Yehuda Adler

Ischemic preconditioning: nearly two decades of research. A comprehensive review

The phenomenon of ischemic preconditioning has been recognized for almost two decades. In experimental animals and humans, a brief period of ischemia has been shown to protect the heart from more prolonged episodes of ischemia, and reduce the degree of impaired ventricular function or subsequent damage. Ischemic preconditioning is classified into two distinct components: the classic early preconditioning and the delayed or late preconditioning, each with its own biologic mechanism of adaptation. A comprehensive understanding of these mechanisms and application to clinical scenarios has the promise of providing unique opportunities, particularly regarding the development of preconditioning mimetic agents. Administration of these mimetic drugs or procedures could potentially advance the use of preconditioning as a therapeutic tool and/or preventive factor for cardiovascular disease.

Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography

This study tests the hypothesis that mitral annular calcium (MAC) detected by transthoracic echocardiography (TTE) is a marker for high prevalence and severity of coronary artery disease (CAD) in patients undergoing coronary angiography. Pathological studies have suggested that there is an association between MAC and calcific deposits in coronary arteries; however, there are no clinical data to support this association. One hundred sixty-five patients with MAC (101 women and 64 men; mean age 71 +/- 8 years) who underwent cardiac catheterization with coronary angiography for various reasons were compared with 147 age-matched controls without MAC who underwent coronary angiography for the same indications during the same period. MAC was defined as a dense, localized, highly reflective area at the base of the posterior mitral leaflet detected by TTE. Obstructive CAD was defined as either > or = 50% reduction of the internal diameter of the left main coronary artery or > or = 70% reduction of the internal diameter of the left anterior descending, right coronary, or left circumflex artery distribution. Compared with controls, the MAC group had a significantly higher prevalence of CAD (89% vs 75%, p = 0.001) and higher rates of 3-vessel disease (45% vs 24%, p = 0.001) and left main CAD (13% vs 5%, p = 0.009). Nonsignificant CAD was more common in the control group (25% vs 11%, p = 0.001). Multivariate analysis identified MAC (p = 0.0002), indications for cardiac angiography (p = 0.02), sex (p = 0.03), and diabetes mellitus (p = 0.03) as independent predictors for the presence and severity of obstructive CAD. MAC detected by TTE may be a marker for high prevalence and severity of CAD in patients undergoing coronary angiography.

Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: therapeutic options beyond statins

Lowering of low-density lipoprotein cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is clearly efficacious in the treatment and prevention of coronary artery disease. However, despite increasing use of statins, a significant number of coronary events still occur and many of such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is being paid now to combined atherogenic dyslipidemia which typically presents in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or lipid quartet): hypertriglyceridemia, low high-density lipoprotein cholesterol levels, a preponderance of small, dense low-density lipoprotein particles and an accumulation of cholesterol-rich remnant particles (e.g. high levels of apolipoprotein B) – emerged as the greatest competitor of low-density lipoprotein-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP – Bezafibrate Infarction Prevention study, HHS – Helsinki Heart Study, VAHIT – Veterans Affairs High-density lipoprotein cholesterol Intervention Trial and FIELD – Fenofibrate Intervention and Event Lowering in Diabetes) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants and cholesteryl ester transfer protein inhibition. In addition, bezafibrate as pan-peroxisome proliferator activated receptor activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism and insulin sensitivity. Because fibrates, niacin, ezetimibe and statins each regulate serum lipids by different mechanisms, combination therapy – selected on the basis of their safety and effectiveness – may offer particularly desirable benefits in patients with combined hyperlipidemia as compared with statins monotherapy.

Nonobstructive aortic valve calcification: a window to significant coronary artery disease

BACKGROUNDnAortic valve calcification without obstruction (AVC) is common in the elderly and is associated with increased cardiovascular mortality and morbidity. We hypothesized that AVC detected by transthoracic echocardiography (TTE) is a marker for significant coronary artery disease in patients undergoing coronary angiography.nnnMETHODSnThe study group included 388 patients with AVC (259 males, 129 females; mean age 72.2+/-9 years) who underwent coronary angiography for various indications. Data were compared with 320, age- and sex-matched patients without AVC who underwent coronary angiography for the same indications. AVC was detected in TTE as focal areas of increased echogenicity and thickening of the aortic-valve leaflets without restriction in motion. Significant obstructive coronary artery disease was defined as either a > or = 70% reduction of the internal diameter of the left anterior descending, right coronary, or left circumflex artery distribution or a > or = 50% reduction of the internal diameter of the left main coronary artery. Risk factors for atherosclerosis including hypertension, smoking, hypercholesterolemia and diabetes were also investigated.nnnRESULTSnCompared with control group, the AVC group had a higher prevalence of significant coronary artery disease (90 vs. 85%, P=0.019), and a trend for lower frequency of coronary arteries without obstruction (6 vs. 9%, P=0.l1); a trend was also noted for 3-vessel disease (38 vs. 33%, P=0.14). Multivariate analysis identified age (P=0.000l), sex (P=0.000l), hypercholesterolemia (P=0.005) and AVC (P=0.02) as independent predictors for significant coronary artery disease.nnnCONCLUSIONSnThere is a significant association between AVC and significant coronary artery disease in patients undergoing coronary angiography. Thus AVC can serve as a window to atherosclerosis of the coronary arteries. These results reinforce a previous observation regarding association between AVC and increased risk of cardiovascular morbidity.

Usefulness of colchicine in preventing recurrences of pericarditis

ventricular exeasystoles and beta-blocking agents. .I Irish Med Assoc 1975;68: 369-375. 2. Abinader EG. Adrenergic beta blockade and ECG changes in the systolic click murmur syndrome. Am Heart J 1976;91:297-302. 3. Abinader EG, Shahar J. Exercise testing in mitral valve prolapse before and afta beta blockade. Br Hearr J 1982;48:130-133. 4. Abmader EG. Clinical considerations in interpretation of the exercise electmcardiogram in the patient with mitral valve prolapse. Pracr Cardiol1983;9: 172-l 8 1. 5. Abmader EG. ‘Ihe effect of beta blockade on the abnormal exercise test in patients with mitral valve prolapse. J Cardiac Rehbil 1984;4:95-100. 6. Deanfield JE, Shea M, Ribezio P, Laodsheere CM, Wilson RA, Horlock P, Selwyn AP. Transient ST-segment depression as a marker of myocardial ischemia during daily life. Am J Cardiol 1984;s 1195-1200. 7. h39:39&402. 8. Imperi GA, Lambert CR, Coy K, Lopez L, Pepine CL. Effects of titrated betablockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease. Am J Cardiol 1987;60519-524. 9. Hill JA, Gonzalez JI, Kolob R, Pepine Cl. Effects of atenolol alone, nifedipine alone and their combination on ambulant myocardial ischemia. Am J Cardioll991; 67:671675. 10. Mulcahy D, Keegan I, Cunningham D, Quyyumi A, Crean P, Park A, Wright C, Fox K. Circadian variation of total ischemic burden and its alteration with antianginal agents. Lancet 1988;2:755-759. ll. Boudoulas H, Reynolds JC, Mazzaferri E, Wooley CF. Metabolic studies in mitral valve prolapse syndrome. A neuroendocrine-cardiovascular process. Circulation 1980;61:1200-1205. 12. Pastemac A, Tubau JF, Puddu PE, Krol RB, De Champlain J. Increased plasma catecholamines in symptomatic mitral valve prolapse. Am J Med 1982; 73:783-790. 28. Bertolet BD, Boyette AF, Hofmann CA, Pepine CJ, Hill JA. Prevalence of pseudoischemic ST-segment changes during ambulatory elecuocardiographic monitoring. Am J Cardiol 1992;70:818-820. l4. The ACIP Investigators. Asymptomatic cardiac ischemia pilot study (ACIP). Am J Cardiol 1992;10:744-741.

Aetiological diagnosis in acute and recurrent pericarditis: when and how.

The cause of acute and recurrent pericarditis is often a major concern for the clinicians in clinical practice. Several possible causes of pericarditis can be listed, as the pericardium may be involved in a large number of systemic disorders or may be diseased, as an isolated process. The reported diagnostic yield of extensive laboratory evaluation and pericardiocentesis is low in the absence of cardiac tamponade or suspected neoplastic, tuberculous, and purulent pericarditis. Patients with pericarditis can be safely managed on an outpatient basis without a thorough diagnostic evaluation unless a specific cause is suspected or the patient has high-risk features, or both. A targeted aetiological search should be directed to the most common cause on the basis of the clinical background, epidemiological issues or specific presentations. In developed countries the clinicians should rule out neoplastic, tuberculous, and purulent pericarditis, as well as pericarditis related to a systemic disease.

Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus.

BackgroundLeft ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.MethodsFive hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.ResultsMean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.ConclusionType 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.

Primary Malignancies of the Heart and Pericardium

Primary malignancies of the heart and pericardium are rare. All the available data come from autopsy studies, case reports, and, in recent years, from large, specialized, single‐center studies. Nevertheless, if primary malignancy is present, it may have a devastating implication for patients. Malignancies may affect heart function, also causing left‐sided or right‐sided heart failure. In addition, they can be responsible for embolic events or arrhythmias. Today, with the widespread use of noninvasive imaging modalities, heart tumors become evident, even as an incidental finding. A multimodality imaging approach is usually required to establish the final diagnosis. Despite the increased awareness and improved diagnostic techniques, clinical manifestations of primary malignancy of the heart and pericardium are so variable that their occurrence may still come as a surprise during surgery or autopsy. No randomized clinical trials have been carried out to determine the optimal therapy for these primary malignancies. Surgery is performed for small tumors. Chemotherapy and radiation therapy can be of help. Partial resection of large neoplasms is performed to relieve mechanical effects, such as cardiac compression or hemodynamic obstruction. Most patients present with marginally resectable or technically nonresectable disease at the time of diagnosis. It seems that orthotopic cardiac transplantation with subsequent immunosuppressive therapy may represent an option for very carefully selected patients. Early diagnosis and radical exeresis are of great importance for long‐term survival of a primary cardiac malignancy. This can rarely be accomplished, and overall results are very disappointing.

Management of acute ischaemic stroke in the elderly. Tolerability of thrombolytics

Stroke and its consequences are of global concern. Although stroke can affect individuals of any age, it primarily affects the elderly. It is among the leading causes of severe disability and mortality. In recent years, acute stroke has become a medical emergency requiring urgent evaluation and treatment. Effective management of patients with acute stroke starts with organisation of the entire stroke care chain, from the community and prehospital scene, through the emergency department, to a dedicated stroke unit and then to comprehensive rehabilitation.Intravenous thrombolysis with alteplase (recombinant tissue plasminogen activator; rt-PA) 0.9 mg/kg (maximum dose 90mg) was shown to significantly improve outcome of acute ischaemic stroke, despite an increased rate of symptomatic intracerebral haemorrhage, if treatment is initiated within 3 hours after the onset of symptoms to patients who meet strict eligibility criteria. Post-marketing studies have demonstrated that intravenous alteplase can be administered appropriately in a wide variety of hospital settings. However, strict adherence to the published protocol is mandatory, as failure to comply may be associated with an increased risk of symptomatic intracerebral haemorrhage. Intra-arterial revascularisation may provide more complete restitution of flow than intravenous thrombolytic therapy and improve the clinical outcome if it can be undertaken in patients with occlusion of the middle cerebral artery, and possibly the basilar artery, within the first hours from stroke onset. However, further data are needed.Although intravenous alteplase is recommended for any age beyond 18 years, elderly patients, in particular patients aged ≥80 years, were often excluded or under-represented in randomised clinical trials of thrombolysis, so that available data on risk/benefit ratio for the very elderly are limited. Small post-marketing series suggest that despite elderly patients over 80 years having greater pre-stroke disability, the use of intravenous alteplase in this patient group does not significantly differ in effectiveness and complications compared with the same treatment in patients aged under age 80 years. Further studies are necessary and elderly patients with acute stroke should be included in future trials of the merits of thrombolytic therapy.

Long-term changes in serum cholesterol level does not influence the progression of coronary calcification

BACKGROUNDnA number of reports controversially describe the influence of cholesterol level and lipid-lowering treatment (LLT) on the progression of coronary calcium (CC). We tested the hypothesis that long-term changes in serum cholesterol (CL) would affect the progression of CC.nnnMETHODSnThe study population comprised 510 patients with stable angina pectoris, mean age of 63 ± 9 years. At baseline 372 patients received statin and/or fibrate (LLT group) while 138 patients did not (No-LLT at baseline group). Spiral CT every 24 months was used to track the progression of CC over a median 5.6 year follow-up.nnnRESULTSnCL decreased during follow-up in both groups, but more pronouncedly in patients with LLT. The changes in total calcium score (TCS) were similar in both groups (p=0.3). Changes in CL during follow-up were not associated with CC: TCS increased by 501 ± 63 from baseline in the 1st (upper) quartile, and by 350 ± 44, 403 ± 41 and 480 ± 56 in the 2nd, 3rd, and 4th quartiles of CL longitudinal changes (p = 0.2), respectively. Baseline TCS and its changes were not correlated with baseline CL and its changes. New calcified lesions were diagnosed in 132 (28.2%) out of the 467 patients available for this analysis, without significant difference between groups (p=0.4). Multivariate analysis demonstrated that only baseline TCS (p < 0.001), body mass index (p = 0.007) and age (p = 0.006) were independent predictors for the TCS changes.nnnCONCLUSIONSnLongitudinal CL changes do not seem to have a measurable effect on the rate of progression of CC.