Stiff Left Ventricle Research Articles

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка

Серцева недостатність зі збереженою фракцією викиду лівого шлуночка є частим явищем, що спостерігається в осіб похилого віку. Вона супроводжується артеріальною гіпертензією та гіпертрофією лівого шлуночка. До симптомів відносять ригідність стінок лівого шлуночка з компенсаторним збільшенням тиску наповнення і знижену здатність збільшувати ударний об’єм за законом Франка Старлінга. Прогнози практично такі ж невтішні, як і при серцевій недостатності зі зниженою фракцією викиду, що певною мірою відображає наявність супутніх захворювань. До встановлення діагнозу серцевої недостатності зі збереженою фракцією викиду важливо виключити кардіологічну природу захворювання. Через неспецифічність симптомів серцевої недостатності необхідно знайти об’єктивне підтвердження діастолічної дисфункції, що за відсутності даних, отриманих інвазивно, має бути підтверджена з використанням ехокардіографії, при якій будуть виявлені ознаки підвищеного тиску наповнення лівого шлуночка, порушення його розслаблення чи збільшення його діастолічної ригідності. Лікування серцевої недостатності зі збереженою фракцією викиду симптоматичне, із застосуванням тих же препаратів, що і при серцевій недостатності зі зниженою фракцією викиду.

Intramyocardial Injections to De-Stiffen the Heart: A Subject-Specific in Silico Approach.

We hypothesized that minimally invasive injections of a softening agent at strategic locations in stiff myocardium could de-stiffen the left ventricle (LV) globally. Physics-based finite element models of the LV were created from LV echocardiography images and pressures recorded during experiments in four swine. Results confirmed animal models of LV softening by systemic agents. Regional de-stiffening of myocardium led to global de-stiffening of LV. The mathematical set up was used to design LV global de-stiffening by regional softening of myocardium. At an end diastolic pressure of 23 mmHg, when 8 ml of the free wall was covered by intramyocardial injections, end diastolic volume (EDV) increased by 15.0%, whereas an increase up to 11 ml due to intramyocardial injections in the septum and free wall led to a 26.0% increase in EDV. Although the endocardial intramyocardial injections occupied a lower LV wall volume, they led to an EDV (44 ml) that was equal compared to intramyocardial injections in the mid-wall (44 ml) and larger compared to intramyocardial injections in the epicardium (41 ml). Using an in silico set up, sites of regional myocardium de-stiffening could be planned in order to globally soften overly stiff LV in heart failure with preserved ejection fraction. This novel treatment is built on subject-specific data. Hypothesis-testing of these simulation findings in animal models is warranted.

Presystolic wave is associated with carotid intima media thickness.

Carotid intima media thickness (CIMT), a direct marker of atherosclerosis, has emerged as a promising means for cardiovascular risk evaluation. Presystolic wave (PSW) is commonly detected by the Doppler interrogation of the left ventricular outflow tract (LVOT). It is thought to be a result of a stiff left ventricle and impaired LV compliance. Herein, we aimed to investigate a possible association between carotid intima media thickness, an atherosclerotic marker, and PSW. We prospectively enrolled 282 patients divided into two groups based on the presence of PSW: 221 (89F; mean age: 49.3±11.5years) had PSW on Doppler examination while 61 patients (32F; mean age: 46.4±10.3years) did not. Both groups were compared with respect to demographic, clinical properties, and CIMT. Both groups had comparable age, body mass index, and diabetes mellitus, hypertension, dyslipidemia, smoking, and family history for coronary heart disease. PSW-positive group had significantly higher CIMT (PSW-positive: 0.59±0.22mm vs PSW-negative: 0.42±0.11mm; P<0.001) than PSW-negative group. Multivariate analysis showed that the independent predictors of increased CIMT were age (95% CI; 1.044-1.101, P<0.001), dyslipidemia (95% CI; 0.147-0.664, P=0.002), and the presence of PSW (95% CI; 2.168-7.836, P<0.001).Correlation analysis showed that PSW velocity is correlated with increased CIMT in PSW-positive group (r: 0.418, P<0.001). Assessment of PSW on TTE is easy and feasible method. Presence of PSW and increased PSW velocity on TTE might provide information that we should be careful in terms of subclinical atherosclerosis.

Abstract 398: Alternative Splicing of Titin Restores Diastolic Function and Improves HFpEF Associated Symptoms

Greater than half of all heart failure (HF) patients suffer from increased diastolic stiffness and impaired relaxation of the left ventricle while their ejection fraction (EF) is preserved (HFpEF). HFpEF is a complex disease characterized by diastolic dysfunction, exercise intolerance, and concentric hypertrophic remodeling. No effective therapy exists for treating this pervasive disease due in part to our limited understanding of the underlying pathophysiology. Titin, the largest known protein and molecular spring in the heart, has emerged as a prime candidate for therapeutic targets aimed at restoring compliance to the sarcomere in order to improve diastolic function. Titin has two main cardiac isoforms; the smaller N2B isoform (~3.0 MDa) and the larger more compliant N2BA isoform (~3.3 MDa). Diastolic stiffness of the left ventricle is in large part dependent upon the N2BA:N2B isoform ratio. Modification of these two primary isoforms can be achieved post-transcriptionally through inhibiting the known titin splicing factor Rbm20. Alternative splicing of messenger RNA occurs primarily in the spring region of titin and therefore regulates the elastic property of titin through changes in contour length of the spring. The current study evaluates whether reduction of titin splicing factor Rbm20 has a beneficial effect on the diastolic function of mice with restrictive cardiomyopathy. A previously published mouse model deficient in titin’s IA junction ( Ttn ΔIAjxn ) places increased strain on the spring region of titin and acts as a mechanical analogue of the titin-based increase in passive myocardial stiffness found in HFpEF patients. This model exhibits a HFpEF-like phenotype apparent as early as 3 months in the adult mouse that becomes exaggerated with age apart from pharmacological or surgical intervention. We report for the first time a rescue of HFpEF in the mouse through inhibiting Rbm20. We demonstrate that Rbm20 reduction restores diastolic function, improves exercise tolerance and attenuates afterload induced pathologic remodeling of the left ventricle. No specific FDA approved therapies exist to treat the pathologically stiff left ventricle, therefore our findings on Rbm20 inhibition are clinically significant.

Perioperative cardiac care - not just systolic

Revised guidelines for the management of heart failure (HF) were published in 2013. 1 HF arises due to a reduction in cardiac output secondary to a reduction in stroke volume (SV). Systolic HF (SHF) arises due to overfilling of a dilated left ventricle (LV) and/or right ventricle with inadequate ejection, and thus a reduced ejection fraction (EF). SHF progressively limits activity and results in increasing back pressure and secondary congestion of the pulmonary and/or systemic venous circulation. 2 However, the majority of patients with HF have preserved or even exaggerated systolic function, with a normal or increased EF owing to diastolic heart failure (DHF). SV is reduced because of underfilling of a stiff LV. Sudden-onset dyspnoea in response to stress or exercise occurs as a result of raised LV end-diastolic pressure (LVEDP). Congestion owing to an intermittent or persistent increase in LVEDP is thus an early, prominent feature of diastolic dysfunction. 3

Heart Failure with Preserved Ejection Fraction – A Review

Heart failure with preserved left ventricular ejection fraction (HF-PEF), sometimes named diastolic heart failure, is a common condition most frequently seen in the elderly and is associated with arterial hypertension and left ventricular (LV) hypertrophy. Symptoms are attributed to a stiff left ventricle with compensatory elevation of filling pressure and reduced ability to increase stroke volume by the Frank-Starling mechanism. LV interaction with stiff arteries aggravates these problems. Prognosis is almost as severe as for heart failure with reduced ejection fraction (HF-REF), in part reflecting co-morbidities. Before the diagnosis of HF-PEF is made, non-cardiac etiologies must be excluded. Due to the non-specific nature of heart failure symptoms, it is essential to search for objective evidence of diastolic dysfunction which, in the absence of invasive data, is done by echocardiography and demonstration of signs of elevated LV filling pressure, impaired LV relaxation, or increased LV diastolic stiffness. Antihypertensive treatment can effectively prevent HF-PEF. Treatment of HF-PEF is symptomatic, with similar drugs as in HF-REF.

Heart Failure with Preserved Ejection Fraction – A Review

Heart failure with preserved left ventricular ejection fraction (HF-PEF), sometimes named diastolic heart failure, is a common condition most frequently seen in the elderly and is associated with arterial hypertension and left ventricular (LV) hypertrophy. Symptoms are attributed to a stiff left ventricle with compensatory elevation of filling pressure and reduced ability to increase stroke volume by the Frank–Starling mechanism. LV interaction with stiff arteries aggravates these problems. Prognosis is almost as severe as for heart failure with reduced ejection fraction (HF-REF), in part reflecting co-morbidities. Before the diagnosis of HF-PEF is made, non-cardiac aetiologies must be excluded. Due to the non-specific nature of heart failure symptoms, it is essential to search for objective evidence of diastolic dysfunction which, in the absence of invasive data, is done by echocardiography and demonstration of signs of elevated LV filling pressure, impaired LV relaxation or increased LV diastolic stiffness. Antihypertensive treatment can effectively prevent HF-PEF. Treatment of HF-PEF is symptomatic, with similar drugs as in HF-REF.

Association of the Fourth Heart Sound With Increased Left Ventricular End-Diastolic Stiffness

Background Although the fourth heart sound (S 4) is thought to be associated with a stiff left ventricle, this association has never been proven. Recently, single-beat estimation of the end-diastolic pressure volume relationship (EDPVR) has been characterized (P = αV β), allowing the estimation of EDPVR in larger groups of patients. We hypothesized that the S 4 is associated with an upward- and leftward-shifted EDPVR, indicative of elevated end-diastolic stiffness. Methods and Results Ninety study participants underwent acoustic cardiographic analysis, echocardiography, and left heart catheterization. We calculated α and β coefficients to define the nonlinear slope of the EDPVR using the single-beat method for measuring left ventricular end-diastolic elastance. In the P = αV β EDPVR estimation, α was similar ( P = .31), but β was significantly higher in the S 4 group (5.96 versus 6.51, P = .002), signifying a steeper, upward- and leftward-shifted EDPVR curve in subjects with an S 4. The intensity of the S 4 was associated with both β ( r = 0.42, P < .0001) and E/E′ ÷ stroke volume index, another index of diastolic stiffness ( r = 0.39, P = .0008). On multivariable analysis, β remained associated with the presence ( P = .008) and intensity ( P < .0001) of S 4 after controlling for age, sex, and ejection fraction. Conclusions The S 4 is most likely generated from an abnormally stiff left ventricle, supporting the concept that the S 4 is a pathologic finding in older patients.

Value of cardiovascular magnetic resonance for determining cardiac involvement in systemic amyloidosis

A 66-year-old woman presented with atypical chest pain, symptoms of heart failure (NYHA class III), and loss of appetite. Her past medical history was notable for previous episode of decompensated heart failure and two transient cerebral ischaemic attacks. Physical examination revealed a raised jugular venous pressure, marked peripheral oedema, hepatomegaly, and bilateral rales. An adjunct S4 heart sound was heard suggesting a stiff left ventricle. Electrocardiogram documented right bundle branch block and Q-waves in the inferior …

Diastolic Heart Failure Demystified

The mystery of diastolic heart failure (DHF), described by authorities as a "puzzle" and a "clinical paradox," stems from the following misperception: (1) that the normal ejection fraction implies normal cardiac output (CO), (2) that therefore low CO is not operative (it is rarely mentioned in relation to the pathophysiology of DHF), and (3) the congestive phenomena are due to the stiff left ventricle. In fact, a normal ejection fraction is not a reliable indicator of normal CO; low CO is the fundamental pathophysiologic abnormality of all heart failure (HF), whether systolic and/or diastolic (or, indeed, "high output"); and increased ventricular stiffness is not the principal cause of congestion in DHF. Pathophysiologic explorations supporting these understandings further reveal the following: (1) the premise that a clinical event as dramatic as acute pulmonary edema (systolic and/or diastolic) would be contingent on similarly dramatic acute hypertensive or ischemic ventricular dysfunction, while intuitive, is unsubstantiated, and there is an alternate explanation satisfying both theoretical and clinical observations; (2) contrary to general perception, DHF is no more vulnerable to diuretic-induced hypotension than systolic HF; (3) heart rate reduction should not yet be considered an established therapeutic goal in DHF; (4) since HF is HF whether systolic and/or diastolic, studies are likely to show that therapeutic similarities outweigh differences except as the various agents might modify the underlying structural and/or functional pathology; (5) although long evident that HF occurs by only two mechanisms (systolic dysfunction and/or diastolic dysfunction), it has only recently been acknowledged that the mere exclusion of one is diagnostic of the other; and (6) the definition of HF currently in widespread use is unnecessarily confounded by neglect of the fundamental distinction between ventricular dysfunction and failure.

Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography

Abnormalities of diastolic filling are increasingly recognized as a cause of symptoms and predictors of outcome in patients with most forms of heart disease. Noninvasive assessment of diastolic filling is possible in almost all patients, but accurate evaluation must relate echocardiographic Doppler measurements to the complex physiologic and hemodynamic factors responsible for normal and abnormal filling. This evaluation has been facilitated by recent correlation of Doppler measurement of mitral and pulmonary venous inflow with hemodynamic studies. These studies have confirmed that when a careful, integrated approach is taken, Doppler flow patterns can document a progressive pattern of abnormality in many conditions. Impaired left ventricular (LV) relaxation is seen early and is recognized by a decrease in early transmitral LV filling and an increased proportion of filling during atrial contraction. As abnormalities progress, increasing LV chamber stiffness and elevated left atrial pressure lead to a “pseudonormal” filling pattern that previously has caused considerable confusion. This can be unmasked by careful evaluation of pulmonary venous inflow and the use of the Valsalva maneuver. When marked diastolic abnormalities are present, LV filling has restrictive features characterized by rapid early filling, a very stiff left ventricle with high filling pressures, and a poor prognosis. Routine measurement of indexes of diastolic filling have been hampered by uncertainty as to what should be measured, what techniques should be used, definition of normal values, and a clear method of reporting findings. This report represents the efforts of a Canadian consensus group to define a national standard for the performance and reporting of echocardiographic Doppler studies of diastolic filling.

Spectrum of restrictive cardiomyopathy: Report of the national survey in Japan

This report describes clinical profiles and echocardiographic, hemodynamic, and histologic findings in 26 cases of idiopathic RCM based on the diagnostic criteria of (1) heart failure resulting from a stiff left ventricle, (2) normal LV size and systolic function, (3) absence of LV hypertrophy, and (4) cause or association unknown. There were 14 male and 12 female patients ranging in age from 5 to 63 years. Ten patients died during the mean follow-up period of 145 months, and five died of heart failure after 10 years. Three had a family history of HCM. Thromboembolism was observed in eight. Echocardiograms showed normal LV wall thickness and contraction. Hemodynamic characteristics included elevated biventricular filling pressures and a pulmonary wedge pressure that was usually higher than the right atrial pressure. Equalization of biventricular filling pressures was seen, however, in almost all patients with severe tricuspid regurgitation (seven of eight). The square root sign was seen in 50% in RV diastolic pressure tracings and 28% in LV tracings. This sign was observed in patients with elevated filling pressures. Interstitial fibrosis (22 of 23), endocardial thickening (13 of 23), and myofibrillar hypertrophy (10 of 23) were common histologic findings. Severe myocardial fiber disarray consistent with HCM was seen in four patients.

Use of calcium channel blockers in hypertrophic cardiomyopathy

Recent studies in patients with either obstructive or nonobstructive hypertrophic cardiomyopathy have suggested that increased resistance to diastolic filling of the stiff left ventricle may be an important mechanism contributing to symptoms. These observations have led to exploration of the effects of calcium channel blockers on systolic and diastolic function in patients with hypertrophic cardiomyopathy. Acute hemodynamic studies using verapamil and nifedipine have shown that these agents tend to cause: (1) a slight fall in systemic arterial pressure and reflex increase in heart rate; (2) a reduction in left ventricular outflow gradient in most but not all patients; and (3) variable effect on left-side heart filling pressures. In contrast to beta-adrenergic blockers, these hemodynamic effects are not associated with depression of systolic function, but appear to be related to improved left ventricular distensibility. Clinical trials have suggested that long-term administration of verapamil in patients with hypertrophic cardiomyopathy promotes improvement in symptomatic status and exercise tolerance in many but not all patients; similar results have been reported in preliminary studies using nifedipine. Potential major adverse effects include depression of sinoatrial activity and atrioventricular conduction with verapamil, and marked hypotension and, rarely, pulmonary edema with both verapamil and nifedipine.

Hypertrophic nonobstructive cardiomyopathy: A precise assessment of hemodynamic characteristics and clinical implications

A precise assessment of left ventricular function was performed in 20 patients with hypertrophic nonobstructive cardiomyopathy to elucidate the basic pathophysiology and the data were compared with those In 22 normal subjects. Whereas end-diastolic pressure was high in those with cardiomyopathy, a more accurate Index of preload, end-diastolic stress, did not differ from normal value. Afterload was about half the normal value. Both isovolumic indexes [peak positive dP/dt and (dP/dt)/DP 40] and ejection phase indexes of contractility (ejection fraction) were in the normal range; however, the end-systolic stress volume ratio was significantly reduced (43% of the normal value). Although the left ventricular minute work index was in the normal range, the unit muscle performance (minute work/mass) was very low (49%). An abnormality of left ventricular relaxation was demonstrated by low peak negative dP/dt (56 %) and prolonged time constant T (191 %) and a stiff left ventricle was demonstrated by a high diastolic elastic stiffness constant (129%). These observations suggest that the contraction of a unit muscle is inappropriate to produce an adequate contraction of the whole ventricle and that hypertrophy might be an adaptive process to maintain normal systolic function by increasing mass and reducing afterload.

Left ventricular volume in man: the relation to heart rate and to end-diastolic pressure.

SummaryResting left ventricular end‐diastolic and end‐systolic volumes were measured by means of a dye‐dilution method in 37 patients, nine with normal cardio‐vascular systems, nine with mitral stenosis, nine with aortic valve disease, and 10 with other conditions. Ventricular volumes were related to heart rate and to the simultaneously measured end‐diastolic pressure. Evidence is presented to indicate that the method is capable of detecting changes in ventricular size, and is not affected by changes in heart rate over the range studied.In the normal subjects there was a significant inverse relationship between heart rate and end‐diastolic volume. There was a direct relationship between the ratio of end‐systolic volume to end‐diastolic volume and heart rate, and an inverse relationship between stroke volume and heart rate. The mean systolic size of the ventricle was smaller at faster heart rates. Such a relationship would tend to minimize increases in myocardial energy expenditure with increases in heart rate.The patients with mitral stenosis had smaller left ventricular volumes than the normal subjects, but the end‐diastolic pressures were also smaller, which finding was consistent with similarity of ventricular distensibility in the two groups. Evidence for an abnormally stiff left ventricle was found in one of the four patients with severe aortic stenosis, in one patient with cardiomyopathy, and in two of the three patients with extreme obesity. The third patient had clinically unsuspected high output left ventricular failure. Evidence for a flabby ventricle was found in two patients with cardiomyopathy and in one patient with predominantly ischæmic heart disease.It seems likely that variations in ventricular stiffness occur during the progression of left ventricular disease and contribute importantly to the production of symptoms, because of effects on left atrial and pulmonary capillary pressures.