Reverse remodeling in a heart failure patient with cardiomegaly treated with sacubitril/valsartan: a case report.

Sacubitril/valsartan (S/V) has shown promise as a tool for decreasing cardiovascular hospitalization and associated mortality among certain patients with heart failure and has been found to exhibit potential renoprotective and antiarrhythmic activity. This report is describing the case of a patient that suffered acute myocardial infarction within one month after undergoing percutaneous coronary intervention (PCI) stent implantation and who underwent standard guideline-directed medical treatment. Upon readmission, echocardiographic evaluation revealed enlargement of the left heart and reduced ejection fraction. While hospitalized, treatment with S/V was begun. Following sustained treatment with this drug for five months, the patient exhibited vascular remodeling, a 30% injection fraction improvement, a 15 mm reduction in left ventricular diastolic diameter, and a significant change in functional class from class III to I. Overall, this case report emphasizes the association between S/V treatment and reverse ventricular remodeling in a patient that experienced cardiomegaly following AMI.

Calorie restriction changes lipidomic profiles and maintains mitochondrial function and redox balance during isoproterenol-induced cardiac hypertrophy.

Typically, healthy cardiac tissue utilizes more fat than any other organ. Cardiac hypertrophy induces a metabolic shift leading to a preferential consumption of glucose over fatty acids to support the high energetic demand. Calorie restriction is a dietary procedure that induces health benefits and lifespan extension in many organisms. Given the beneficial effects of calorie restriction, we hypothesized that calorie restriction prevents cardiac hypertrophy, lipid content changes, mitochondrial and redox dysregulation. Strikingly, calorie restriction reversed isoproterenol-induced cardiac hypertrophy. Isolated mitochondria from hypertrophic hearts produced significantly higher levels of succinate-driven H2O2 production, which was blocked by calorie restriction. Cardiac hypertrophy lowered mitochondrial respiratory control ratios, and decreased superoxide dismutase and glutathione peroxidase levels. These effects were also prevented by calorie restriction. We performed lipidomic profiling to gain insights into how calorie restriction could interfere with the metabolic changes induced by cardiac hypertrophy. Calorie restriction protected against the consumption of several triglycerides (TGs) linked to unsaturated fatty acids. Also, this dietary procedure protected against the accumulation of TGs containing saturated fatty acids observed in hypertrophic samples. Cardiac hypertrophy induced an increase in ceramides, phosphoethanolamines, and acylcarnitines (12:0, 14:0, 16:0, and 18:0). These were all reversed by calorie restriction. Altogether, our data demonstrate that hypertrophy changes the cardiac lipidome, causes mitochondrial disturbances, and oxidative stress. These changes are prevented (at least partially) by calorie restriction intervention in vivo. This study uncovers the potential for calorie restriction to become a new therapeutic intervention against cardiac hypertrophy, and mechanisms in which it acts.

Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease.

A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.

[Natriuretic peptides: anything new in cardiology?]. / Peptydy natriuretyczne: cos nowego w kardiologii?

Twenty-five years after the first publication of the strong natriuretic effect of rat cardiac atria extract, natriuretic peptides play an important part in everyday, not only cardiological, practice. In the current review the authors briefly describe the role of natriuretic peptides (ANP, BNP, and CNP) in clinical practice, concentrating on the possibilities of their therapeutic use. They also summarize their role in the mechanisms of endogenous cardioprotection and regulation of LVH, which is the endpoint of many cardiovascular pathologies.

Hypertension and sudden death. Disparate effects of calcium entry blocker and diuretic therapy on cardiac dysrhythmias.

This study was designed to evaluate the impact of antihypertensive therapy on cardiac dysrhythmias in 13 hypertensive patients who received calcium entry blockers and in 10 hypertensive patients who received hydrochlorothiazide. Mean arterial pressure fell to a similar extent in both treatment groups; however, left ventricular mass index decreased (from 102 +/- 4 to 95 +/- 2 g/m2) only in patients receiving calcium entry blockers, but not in those taking hydrochlorothiazide. The prevalence of premature ventricular contractions decreased 74% from 21 +/- 14/h to 5.7 +/- 6/h in the calcium entry blocker group, but did not change in the hydrochlorothiazide group (15 +/- 17/h to 16 +/- 13/h). Couplets, multiform contractions, ventricular tachycardia, and supraventricular tachycardia were completely abolished after calcium entry blocker therapy, whereas the prevalence of these arrhythmias remained unchanged during treatment with hydrochlorothiazide. We conclude that antihypertensive therapy with calcium entry blockers (but not with thiazide diuretics) reduces left ventricular mass and the prevalence and severity of ventricular dysrhythmias. Whether this reduction will improve the ominous prognosis of left ventricular hypertrophy and diminish the risk of sudden death remains unknown.

Antihypertensive therapy in diabetic patients.

Diabetes mellitus (DM)-linked metabolic alterations and hypertension concomitantly accelerate or precipitate cerebrovascular and coronary heart disease, nephropathy, retinopathy and widespread macroangiopathy, thereby conferring to diabetic patients a very high risk of morbidity, disability and early death. Therefore, the long-term care for diabetic patients should be aimed at concomitant metabolic and blood pressure (BP) control. Dietary measures are indispensable; a high fibre, low fat, low salt diet is recommended, complemented with caloric restriction and physical exercise when body weight is above the ideal. Antidiabetic pharmacotherapy involves an unresolved dilemma. The desired achievement of euglycemia necessitates effective levels of insulin, but hyperinsulinemia (due to parenteral [over]treatment in insulin-dependent DM) is suspected to promote atherogenesis and represents a coronary risk factor and perhaps even facilitates hypertension. Considering antihypertensive pharmacotherapy, thiazide-type or loop diuretics are problematic drugs in DM because they can aggravate metabolic alterations. These agents also seem to exert only a limited preventive or regressive effect on left ventricular hypertrophy (LVH); beta-blockers are also not considered ideal, since they decrease the awareness of hypoglycemia and tend to promote glucose intolerance. Unselective beta-blockers in particular promote peripheral ischemia and insulin-induced hypoglycemia, while beta-blockers without intrinsic sympathomimetic activity lower serum HDL-cholesterol. Calcium antagonists and ACE inhibitors have equivalent antihypertensive efficacy, do not impair carbohydrate and lipid homeostasis or peripheral perfusion and can effectively improve LVH. Certain ACE inhibitors may even slightly ameliorate abnormal insulin sensitivity and plasma glucose levels. While alpha-blockers share most of these desirable properties, these agents are more prone to precipitate orthostatic hypotension in the diabetic patient. The non-thiazide diuretic indapamide and the serotonin2-antagonist ketanserin also combine antihypertensive efficacy with metabolic neutrality. The ultimate goal of therapy is to improve life prognosis. In essential hypertension, conventional drug treatment based on diuretics in high dosage satisfactorily reduced cerebrovascular but not coronary complications or sudden death. In diabetic patients, the influence of antihypertensive therapy on prognosis has not been assessed prospectively. Based on retrospective analyses, Warram et al reported a 3.8 times higher mortality in diabetics treated with diuretics alone, than in diabetics with untreated hypertension (Arch Intern Med. 1991;151:1350). H. H. Parving calculated that effective BP control in patients with diabetic nephropathy might reduce 10 year-mortality from about 65 to 20 percent (J Hypertension. 1990; 8[Suppl 7]:187).(ABSTRACT TRUNCATED AT 400 WORDS)

Regression of cardiac hypertrophy by 1,4 dihydropyridines in hypertensive patients.

BACKGROUND: Left ventricular hypertrophy (LVH) represents an important intermediate end-point for, for example, the progression to heart failure. The persistence or progression of LVH despite antihypertensive therapy probably reflects the persistence or activation of mechanisms that negatively affect the cardiovascular system and, consequently, long-term outcome. EFFECT OF MODERN ANTIHYPERTENSIVE AGENTS: Long-term treatment with rapid-onset (and usually short-acting) dihydropyridine calcium antagonists is significantly less effective than angiotensin converting enzyme (ACE) inhibition in reducing left ventricular mass (LVM) in hypertensive patients. Both intermittent, and probably only partial, blood pressure control and an increase in sympathetic activity resulting from rapid decreases in blood pressure following dosing with such calcium antagonists may contribute to this relative ineffectiveness. In contrast, more recent studies have demonstrated that the longer acting dihydropyridines can reduce LVM as effectively as ACE inhibitors. DISTINCTIONS AMONG DIHYDROPYRIDINE CALCIUM ANTAGONISTS: Among the 1,4-dihydropyridines, drugs such as amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) maintain good blood pressure control over the full 24-h dosing period and do not cause dose-related increases in sympathetic activity. In contrast, extended-release felodipine has been shown to provide only intermittent blood pressure control, still leading to sympathetic activation. Notably, during short periods of noncompliance, blood pressure control is maintained with intrinsically long-acting agents such as amlodipine but not with slow-release formulations of short-acting agents such as nifedipine GITS. CONCLUSIONS: It is possible that the rate of onset and duration of action of various dihydropyridines may be pivotal factors in determining their effects on cardiovascular outcomes. Thus, the least beneficial dihydropyridines may be rapid-onset, short-acting agents, such as nifedipine capsules, and the most beneficial may be the slow-onset, long-acting agents such as amlodipine.

[Case of Wernicke's encephalopathy and subacute combined degeneration of the spinal cord due to vitamin deficiency showing changes in the bilateral corpus striatum and cardiac arrest due to beriberi heart disease].

A 52-year-old woman was admitted to the hospital because of appetite loss, unsteadiness, psychogenic symptoms, ataxia, and consciousness disturbance as a result of the ingestion of a diet restricted to only carbohydrates for a long term. Laboratory examination indicated the presence of pancytopenia with macrocytic anemia; further, decreased vitamin B1 and B12 levels were detected in her serum. Magnetic resonance imaging fluid attenuated inversion recovery (FLAIR), revealed high-signal intensity in the bilateral corpus striatum, third ventricle circumference, and cerebellar cortex. Thereafter, she received drip infusion that did not include vitamin B1 or B12 and subsequently suffered a cardiac arrest due to the aggravation of cardiac insufficiency; consequently, she was transferred to our hospital. Upon admission the patient was diagnosed to have obvious cardiomegaly with pleural effusion; further, a negative T-wave was obtained on the electrocardiogram. A diagnosis of beriberi heart disease was made because of thiamine deficiency. She was treated by thiamine administration, following which the cardiac symptoms improved immediately. Various neurological symptoms caused by encephalopathy, peripheral neuropathy and subacute combined spinal cord degeneration improved by treatment with thiamine and cyanocobalamine administration; however, some of these symptoms still remained. General awareness of the fact that neurological symptoms can be caused by vitamin deficiency is essential.

[ACE-inhibitors and cardiovascular protection]. / ACE-inibitori e protezione cardiovascolare.

Aim of recent experimental and clinical studies has been to evaluate the important role of the renin-angiotensin system in the development of cardiac hypertrophy, of vascular hypertrophy and of left ventricular fibrosis and remodelling in essential hypertension and ischemic heart disease. It has been suggested that ACE-inhibitors are the class of antihypertensive drugs more effective in reducing left ventricular hypertrophy (LVH) in hypertensive patients. The possible mechanisms are, beyond the decrease in blood pressure, the possibility of interfering not only with the renin-angiotensin system activity, but also with the sympathetic nervous system activity as well as with aortic distensibility, all factors that can influence the development of LVH. Vascular changes in essential hypertension are complex and depend not only on the severity of blood pressure levels, but are related to diameter and structure of the vessels and to the presence of other atherosclerosis risk factors. ACE-inhibitors are effective in inducing the regression of structural changes in resistance arterioles and furthermore can increase arterial compliance in large arteries; new studies are undergoing in order to assess the effects of these drugs on atherosclerotic plaque progression/regression. The results of large clinical trials have shown the efficacy of ACE-inhibitors in the treatment of heart failure, in addition, after it has been demonstrated that ACE-inhibitors can influence the structural remodelling process after myocardial infarction, their use has been extended to patients with ischaemic heart disease.

Can inhibition of the renin-angiotensin system have a cardioprotective effect?

The inhibition of the renin-angiotensin system (RAS) has important effects on different parameters of left ventricular function. Chronic inhibition of the RAS avoids hypokalemia and potassium losses by increasing aldosterone release. This potassium-sparing effect is likely to prevent cardiac arrhythmia. Inhibition of the RAS reverses cardiac hypertrophy in renovascular and in spontaneously hypertensive rats (SHR), but not in DOCA salt hypertensive rats. Inhibition of the RAS also reverses the decrease in myocardial contractility, as demonstrated by the reversion of isoenzyme profile of cardiac myosin in renovascular hypertensive rats. In DOCA salt hypertensive rats, RAS inhibition has no effect on blood pressure or on cardiac contractility. Despite its peripheral vasodilatory property, inhibition of the RAS does not increase heart rate in relation to a direct negative chronotropic effect of angiotensin II inhibition and to the absence of activation of the baroreflex system. When RAS is activated, its inhibition has a coronary vasodilatory effect, but this coronary vasodilation is associated with a decrease in perfusion pressure and with an increase in intrinsic cardiac contractility. These concomitant effects lead us to conclude that inhibition of RAS probably has no important beneficial effect on the oxygen demand/oxygen supply ratio in the myocardium distal to the coronary artery stenosis.

Treatment of hypertensive heart disease with ACE inhibitors.

Hypertensive left ventricular hypertrophy is associated with a variety of complications including congestive heart failure, arrhythmias, and ischemic heart disease. Unloading the system in time by antihypertensive drug treatment should prevent or reverse left ventricular hypertrophy. Although most antihypertensive agents can control blood pressure in a majority of patients, only a select subset of these pharmacologic agents will reverse left ventricular mass. There is evidence to suggest that angiotensin-converting enzyme (ACE) inhibitors can play an important role in protecting the heart during the various phases of evolution of hypertensive heart disease both acutely and on a long-term basis. Several studies in hypertensive humans and experimental animals have documented the effectiveness of ACE inhibitors in reducing cardiac hypertrophy. In hypertensive patients with left ventricular hypertrophy, the ACE inhibitor captopril 3 and 9 months after starting treatment significantly reduced left ventricular mass as well as left ventricular posterior wall and septal wall thickness. The mechanism of regression of left ventricular mass by ACE inhibition is speculative. The absence of a reflex hyperadrenergic state in the face of blood pressure control may be of importance. In addition, interference with angiotensin II generation by these agents may also play a role either through the myocardial effects of angiotensin II on protein synthesis or because of its facilitation of cardiac sympathetic neurotransmitter release. ACE inhibition appears to be associated with the maintenance of normal coronary flow reserve and in high renin states ACE inhibition may increase coronary blood flow. ACE inhibitors are also indicated under conditions of hypertensive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin-converting enzyme inhibitors in preventing or reducing end-organ damage in hypertension.

Angiotensin-converting enzyme inhibitors have been shown to be effective therapy for hypertension, and also for severe congestive heart failure, whether due to hypertension or to other causes. The reduction in cardiac hypertrophy that follows the use of these drugs is undoubtedly due in part to their favorable hemodynamic effects of reducing peripheral resistance and inducing venodilation. The same factors reduce cardiac dilation and left ventricular remodeling after myocardial infarction. The prevention of the hemodynamic effects of angiotensin II (Ang II) is probably the major factor in preventing end-organ damage, but there are some indications that Ang II may have an effect independent of blood pressure in promoting vascular hypertrophy. The separation of vasoconstrictor effects from any metabolic effects of Ang II is not easy, and final elucidation of the mechanisms involved is not yet available.