE: To compare the findings from digital 7-field color fundus (CF) photography and fundus fluorescein angiography (FFA) in young patients with diabetes mellitus (DM) type 1 without known diabetic retinopathy. METHODS: In this prospective, observational cohort study, 54 type 1 diabetic patients were recruited. Participants had been diagnosed with diabetes mellitus (DM) for at least 6 years, had Best Corrected Visual Acuity of 20/25 or better and did not have any known retinal pathology. One hundred and seven eyes were analyzed. All patients underwent a complete ophthalmic examination in the Retina Service of a University Eye Clinic including digital CF imaging and FFA. RESULTS: The mean age of the patients was 18.6 years. Mean duration of DM was 11.3 years, and mean haemoglobin A1c (HbA1c) level was 8.6%. Of the 107 eyes, 8 eyes (7.5%) showed microvascular abnormalities on CF images, while FFA images revealed changes in 26 eyes (24.3%). Hence, 18 of the 26 eyes showing abnormalities on FFA did not show any abnormalities on CF images. Mean DM duration in the patient group with detectable microvascular changes was found to be significantly higher compared to patients without changes, while no difference in HbA1c levels, serum lipid levels or blood pressure was observed. CONCLUSIONS: Comparison of digital CF and FFA findings for the detection of diabetic microvascular changes in type 1 diabetic patients showed that FFA reveals more information about retinal vascular pathology for early detection of diabetic retinopathy.

The value of contrast sensitivity in diagnosing central serous chorioretinopathy.

A 39-year-old hyperopic male was referred for laser refractive treatment. In the course of the pre-operative evaluation he complained of a recent deterioration of vision. The suspicion of unilateral central serous chorioretinopathy (CSCR) was confirmed by contrast sensitivity testing and by ocular fundus examination. Contrast sensitivity (CS) for six spatial frequencies (1, 2, 4, 8, 12 and 16 c/deg) was evaluated using Gabor patches of gratings projected on a high-resolution display by means of a stimulus generator card. Although VA remained unaltered, the pattern of contrast sensitivity function varied at different stages of CSCR: during the acute stage, performance at all spatial frequencies was depressed, while at two-month follow up, intermediate and high spatial frequencies were mainly affected. It is concluded that the level of visual deficit in CSCR cannot be evaluated by measuring visual acuity. History and contrast sensitivity can play a central role in setting the correct diagnosis and characterising its stage.

Genotype-phenotype assessment in autosomal recessive arrhythmogenic right ventricular cardiomyopathy (Naxos disease) caused by a deletion in plakoglobin.

OBJECTIVES: The purpose of this study was to examine the genotype-phenotype relation with respect to penetrance, age and severity of expression, disease progression and prognosis in a recessively inherited arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with palmoplantar keratoderma and woolly hair. METHODS: Twelve families with Naxos disease underwent cardiac and molecular genetic investigation. Serial cardiac assessment with annual resting 12-lead and 24-h ambulatory electrocardiogram (ECG) and two-dimensional echocardiography was performed during 1 to 16 years, median 7 +/- 6 years in all 78 surviving members. RESULTS: Twenty-eight surviving members were homozygous and 40 were heterozygous for the mutation. All adults who were homozygous (n = 26) fulfilled the diagnostic criteria for ARVC, the youngest by the age of 13 years. In eight who were heterozygous, minor ECG or echocardiographic abnormalities were observed. Of the 26 subjects who were affected homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right ventricular structural alterations and 27% left ventricular involvement. During follow-up (10 +/- 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmic events and 7 (27%) heart failure. The annual disease-related and sudden death mortality was 3% and 2.3%, respectively. CONCLUSIONS: Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by adolescence. Affected subjects who were homozygous experienced progressive disease with adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/echocardiographic changes, but clinically significant disease did not develop.

Usefulness of noninvasive detection of left ventricular diastolic abnormalities during isometric stress in hypertrophic cardiomyopathy and in athletes.

We showed previously that the handgrip apexcardiographic test (HAT) is a useful method for detecting left ventricular (LV) diastolic abnormalities in patients with coronary artery disease and systemic hypertension. This study evaluates the use of HAT for assessing the prevalence and types of exercise-induced diastolic abnormalities in patients with obstructive (n = 31) and nonobstructive (n = 35) hypertrophic cardiomyopathy (HC) as well as its potential value for separating healthy subjects and athletes from patients with HC. We obtained a HAT in 66 consecutive patients with HC and in 72 controls (52 healthy volunteers and 20 athletes). A positive HAT was defined by the presence of one of the following: (1) relative A wave to total height (A/H) during or after handgrip > 21% (compliance type), (2) total apexcardiographic relaxation time (TART) > 143 ms or the heart rate corrected TART (TARTI) during handgrip < 0.14, (relaxation type), (3) both types present (mixed type), and (4) diastolic amplitude time index (DATI = TARTI/[A/D]) during handgrip < 0.27. Of the controls, only 1 of 52 healthy subjects and 1 of 20 athletes showed a positive HAT, whereas of the total HC cohort 63 of 66 patients (95%) had a positive result. There was no significant difference in the distribution of these types between obstructive and nonobstructive HC. Further, no LV diastolic abnormalities were present in 10 of 35 patients (29%) with nonobstructive HC at rest and in 3 of 35 patients (9%) during handgrip, whereas of the patients with obstructive HC only 1 of 31 (3%) had no LV diastolic abnormalities at rest and none during handgrip. Based on HAT data, our study demonstrates that in HC (1) LV diastolic abnormalities are very frequent during handgrip; (2) patients with nonobstructive HC show significantly fewer LV diastolic abnormalities at rest than those with obstructive HC; and (3) no significant difference exists between obstructive and nonobstructive HC in the prevalence of types of handgrip-induced LV diastolic abnormalities. Consequently, HAT appears to be of clinical value as an additional tool for separating normal patients and athletes from patients with HC.

Hypertrophic cardiomyopathy in Greece: clinical course and outcome.

OBJECTIVE: Evaluation of clinical course and outcome of hypertrophic cardiomyopathy in a representative Greek population. BACKGROUND: Hypertrophic cardiomyopathy is characterized by unexplained left ventricular hypertrophy and varied clinical expression. Recent studies suggest ethnic differences. MATERIALS AND METHODS: One hundred seventy-four consecutive Greek patients (117 male, 57 female, age 47+/-16 years) from 143 different families were assessed at the Department of Cardiology of the University of Athens, Greece, and the State Cardiac Department, Hippokration Hospital, both located in Athens, Greece. To reduce selection bias, referral was based on disease diagnosis irrespective of clinical status or treatment needs. All patients were examined clinically, echocardiographically, and by ECG ambulatory monitoring at 6-month intervals for a period of 74+/-22 months (range, 8 to 108 months). RESULTS: Most patients (n = 156, 89.7%) were in New York Heart Association (NYHA) functional class I or II. The disease was familial (at least one affected first-degree relative) in 81 of the 143 families (56.6%), and in 19 of these (13.3%) there was familial history of sudden cardiac death. At initial examination, intraventricular septal thickness was 17.3+/-4.1 mm and posterior wall thickness was 13.7+/-3.8 mm and a left ventricular outflow gradient >30 mm Hg was present in 58 patients (33.3%). Similar were the findings during the last examination (17.5+/-4.3 mm, 13.5+/-4.4 mm, and 56 (32.2%, respectively, p = not significant). Episodes of nonsustained ventricular tachycardia were noted in 15 patients (8.6%). There were eight deaths during follow-up: four sudden deaths and four from intractable heart failure. Syncope was reported by all patients who died. The annual mortality in this study was 1%. Syncope and NYHA class were the only predictors of outcome. CONCLUSIONS: In this representative Greek patient cohort with hypertrophic cardiomyopathy, the arrhythmogenic substrate was modest and the clinical course benign. Sudden cardiac death was infrequent and syncope, functional class, and ventricular arrhythmias were the only predictors of a poor outcome.

Clinical value, normative retinal sensitivity values, and intrasession repeatability using a combined spectral domain optical coherence tomography/scanning laser ophthalmoscope microperimeter.

PURPOSE: To establish normative values for macular light sensitivity and to determine the intrasession fluctuation of perimetric responses using the OPKO/OTI microperimeter. METHODS: A total of 32 visually normal subjects participated in the study. A standardized grid pattern was used for testing, which consisted of 28 points arranged concentrically in three circles that occupied an area of 11° (in diameter) within the central macula. Each subject participated in at least two tests. Parameters evaluated included: overall mean macular sensitivity for test 1 and 2, overall difference in mean macular sensitivity between tests, and the mean sensitivity for each circle. The relationship between sensitivity and age was also examined. RESULTS: The overall median sensitivity for test 1 was 16.8 decibels (dB) and for test 2 was 16.9 dB. The median sensitivities for test 1 and test 2 were not significantly different (P = 0.72). The mean intrasession sensitivity difference was 0.13 dB. The variability of the sensitivity difference between tests decreased as mean sensitivity increased. The sensitivity values averaged across the two tests for inner, middle, and outer circles ranged from 14.3 to 18.8 dB (median value of 16.9 dB), 13.8-18.3 dB (median value of 17.2 dB), and 11.3-18.3 dB (median value of 16.6 dB), respectively. Linear regression analysis showed a 0.5 dB sensitivity loss for each decade of life. CONCLUSION: We documented a narrow range of intrasession fluctuation using the OPKO/OTI microperimeter. The establishment of normative sensitivity values will facilitate monitoring the loss of macular visual function in patients with retinal disease.

Cardiac ion channel gene mutations in Greek long QT syndrome patients.

The long QT syndrome (LQTS) is an inherited cardiac arrhythmia that may lead to sudden death in the absence of structural heart disease. Mutations in the cardiac potassium and sodium channel genes can be found in approximately 70 percent of patients with a highly probable clinical diagnosis. In this study, we aimed to genotype and explore the yield of genetic testing of LQTS patients from Greece, for whom there are no collective published data available. We clinically evaluated and genetically screened 17 unrelated patients for mutations in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 cardiac ion channel genes. Genetic testing was positive in 6 out of 8 patients with a highly probable clinical diagnosis of LQTS and negative for all the other patients. Two patients carried KCNQ1 mutations (c.580G>C, c.1022C>T), while 4 patients carried KCNH2 mutations (c.202T>C, c.1714G>A, c.3103delC, c.3136C>T). To the best of our knowledge, the last mentioned mutation (c.3136C>T) is novel. Moreover, 27 single-nucleotide polymorphisms (SNPs) were detected, 5 of which are novel. Our preliminary data indicate a low genetic diversity of the Greek LQTS genetic pool, and are in accordance with international data that genetic testing of the major LQTS genes is efficient in genotyping the majority of patients with a strong clinical diagnosis. Therefore, the transition of an LQTS genetic screening program from research to the diagnostic setting within our ethnic background is feasible.

Myocardial contusion presented as acute myocardial infarction after chest trauma.

A 46-year-old male patient developed an acute myocardial infarction and congestive heart failure following blunt chest trauma. Electrocardiogram (ECG) revealed acute anterior myocardial infarction. Echocardiography showed akinesis of interventricular septum, dyskinesis in apical anterior wall, and severe impairment of left ventricular overall systolic function. Coronary angiography revealed normal coronary arteries. The patient followed a low-intensity physical medicine rehabilitation program. Follow-up was without new complications or deterioration of congestive heart failure. Five months later the patient presented with fulminant acute pulmonary edema and cardiogenic shock. Cardiopulmonary resuscitation was unsuccessful.

Implantable defibrillator therapy in Naxos disease.

Naxos disease is a unique form of right ventricular cardiomyopathy with a high prevalence of malignant ventricular arrhythmias, including sudden cardiac death. As a hereditary systemic disease confined to a small island, it has been closely studied over the last 15 years. The implantation of an automatic defibrillator provides an alternative form of antiarrhythmic management to improve life expectancy in these high risk cardiac patients. We present the first two Naxos disease patients with malignant ventricular arrhythmias who had defibrillator implantation.

Electromyographic evidence of subclinical myopathy in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is due to a number of mutations of contractile protein genes such as beta-cardiac myosin, myosin binding protein-C, and troponin-T. Unlike troponin-T, beta-myosin is a constituent of slow skeletal muscle and its mutations generally have a better prognosis. In order to investigate the usefulness of electromyography in detecting skeletal muscle involvement in HCM, 46 patients were examined using both conventional electromyography (EMG) and quantitative electromyography (QEMG) methods. The QEMG involved motor unit potential (MUP) analysis, turns/amplitude (TAA) analysis, and power spectrum analysis of the interference pattern. Using conventional EMG, myopathic findings were demonstrated in 13 patients (28%). Receiver operating characteristic (ROC) analysis of the results of a discriminant function extracted using QEMG values, identified correctly 10 out of 11 normal controls and all 9 myopathic control patients, and displayed a 15% presence of myopathy (7 patients) among the cardiomyopathy group. The duration of MUPs was the most sensitive among the quantitative parameters in differentiating normal from myopathic subjects. Since skeletal muscle involvement may be due to distinct gene mutations, normal and myopathic EMG findings may reflect HCM subpopulations with a different genetic substrate.

Use of troponin-T concentration and kinase isoforms for quantitation of myocardial injury induced by radiofrequency catheter ablation.

BACKGROUND: Although there remains particular concern about late malignant ventricular arrhythmias arising from myocardial damage induced by catheter ablation, the extent of myocardial injury resulting from clinical ablation procedures has not been fully studied. We conducted a prospective, controlled study to investigate the use of two newer markers of myocardial integrity, troponin-T concentration and creatine kinase isoforms, and a traditional marker, creatine kinase-MB concentration, in the assessment of myocardial injury following radiofrequency catheter ablation. METHODS AND RESULTS: The study population consisted of 28 consecutive patients subjected to radiofrequency catheter ablation, and the control group comprised eight subjects undergoing diagnostic electrophysiology study. Prior to ablation and at 30 min, 1, 2, 6, and 12 h following the procedure, blood samples were taken to measure troponin-T and creatine kinase-MB concentrations, and the separation of creatine kinase isoforms (MM3/MM1 and MB2/MB1 ratios). The troponin-T concentration was above normal in all but two patients following radiofrequency ablation, and the MB2/MB1 ratio was raised in all but one patient following ablation, but was also abnormal in the pre-ablation samples in seven patients. The MM3/MM1 ratio failed to detect myocardial injury in 75% of patients. Of patients subjected to ablation, in only 36% was the creatine kinase-MB concentration raised at least once post-ablation. Thirty minutes post-ablation, there was a statistically significant difference between the control and patient groups only as regards troponin-T concentration. There was a significant association between troponin-T concentration immediately post-procedure, the number of discharges delivered (r = 0.52, P = 0.006) and maximum power used (r = 0.48, P = 0.009). CONCLUSION: Our results indicate that catheter ablation inflicts a cumulative, detectable injury upon the myocardium. This injury can be quantitated by using newer analytical techniques, such as serial, post-ablation measurements of troponin-T concentration.

Myocardial injury induced by radiofrequency and low energy ablation: a quantitative study of CK isoforms, CK-MB, and troponin-T concentrations.

We conducted a prospective, controlled study to investigate the use of CK-MB concentration and newer methods such as troponin-T concentration and CK isoforms, in the assessment of myocardial damage caused by radiofrequency current or low energy DC catheter ablation. The study population consisted of 3 consecutive patients who underwent low energy catheter ablation, 28 consecutive patients subjected to radiofrequency ablation, and 4 patients who were subjected to radiofrequency energy ablation but also had external DC shocks for cardioversion of atrial fibrillation that occurred during the procedure. The control group comprised eight subjects undergoing electrophysiological study. Prior to ablation and at 30 minutes, 1, 2, 6, and 12 hours following the procedure, serial blood samples were taken for measurement of troponin-T and CK-MB concentrations, and calculation of the MM3/MM1 and MB2/MB1 ratios. Troponin-T concentration was raised above normal in all patients subjected to low energy ablation and in all but two patients subjected to radiofrequency ablation. Only 42% of all patients subjected to ablation had at least one raised CK-MB concentration postablation. The MB2/MB1 ratio was raised in all but had at least one raised CK-MB concentration postablation. The MB2/MB1 ratio was raised in all but two patients following radiofrequency or low energy ablation but it was also abnormal in the preablation samples in nine patients. The MM3/MM1 ratio failed to detect myocardial damage in 71% of all patients. There was a statistically significant difference between the control and patient groups regarding all four indices of myocardial damage. Low energy ablation caused a significantly higher degree of myocardial damage compared with radiofrequency (RF); this effect could not be attributed to different numbers of total energy discharges. Our results indicate that catheter ablation, regardless of the mode of energy used, inflicts detectable injury upon the myocardium. This injury can be quantitated by using newer analytical techniques, such as serial, postablation measurements of troponin-T concentration.

Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an autosomal dominant heart muscle disorder that causes arrhythmia, heart failure, and sudden death. Previously we mapped the genetic locus for the triad of autosomal recessive ARVC, palmoplantar keratoderma, and woolly hair (Naxos disease) to chromosome 17q21, in which the gene for plakoglobin is encoded. This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin. METHODS: We studied 19 individuals with Naxos disease, as well as unaffected family members and unrelated individuals from the neighbouring Greek islands of Naxos and Milos. Gene sequence was determined by reverse transcriptase PCR from RNA isolated from the skin of an affected individual and mutations in other cases were confirmed by restriction-enzyme analysis. FINDINGS: A homozygous 2 base pair deletion in the plakoglobin gene was identified only in the 19 affected individuals. This deletion caused a frameshift and premature termination of the protein, which was shown by western blot analysis. 29 clinically unaffected family members were heterozygous for the mutation; 20 unrelated individuals from Naxos and 43 autosomal dominant ARVC probands were homozygous for the normal allele. INTERPRETATION: The finding of a deletion in plakoglobin in ARVC suggests that the proteins involved in cell-cell adhesion play an important part in maintaining myocyte integrity, and when junctions are disrupted, cell death, and fibrofatty replacement occur. Therefore, the discovery of a mutation in a protein with functions in maintaining cell junction integrity has important implications for other dominant forms of ARVC, related cardiomyopathies, and other cutaneous diseases.

Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: In this study, we both investigated coronary flow velocity in hypertrophic obstructive cardiomyopathy (HOCM) and tested the hypothesis of differing coronary flow reserve (CFR) of coronary arteries perfusing left ventricular regions with nonuniform myocardial hypertrophy by measuring the relative CFR. METHODS AND RESULTS: Coronary flow velocity was assessed in left anterior descending coronary (LAD) and left circumflex (LCX) arteries in 18 patients with HOCM and marked hypertrophy only in the ventricular septum, in 13 patients without obstruction (HCM), and in 9 age- and sex-matched normal subjects at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 microg/kg per minute). Relative CFR was estimated as the ratio between absolute CFR of the LAD and absolute CFR of the LCX (LAD/LCX(CF)). At the peak of rapid atrial pacing and during dobutamine stress, LAD/LCX(CF) was reversed in HOCM patients (from 1.25+/-0.11 to 0.82+/-0.07 and 0.79+/-0.06, respectively), whereas it remained unchanged in control subjects (from 1.0+/-0.1 to 1.0+/-0.05 and 1.0+/-0.05, respectively; P<.001). In HCM patients, LAD/LCX(CF) at rest was 1.10+/-0.11, whereas during rapid atrial pacing and dobutamine stress, it was 0.92+/-0.08 and 0.90+/-0.09, respectively. Relative CFR was 0.62+/-0.05 in HOCM patients and 1.05+/-0.05 (P<.001) in normal subjects. There was an inverse correlation between relative CFR and peak systolic outflow tract gradient (r2=.74, P<.001). CONCLUSIONS: Regional distribution of hypertrophy in some patients with HOCM resulted in regional impairment of coronary flow. Relative CFR can be used to estimate regional disturbances of coronary flow and may help in patient selection for new interventional therapeutic techniques.